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Reghelin CK, Bastos MS, de Souza Basso B, Costa BP, Cruz de Sousa A, Martha BA, Antunes GL, Nassr MT, Rosa Garcia MC, Matzenbacher LS, Schneider Levorse VG, Costa Rodrigues Guma FT, Donadio MVF, Rodrigues de Oliveira J, Alberto da Silva Melo D. Hepatic antifibrotic effects of bezafibrate in vitro and in vivo models of liver fibrosis. Food Chem Toxicol 2025; 200:115351. [PMID: 40024562 DOI: 10.1016/j.fct.2025.115351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 01/23/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025]
Abstract
Bezafibrate (BZF) is a drug that reduces cholesterol and triglyceride levels in the blood. Research indicates that BZF, through activation of PPAR receptors, regulates the expression of genes involved in lipid homeostasis, inflammation, cell differentiation, and proliferation. This study investigated the in vitro and in vivo effects of BZF on activated hepatic stellate cells (HSCs) and on carbon tetrachloride-induced liver fibrosis in mice. After 72 h of treatment in vitro, BZF decreased cell proliferation, reversed the phenotype, decreased cell contraction, and induced autophagy. In addition, BZF promoted a protective effect on tetrachloride-induced liver fibrosis in mice, through antifibrotic actions. These findings suggest that BZF may have a potential antifibrotic effect, which could emerge as a possible new therapy for the treatment of liver fibrosis.
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Affiliation(s)
- Camille Kirinus Reghelin
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Matheus Scherer Bastos
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil.
| | - Bruno de Souza Basso
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Bruna Pasqualotto Costa
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Arieli Cruz de Sousa
- Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP 90035-003, Brazil
| | - Bianca Andrade Martha
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Géssica Luana Antunes
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Marcella Tornquist Nassr
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Maria Claudia Rosa Garcia
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Lucas Strassburger Matzenbacher
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Vitor Giancarlo Schneider Levorse
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Fatima Theresinha Costa Rodrigues Guma
- Departamento de Bioquímica, ICBS, Universidade Federal Do Rio Grande Do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo I, Porto Alegre, RS, CEP 90035-003, Brazil
| | - Márcio Vinícius Fagundes Donadio
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Jarbas Rodrigues de Oliveira
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
| | - Denizar Alberto da Silva Melo
- Laboratório de Pesquisa em Biofísica Celular e Inflamação, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Porto Alegre - RS, Brazil
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Li X, Chen WW, Wu JJ, Yuan ZD, Yuan FL, Chen J. METTL3-dependent epigenetic regulation of ULK2 autophagy in hypertrophic scarring. Int J Biol Macromol 2025; 315:144507. [PMID: 40409645 DOI: 10.1016/j.ijbiomac.2025.144507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Revised: 05/08/2025] [Accepted: 05/20/2025] [Indexed: 05/25/2025]
Abstract
Increased autophagy in fibroblasts drives their differentiation into myofibroblasts, a key process in dermal fibrosis during hypertrophic scar (HS) progression. While N6-methyladenosine (m6A) modification is implicated in fibrosis and autophagy, its mechanistic role in HS remains unclear. In this study, we investigated the involvement of fibroblast autophagy in HS progression and the regulatory mechanisms underlying this process. Our findings demonstrated that HS development is associated with significant autophagy in both human patients and rabbit models, as evidenced by the activation of fibroblast-associated alpha-smooth muscle actin (α-SMA) and type I collagen. Pharmacological inhibition of autophagy using 3-methyladenine effectively suppressed fibroblast-to-myofibroblast differentiation. We further discovered that excessive m6A modifications enhanced autophagy in fibroblasts derived from HS tissues. Mechanistically, we elucidated that methyltransferase-like 3 (METTL3)-mediated m6A modification upregulated unc-51-like kinase 2 (ULK2), a key regulator of autophagy initiation, through techniques such as m6A RNA immunoprecipitation sequencing (MeRIP-seq), qRT-PCR, and Western blotting. Silencing METTL3 impaired autophagic flux, as confirmed by transmission electron microscopy and LC3-II/I ratio analysis, thereby inhibiting fibroblast-to-myofibroblast differentiation. Notably, subcutaneous injection of METTL3 small interfering RNA (siRNA) attenuated cellular autophagy in HS tissues and mitigated HS formation in rabbit ears. These results clarify the causal relationship between METTL3-mediated m6A modification, autophagy, and fibroblast-to-myofibroblast differentiation, providing a mechanistic basis for the therapeutic potential of targeting METTL3 in HS treatment.
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Affiliation(s)
- Xia Li
- Institute of Integrated Chinese and Western Medicine, The Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu 214041, China
| | - Wei-Wei Chen
- Institute of Integrated Chinese and Western Medicine, The Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu 214041, China
| | - Jun-Jie Wu
- Institute of Integrated Chinese and Western Medicine, The Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu 214041, China
| | - Zheng-Dong Yuan
- Institute of Integrated Chinese and Western Medicine, The Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu 214041, China
| | - Feng-Lai Yuan
- Institute of Integrated Chinese and Western Medicine, The Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu 214041, China.
| | - Jinghua Chen
- Institute of Integrated Chinese and Western Medicine, The Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu 214041, China; Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, China.
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3
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Gao L, Zhuang Y, Liu Z. Nogo-B Silencing Expedites the Senescence of Platelet-Derived Growth Factor-BB-Induced Human Hepatic Stellate Cells Via Autophagy. Mol Biotechnol 2025; 67:2023-2034. [PMID: 38727882 DOI: 10.1007/s12033-024-01179-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 04/15/2024] [Indexed: 04/10/2025]
Abstract
Liver fibrosis is a severe liver pathology in response to chronic or iterative liver injury. Senescence has emerged as a protective mechanism against liver fibrosis. Nogo-B has been well established as a significant contributor to liver fibrosis. Nonetheless, researches regarding the role of Nogo-B in cell senescence during liver fibrosis are few. In platelet-derived growth factor-BB (PDGF-BB)-treated human hepatic stellate cell line LX-2, cell proliferation was assayed by CCK-8 method. Western blotting estimated the expression of Nogo-B and fibrosis markers. After Nogo-B was silenced in LX-2 cells pretreated by an autophagy activator Rapamycin and PDGF-BB, CCK-8 method was used to assess cell proliferation. Fibrosis was measured by western blotting and immunofluorescence. Cell cycle was subjected to flow cytometry analysis and cell senescence was evaluated by SA-β-gal staining. Immunofluorescence staining assessed autophagy. Nogo-B was elevated in PDGF-BB-exposed LX-2 cells. Nogo-B silencing suppressed the proliferation, fibrosis, and autophagy while induced cell cycle arrest and senescence of LX-2 cells. Additionally, pretreatment with Rapamycin partially restored the effects of Nogo-B knockdown on the autophagy, proliferation, fibrosis, cell cycle, and senescence of LX-2 cells upon exposure to PDGF-BB. Collectively, inactivation of autophagy mediated by Nogo-B deficiency might elicit protective activities against the development of liver fibrosis.
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Affiliation(s)
- Lili Gao
- Department of Gastroenterology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, West Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China.
| | - Yingjie Zhuang
- Department of Gastroenterology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, West Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
| | - Zhengyi Liu
- Department of Gastroenterology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, West Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, People's Republic of China
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Bao Z, Xu M, Kan Y, Guo X, Li M, Wang J, Zhou Y, Zhang Z, Shao J, Zhang F, Chen L, Zheng S, Xuan J. Dihydroartemisinin requires NR1D1 mediated Rab7 ubiquitination to regulate hepatic stellate cells lipophagy in liver fibrosis. Int J Biol Macromol 2025; 305:141055. [PMID: 39956231 DOI: 10.1016/j.ijbiomac.2025.141055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 02/06/2025] [Accepted: 02/13/2025] [Indexed: 02/18/2025]
Abstract
The activation of hepatic stellate cells (HSCs) is a core event in the pathogenesis of liver fibrosis, typically accompanied by the disappearance of lipid droplets (LDs). Reversing the disappearance of HSCs LDs is a strategy to inhibit HSCs activation and alleviate liver fibrosis. Previous studies have shown that nuclear receptor subfamily 1 group d member 1 (NR1D1), as an important component of the biological clock system, is closely related to lipid metabolism. Our previous evidence indicated that Dihydroartemisinin (DHA) can regulate the lipid droplet metabolism of activated HSCs. Moreover, in CCl4 induced liver fibrosis mice, the liver clock gene NR1D1 is dysregulated. On this basis we explored the potential molecular mechanism of DHA inhibiting liver fibrosis through NR1D1. We found that DHA can inhibit liver fibrosis by restoring activated LDs of HSCs through inhibiting HSCs lipophagy. In summary, our study emphasizes the importance of NR1D1 in liver fibrosis and the potential of DHA to regulate NR1D1 in the treatment of liver fibrosis, providing a new direction for the treatment of liver fibrosis.
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Affiliation(s)
- Zhengyang Bao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Min Xu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yifan Kan
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xiaohan Guo
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Mengran Li
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Junrui Wang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ya Zhou
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zili Zhang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jiangjuan Shao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Feng Zhang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Li Chen
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Shizhong Zheng
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Ji Xuan
- Department of Gastroenterology, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, 305 Zhongshan East Road, Xuanwu Avenue, Nanjing, Jiangsu 210002, China.
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5
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Roh YJ, Kim H, Choi DW. Metabolic Sparks in the Liver: Metabolic and Epigenetic Reprogramming in Hepatic Stellate Cells Activation and Its Implications for Human Metabolic Diseases. Diabetes Metab J 2025; 49:368-385. [PMID: 40367987 PMCID: PMC12086559 DOI: 10.4093/dmj.2025.0195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2025] [Accepted: 04/17/2025] [Indexed: 05/16/2025] Open
Abstract
The liver plays a fundamental role in metabolic homeostasis, integrating systemic fuel utilization with the progression of various metabolic diseases. Hepatic stellate cells (HSCs) are a key nonparenchymal cell type in the liver, which is essential for maintaining hepatic architecture in their quiescent state. However, upon chronic liver injury or metabolic stress, HSCs become activated, leading to excessive extracellular matrix deposition and pro-fibrotic signaling, ultimately positioning them as key players in liver pathology. Emerging evidence highlights the critical roles of metabolic reprogramming and epigenetic regulation in HSCs activation. HSCs activation is driven by both intrinsic fuel metabolism reprogramming and extrinsic metabolic cues from the microenvironment, while the metabolic intermediates actively reshape the epigenetic landscape, reinforcing fibrogenic transcriptional programs. In this review, we summarize recent advances in understanding how metabolic and epigenetic alterations drive HSCs activation, thereby shaping transcriptional programs that sustain fibrosis, and discuss potential therapeutic strategies to target these interconnected pathways in human metabolic diseases.
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Affiliation(s)
- Yeon Jin Roh
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Hyeonki Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
| | - Dong Wook Choi
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea
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Mak KM, Shekhar AC, Ding SY. Neutrophil extracellular traps mediate pathophysiology of hepatic cells during liver injury. Anat Rec (Hoboken) 2025. [PMID: 40219700 DOI: 10.1002/ar.25673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
Neutrophil extracellular traps (NETs) are web-like, bactericidal structures produced by neutrophils and are composed principally of extracellular DNA, histones, elastase, and myeloperoxidase, among other components. NET formation is an innate immune response that is beneficial for pathogen killing and clearance. However, excessive NET formation and clearance defects can lead to inflammation and induce damage to host organs. NETs are also implicated in the development of noninfectious inflammatory disorders, such as liver injury in chronic liver diseases. The liver parenchyma contains hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells. Each of these cells possesses unique structures and functions, and their interactions with NETs result in pathophysiological changes contributing to liver injury. This review updates the findings related to the modes of action and molecular mechanisms by which NETs modulate the pathophysiology of various hepatic cells and potentiate liver injury. The article also reviews the roles of NETs in hepatic ischemia reperfusion injury, hepatocellular carcinoma pathogenesis, and cancer metastasis. Last, we examine data to determine whether NETs induce crosstalk among various hepatic cells during liver injury and to identify future research directions.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Aditya C Shekhar
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Selena Y Ding
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Irshad I, Alqahtani SA, Ikejima K, Yu ML, Romero-Gomez M, Eslam M. Energy metabolism: An emerging therapeutic frontier in liver fibrosis. Ann Hepatol 2025; 30:101896. [PMID: 40057035 DOI: 10.1016/j.aohep.2025.101896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 02/04/2025] [Indexed: 03/18/2025]
Abstract
Liver fibrosis is a progressive response to chronic liver diseases characterized by a wound-healing process that leads to the accumulation of fibrillary extracellular matrix (ECM) proteins in and around the liver tissue. If left untreated, liver fibrosis can advance to cirrhosis and ultimately result in liver failure. Although there have been significant advancements in understanding the molecular mechanisms involved in liver fibrosis, effective therapeutic strategies to reverse or halt the condition remain limited. Recent research has underscored the critical role of energy metabolism in the initiation and progression of liver fibrosis. In response to liver injury, hepatic cells undergo metabolic reprogramming to meet the energy demands of myofibroblasts. This reprogramming involves various metabolic changes, including mitochondrial dysfunction, alterations in cellular bioenergetics, shifts in glycolysis and oxidative phosphorylation, as well as changes in lipid metabolism. These modifications can disrupt cellular energy homeostasis and increase energy release, activating hepatic cells, primarily hepatic stellate cells (HSCs). Activated HSCs then stimulate fibrogenic pathways, leading to the accumulation of ECM proteins in the liver, which exacerbates the progression of fibrosis. This review aims to explore the emerging connection between energy metabolism and liver fibrosis, focusing on the metabolic alterations and molecular mechanisms that drive this condition. We also examine the therapeutic implications of modulating energy metabolism to reduce energy release and mitigate liver fibrosis. Altering energy metabolism to decrease energy release may represent a promising approach for treating liver fibrosis and chronic liver diseases.
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Affiliation(s)
- Iram Irshad
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia
| | - Saleh A Alqahtani
- Liver, Digestive, & Lifestyle Health Research Section, and Organ Transplant Center of Excellence, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Kenichi Ikejima
- Department of Gastroenterology, Juntendo University School of Medicine, Japan
| | - Ming-Lung Yu
- School of Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan; Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital; College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Manuel Romero-Gomez
- Digestive Diseases Department and Ciberehd, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville (HUVR/CSIC/US), University of Seville, Seville, Spain
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
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Yuasa H, Matsubara T, Urushima H, Daikoku A, Ikenaga H, Kadono C, Kinoshita M, Kimura K, Ishizawa T, Ohta K, Kawada N, Ikeda K. Cdc42 is crucial for the early regulation of hepatic stellate cell activation. Am J Physiol Cell Physiol 2025; 328:C757-C775. [PMID: 39871537 DOI: 10.1152/ajpcell.00987.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 12/28/2024] [Accepted: 01/16/2025] [Indexed: 01/29/2025]
Abstract
The activation of hepatic stellate cells (HSCs) from a quiescent state is a cause of liver fibrosis and a therapeutic target. HSCs are resident mesenchymal cells located in the space of Disse, exhibiting specialized morphological characteristics such as a stellate shape, large lipid droplets, and direct adhesions to hepatocytes via microprojections called HSC spines. Morphological alterations in HSCs play a crucial role in initiating their activation. However, the mechanisms regulating these changes remain unexplored. In this study, we analyzed the morphological alterations associated with HSC activation in vivo using carbon tetrachloride treatment and identified the key factors regulating these changes in vitro. Following carbon tetrachloride treatment, HSCs exhibited shortened cell processes and HSC spines, adopting an oval shape. Subsequently, the HSCs underwent further morphological changes into two activated forms: flattened and complex shapes. In vitro, activation of cell division cycle 42 (Cdc42) maintained the morphological characteristics of quiescent HSCs. Cdc42 activation in HSC cell lines inhibited the expression of markers associated with activated HSCs. Cdc42 inhibitor treatment in vivo prevented quiescent HSCs from maintaining their morphological characteristics and hindered activated HSCs from reverting to the quiescent state. In addition, HSCs around fibrotic areas in the human liver exhibited morphological alterations indicative of early activation. These findings demonstrate that Cdc42 is a crucial regulator of morphological and molecular alterations associated with HSC activation, identifying it as a novel target for the development of therapeutic agents against liver fibrosis.NEW & NOTEWORTHY The activation of hepatic stellate cells from a quiescent state is a cause and a therapeutic target for liver fibrosis. Morphological alterations in the hepatic stellate cells play a critical role in initiating their activation. However, the mechanisms that regulate these alterations remain unexplored. Our results indicate that cell division cycle 42 is a crucial regulator of hepatic stellate cell activation and a novel target for the development of therapeutic agents against liver fibrosis.
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Affiliation(s)
- Hideto Yuasa
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Research Institute for Light-induced Acceleration System, Osaka Metropolitan University, Sakai, Japan
| | - Hayato Urushima
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Atsuko Daikoku
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hiroko Ikenaga
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Chiho Kadono
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Masahiko Kinoshita
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kenjiro Kimura
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Takeaki Ishizawa
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Keisuke Ohta
- Division Microscopic and Development Anatomy, Department of Anatomy, School of Medicine, Kurume University, Kurume, Japan
- Advanced Imaging Research Center, School of Medicine, Kurume University, Kurume, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kazuo Ikeda
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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Liu Y, Yao L, Liu Y, Yang Y, Liang A, He H, Lei Y, Cao W, Chen Z. Micheliolide Alleviates Hepatic Fibrosis by Inhibiting Autophagy in Hepatic Stellate Cells via the TrxR1/2-Mediated ROS/MEK/ERK Pathway. Pharmaceuticals (Basel) 2025; 18:287. [PMID: 40143066 PMCID: PMC11944820 DOI: 10.3390/ph18030287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/25/2025] [Accepted: 02/14/2025] [Indexed: 03/28/2025] Open
Abstract
Background: Hepatic fibrosis is a major global health issue without an optimal drug treatment, highlighting the urgent need to find effective therapies. This study aimed to clarify the role and mechanism of micheliolide in treating hepatic fibrosis. Methods: The efficacy of MCL was evaluated in a mouse model of CCl4-induced hepatic fibrosis. LX-2 cells were subjected to MCL treatment, and subsequent changes in fibrosis markers, autophagy, and the MEK/ERK pathway were analyzed using transcriptomics and Western blotting. The interaction between MCL and TrxR1 or TrxR2 were validated using cellular thermal shift assays (CETSA) and drug affinity responsive target stability (DARTS) assays. Results: Our findings indicated that MCL significantly alleviated CCl4-induced hepatic fibrosis, improved liver function, and downregulated the expression of fibrosis markers. Additionally, MCL significantly inhibited LX-2 cell activation by suppressing cell proliferation, extracellular matrix (ECM) production, and autophagy, while activating the MEK/ERK pathway. Moreover, MCL elevated intracellular and mitochondrial reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential, and altered mitochondrial morphology. The ROS scavenger N-acetylcysteine (NAC) attenuated MCL-induced MEK/ERK pathway activation and increased collagen type I alpha 1 (COL1A1) and fibronectin (FN) expression. Further analysis confirmed that MCL directly interacts with TrxR1 and TrxR2, leading to the inhibition of their enzymatic activities and the induction of ROS generation. Ultimately, MCL attenuated the fibrotic process and autophagic flux in LX-2 cells. Conclusions: The findings of our study confirmed that MCL has the potential to alleviate hepatic fibrosis, thereby introducing a novel candidate drug and therapeutic strategy for management of this condition.
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Affiliation(s)
- Yi Liu
- Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Ling Yao
- College of Traditional Chinese Medicine, Chongqing University of Chinese Medicine, Chongqing 402760, China
| | - Yuanyuan Liu
- Department of Radiological Medicine, School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
| | - Yunheng Yang
- Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Ailing Liang
- Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Honglin He
- Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yao Lei
- Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Wenfu Cao
- Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Zhiwei Chen
- Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China
- College of Traditional Chinese Medicine, Chongqing University of Chinese Medicine, Chongqing 402760, China
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Gan C, Yuan Y, Shen H, Gao J, Kong X, Che Z, Guo Y, Wang H, Dong E, Xiao J. Liver diseases: epidemiology, causes, trends and predictions. Signal Transduct Target Ther 2025; 10:33. [PMID: 39904973 PMCID: PMC11794951 DOI: 10.1038/s41392-024-02072-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/06/2024] [Accepted: 11/12/2024] [Indexed: 02/06/2025] Open
Abstract
As a highly complex organ with digestive, endocrine, and immune-regulatory functions, the liver is pivotal in maintaining physiological homeostasis through its roles in metabolism, detoxification, and immune response. Various factors including viruses, alcohol, metabolites, toxins, and other pathogenic agents can compromise liver function, leading to acute or chronic injury that may progress to end-stage liver diseases. While sharing common features, liver diseases exhibit distinct pathophysiological, clinical, and therapeutic profiles. Currently, liver diseases contribute to approximately 2 million deaths globally each year, imposing significant economic and social burdens worldwide. However, there is no cure for many kinds of liver diseases, partly due to a lack of thorough understanding of the development of these liver diseases. Therefore, this review provides a comprehensive examination of the epidemiology and characteristics of liver diseases, covering a spectrum from acute and chronic conditions to end-stage manifestations. We also highlight the multifaceted mechanisms underlying the initiation and progression of liver diseases, spanning molecular and cellular levels to organ networks. Additionally, this review offers updates on innovative diagnostic techniques, current treatments, and potential therapeutic targets presently under clinical evaluation. Recent advances in understanding the pathogenesis of liver diseases hold critical implications and translational value for the development of novel therapeutic strategies.
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Affiliation(s)
- Can Gan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Yuan
- Aier Institute of Ophthalmology, Central South University, Changsha, China
| | - Haiyuan Shen
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Jinhang Gao
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Xiangxin Kong
- Engineering and Translational Medicine, Medical College, Tianjin University, Tianjin, China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yangkun Guo
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
| | - Erdan Dong
- Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital, School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
| | - Jia Xiao
- Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
- Department of Gastroenterology, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China.
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11
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Sun Y, Yuan X, Hu Z, Li Y. Harnessing nuclear receptors to modulate hepatic stellate cell activation for liver fibrosis resolution. Biochem Pharmacol 2025; 232:116730. [PMID: 39710274 DOI: 10.1016/j.bcp.2024.116730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 12/04/2024] [Accepted: 12/19/2024] [Indexed: 12/24/2024]
Abstract
With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis. Therefore, harnessing nuclear receptors to modulate HSC activation may be an effective approach to resolving the complex liver fibrosis caused by various factors. In this comprehensive review, we systematically explore the structure and physiological functions of nuclear receptors, shedding light on their multifaceted roles in HSC activation. Recent advancements in drug development targeting nuclear receptors are discussed, providing insights into their potential as rational and effective therapeutic targets for modulating HSC activation in the context of liver fibrosis. By elucidating the intricate interplay between nuclear receptors and HSC activation, this review contributes to the discovery of new nuclear receptor targets in HSCs for resolving hepatic fibrosis.
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Affiliation(s)
- Yaxin Sun
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Xiaoyan Yuan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhenhua Hu
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; Department of Health and Nursing, Nanfang College of Sun Yat-sen University, Guangzhou, China.
| | - Yuanyuan Li
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China; University of Chinese Academy of Sciences, Beijing, China.
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12
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Zhang L, Huang W, Ma T, Shi X, Chen J, Hu YL, Liu YX, Liu ZX, Lu CH. Targeting CFTR restoring aggrephagy to suppress HSC activation and alleviate liver fibrosis. Int Immunopharmacol 2025; 145:113754. [PMID: 39667045 DOI: 10.1016/j.intimp.2024.113754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/20/2024] [Accepted: 11/27/2024] [Indexed: 12/14/2024]
Abstract
BACKGROUND AND AIMS Multiple studies have shown that hepatic fibrosis, a progressive condition that represents the endpoint of various chronic liver diseases, is primarily marked by the extensive activation of hepatic stellate cells (HSCs). However, the exact impact of cystic fibrosis transmembrane conductance regulator (CFTR) on HSCs during the development of hepatic fibrosis remains unclear. METHODS In our study, we measured CFTR levels in tissue samples and in HSCs activated by TGF-β stimulation. We established mouse models of liver fibrosis using carbon tetrachloride (CCl4) and bile duct ligation (BDL). In vitro, we investigated the specific mechanisms of CFTR action in HSCs by exploring aggrephagy. We employed co-immunoprecipitation (co-IP) experiments to identify potential downstream targets of CFTR. Finally, through rescue experiments, we examined the impact of GTPase-activating protein - binding protein 1 (G3BP1) on CFTR-mediated activation of hepatic stellate cells. RESULT In activated HSCs induced by TGF-β, the reduction of CFTR, various liver fibrosis models, and fibrotic tissue samples were identified. In vitro functional experiments confirmed that CFTR promoted the expression of fibrosis-related markers and aggrephagy in HSCs. Mechanistically, we found that CFTR directly interacts with G3BP1, thereby further promoting the TGF-β/Smad2/3 pathway. The inhibition of G3BP1 caused by CFTR knockdown reduced extracellular matrix deposition, contributing to alleviating liver fibrosis. CONCLUSION We emphasize that CFTR activates aggrephagy and promotes HSC activation and hepatic fibrosis by targeting G3BP1, participating in the TGF-β/Smad2/3 signaling pathway. Overall, CFTR has been identified as a potential therapeutic target for liver fibrosis.
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Affiliation(s)
- Lu Zhang
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China
| | - Wei Huang
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China
| | - Tao Ma
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China
| | - Xiang Shi
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China
| | - Jing Chen
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China
| | - Yi-Lin Hu
- Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China
| | - Yong-Xia Liu
- Department of Gastroenterology, Tongzhou District Traditional Chinese Medicine Hospital, Nantong, China
| | - Zhao-Xiu Liu
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China.
| | - Cui-Hua Lu
- Department Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001 China.
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13
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Gilgenkrantz H, Paradis V, Lotersztajn S. Cell metabolism-based therapy for liver fibrosis, repair, and hepatocellular carcinoma. Hepatology 2025; 81:269-287. [PMID: 37212145 PMCID: PMC11643143 DOI: 10.1097/hep.0000000000000479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/21/2023] [Indexed: 05/23/2023]
Abstract
Progression of chronic liver injury to fibrosis, abnormal liver regeneration, and HCC is driven by a dysregulated dialog between epithelial cells and their microenvironment, in particular immune, fibroblasts, and endothelial cells. There is currently no antifibrogenic therapy, and drug treatment of HCC is limited to tyrosine kinase inhibitors and immunotherapy targeting the tumor microenvironment. Metabolic reprogramming of epithelial and nonparenchymal cells is critical at each stage of disease progression, suggesting that targeting specific metabolic pathways could constitute an interesting therapeutic approach. In this review, we discuss how modulating intrinsic metabolism of key effector liver cells might disrupt the pathogenic sequence from chronic liver injury to fibrosis/cirrhosis, regeneration, and HCC.
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Affiliation(s)
- Hélène Gilgenkrantz
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
| | - Valérie Paradis
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
- Pathology Department, Beaujon Hospital APHP, Paris-Cité University, Clichy, France
| | - Sophie Lotersztajn
- Paris-Cité University, INSERM, Center for Research on Inflammation, Paris, France
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14
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Liu X, Liang Q, Wang Y, Xiong S, Yue R. Advances in the pharmacological mechanisms of berberine in the treatment of fibrosis. Front Pharmacol 2024; 15:1455058. [PMID: 39372209 PMCID: PMC11450235 DOI: 10.3389/fphar.2024.1455058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 09/09/2024] [Indexed: 10/08/2024] Open
Abstract
The rising incidence of fibrosis poses a major threat to global public health, and the continuous exploration of natural products for the effective treatment of fibrotic diseases is crucial. Berberine (BBR), an isoquinoline alkaloid, is widely used clinically for its anti-inflammatory, anti-tumor and anti-fibrotic pharmacological effects. Until now, researchers have worked to explore the mechanisms of BBR for the treatment of fibrosis, and multiple studies have found that BBR attenuates fibrosis through different pathways such as TGF-β/Smad, AMPK, Nrf2, PPAR-γ, NF-κB, and Notch/snail axis. This review describes the anti-fibrotic mechanism of BBR and its derivatives, and the safety evaluation and toxicity studies of BBR. This provides important therapeutic clues and strategies for exploring new drugs for the treatment of fibrosis. Nevertheless, more studies, especially clinical studies, are still needed. We believe that with the continuous implementation of high-quality studies, significant progress will be made in the treatment of fibrosis.
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Affiliation(s)
- Xiaoqin Liu
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qingzhi Liang
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | | | - Shuai Xiong
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Rensong Yue
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Clinical Medical School, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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15
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Hu X, Lin H, Qian S, Xu Z, Li Z, Qian S, Yang F, Hou H, Xie Q, Wu W, Hu C, Abou-Elnour A, He Y, Huang Y. A novel experimental mouse model of diabetic nonalcoholic steatohepatitis: A critical role for acid-sensitive Ion Channel 1a. Biomed Pharmacother 2024; 178:117184. [PMID: 39142252 DOI: 10.1016/j.biopha.2024.117184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 07/17/2024] [Accepted: 07/22/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND A two-way relationship exists between type 2 diabetes (T2DM) and human nonalcoholic steatohepatitis (NASH). Several diabetic NASH models have the disadvantages of long cycles or inconsistent with the actual incidence of human disease, which would be costly and time-consuming to investigate disease pathogenesis and develop drugs. Therefore, there is an urgent need to establish a diabetic NASH mouse model. METHODS The combination between Fructose-palmitate-cholesterol diet (FPC) and Streptozotocin (STZ) (FPC+STZ) was used to construct diabetic NASH mouse model. The in vivo effects of silencing acid-sensitive Ion Channel 1a (ASIC1a) were examined with an adeno-associated virus 9 (AAV9) carrying ASIC1a short hairpin RNA (shRNA) in FPC+STZ model. RESULTS The mice fed with FPC for 12 weeks had insulin resistance, hyperinsulinemia, lipid accumulation, and increased hepatic levels of inflammatory factors. However, it still did not develop remarkable liver fibrosis. Most interestingly, noticeable fibrotic scars were observed in the liver of mice from FPC+STZ group. Furthermore, insulin therapy significantly ameliorated FPC+STZ-induced NASH-related liver fibrosis, indicating that hyperglycemia is of great significance in NASH development and progression. Importantly, ASIC1a was found to be involved in the pathogenesis of diabetic NASH as demonstrated that silencing ASIC1a in HSCs significantly ameliorated FPC+STZ-induced NASH fibrosis. Mechanistically, ASIC1a interacted with Poly Adp-adenosine ribose polymerase (PARP1) to promote HSC activation by inducing autophagy. CONCLUSION A FPC diet combined with an injection of STZ induces a diabetic NASH mouse model in a shorter period. Targeting ASIC1a may provide a novel therapeutic target for the treatment of diabetic NASH.
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Affiliation(s)
- Xiaojie Hu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Huimin Lin
- Department of Pharmacy, the Second Affiliated Hospital of Anhui Medical University, China
| | - Shengying Qian
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
| | - Zhou Xu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Zihao Li
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Shishun Qian
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Furong Yang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hui Hou
- Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qinxiu Xie
- Department of Infection, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wenyong Wu
- Hospital of The Second People's Hospital of Anhui Province, Hefei, China
| | - Chengmu Hu
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Amira Abou-Elnour
- School of International Education, Anhui Medical University, Hefei, China
| | - Yong He
- Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
| | - Yan Huang
- Anhui Province Key Laboratory of Major Autoimmune Diseases, School of Pharmacy, Anhui Medical University, Hefei, China.
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Akkız H, Gieseler RK, Canbay A. Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells. Int J Mol Sci 2024; 25:7873. [PMID: 39063116 PMCID: PMC11277292 DOI: 10.3390/ijms25147873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
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Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, University of Bahçeşehir, Beşiktaş, Istanbul 34353, Turkey
| | - Robert K. Gieseler
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
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17
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Horn P, Tacke F. Metabolic reprogramming in liver fibrosis. Cell Metab 2024; 36:1439-1455. [PMID: 38823393 DOI: 10.1016/j.cmet.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/30/2024] [Accepted: 05/06/2024] [Indexed: 06/03/2024]
Abstract
Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression.
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Affiliation(s)
- Paul Horn
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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18
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Liu XY, Zhang W, Ma BF, Sun MM, Shang QH. Advances in Research on the Effectiveness and Mechanism of Active Ingredients from Traditional Chinese Medicine in Regulating Hepatic Stellate Cells Autophagy Against Hepatic Fibrosis. Drug Des Devel Ther 2024; 18:2715-2727. [PMID: 38974122 PMCID: PMC11227309 DOI: 10.2147/dddt.s467480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 06/10/2024] [Indexed: 07/09/2024] Open
Abstract
Hepatic fibrosis (HF) is a pathological process of structural and functional impairment of the liver and is a key component in the progression of chronic liver disease. There are no specific anti-hepatic fibrosis (anti-HF) drugs, and HF can only be improved or prevented by alleviating the cause. Autophagy of hepatic stellate cells (HSCs) is closely related to the development of HF. In recent years, traditional Chinese medicine (TCM) has achieved good therapeutic effects in the prevention and treatment of HF. Several active ingredients from TCM (AITCM) can regulate autophagy in HSCs to exert anti-HF effects through different pathways, but relevant reviews are lacking. This paper reviewed the research progress of AITCM regulating HSCs autophagy against HF, and also discussed the relationship between HSCs autophagy and HF, pointing out the problems and limitations of the current study, in order to provide references for the development of anti-HF drugs targeting HSCs autophagy in TCM. By reviewing the literature in PubMed, Web of Science, Embase, CNKI and other databases, we found that the relationship between autophagy of HSCs and HF is currently controversial. HSCs autophagy may promote HF by consuming lipid droplets (LDs) to provide energy for their activation. However, in contrast, inducing autophagy in HSCs can exert the anti-HF effect by stimulating their apoptosis or senescence, reducing type I collagen accumulation, inhibiting the extracellular vesicles release, degrading pro-fibrotic factors and other mechanisms. Some AITCM inhibit HSCs autophagy to resist HF, with the most promising direction being to target LDs. While, others induce HSCs autophagy to resist HF, with the most promising direction being to target HSCs apoptosis. Future research needs to focus on cell targeting research, autophagy targeting research and in vivo verification research, and to explore the reasons for the contradictory effects of HSCs autophagy on HF.
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Affiliation(s)
- Xin-Yu Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250000, People’s Republic of China
| | - Wei Zhang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
| | - Bao-Feng Ma
- The third department of encephalopathy, Jinan Integrated Traditional Chinese and Western Medicine Hospital, Jinan, Shandong, 271100, People’s Republic of China
| | - Mi-Mi Sun
- Diagnosis and Treatment Center for Liver Diseases, Tai’an 88 Hospital, Tai’an, Shandong, 271000, People’s Republic of China
| | - Qing-Hua Shang
- Department of Liver Disease, The 960th Hospital of the PLA Joint Logistics Support Force, Jinan, Shandong, 250000, People’s Republic of China
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Wang Q, Bu Q, Xu Z, Liang Y, Zhou J, Pan Y, Zhou H, Lu L. Macrophage ATG16L1 expression suppresses metabolic dysfunction-associated steatohepatitis progression by promoting lipophagy. Clin Mol Hepatol 2024; 30:515-538. [PMID: 38726504 PMCID: PMC11261221 DOI: 10.3350/cmh.2024.0107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/28/2024] [Accepted: 05/10/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND/AIMS Metabolic dysfunction-associated steatohepatitis (MASH) is an unmet clinical challenge due to the rapid increased occurrence but lacking approved drugs. Autophagy-related protein 16-like 1 (ATG16L1) plays an important role in the process of autophagy, which is indispensable for proper biogenesis of the autophagosome, but its role in modulating macrophage-related inflammation and metabolism during MASH has not been documented. Here, we aimed to elucidate the role of ATG16L1 in the progression of MASH. METHODS Expression analysis was performed with liver samples from human and mice. MASH models were induced in myeloid-specific Atg16l1-deficient and myeloid-specific Atg16l1-overexpressed mice by high-fat and high-cholesterol diet or methionine- and choline-deficient diet to explore the function and mechanism of macrophage ATG16L1 in MASH. RESULTS Macrophage-specific Atg16l1 knockout exacerbated MASH and inhibited energy expenditure, whereas macrophage-specific Atg16l1 transgenic overexpression attenuated MASH and promotes energy expenditure. Mechanistically, Atg16l1 knockout inhibited macrophage lipophagy, thereby suppressing macrophage β-oxidation and decreasing the production of 4-hydroxynonenal, which further inhibited stimulator of interferon genes(STING) carbonylation. STING palmitoylation was enhanced, STING trafficking from the endoplasmic reticulum to the Golgi was promoted, and downstream STING signaling was activated, promoting proinflammatory and profibrotic cytokines secretion, resulting in hepatic steatosis and hepatic stellate cells activation. Moreover, Atg16l1-deficiency enhanced macrophage phagosome ability but inhibited lysosome formation, engulfing mtDNA released by pyroptotic hepatocytes. Increased mtDNA promoted cGAS/STING signaling activation. Moreover, pharmacological promotion of ATG16L1 substantially blocked MASH progression. CONCLUSION ATG16L1 suppresses MASH progression by maintaining macrophage lipophagy, restraining liver inflammation, and may be a promising therapeutic target for MASH management.
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Affiliation(s)
- Qi Wang
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Qingfa Bu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Department of General Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
| | - Zibo Xu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Yuan Liang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Jinren Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Yufeng Pan
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
| | - Ling Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China
- Department of General Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, China
- Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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20
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Zhang Y, Tian T, Liang C, Wang J, Zhang J, Tian S, Xie R, Yang T, Han B. Lysine specific demethylase 1 inhibits sodium arsenite activation of HSCs by regulating SESN2/AMPK/ULK1 signaling pathway activity. ENVIRONMENTAL TOXICOLOGY 2024; 39:3563-3577. [PMID: 38477077 DOI: 10.1002/tox.24184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/10/2024] [Accepted: 02/10/2024] [Indexed: 03/14/2024]
Abstract
Lysine specific demethylase 1 (LSD1) is a histone demethylase that specifically catalyzes the demethylation of histone H3K4 (H3K4me1/2) and regulates gene expression. In addition, it can mediate the process of autophagy through its demethylase activity. Sestrin2 (SESN2) is a stress-induced protein and a positive regulator of autophagy. In NaAsO2-induced mouse fibrotic livers and activated hepatic stellate cells (HSCs), LSD1 expression is decreased, SESN2 expression is increased, and autophagy levels are also increased. Overexpression of LSD1 and silencing of SESN2 decreased the level of autophagy and attenuated the activation of HSCs induced by NaAsO2. LSD1 promoted SESN2 gene transcription by increasing H3K4me1/2 in the SESN2 promoter region. 3-methyladenine (3-MA) and chloroquine were used to inhibit autophagy of HSCs, and the degree of activation was also alleviated. Taken together, LSD1 positively regulates SESN2 by increasing H3K4me1/2 enrichment in the SESN2 promoter region, which in turn increases the level of autophagy and promotes the activation of HSCs. Our results may provide new evidence for the importance of LSD1 in the process of autophagy and activation of HSCs induced by arsenic poisoning. Increasing the expression and activity of LSD1 is expected to be an effective way to reverse the autophagy and activation of HSCs induced by arsenic poisoning.
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Affiliation(s)
- Yingwan Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, China
| | - Tian Tian
- Department of Eugenic Genetics, Guiyang Maternal and Child Health Care Hospital, Guiyang, Guizhou, China
| | - Cai Liang
- Southwest Hospital, Army Medical University, Chongqing, China
| | - Junli Wang
- The Second People's Hospital of Guiyang, Guizhou, China
| | - Jiayuan Zhang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, China
| | - Shanshan Tian
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, China
| | - Rujia Xie
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, China
| | - Ting Yang
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, China
| | - Bing Han
- Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, China
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang, Guizhou, China
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Jiang S, Xu L, Chen Y, Shu Z, Lv L, Zhao Y, Bi K, Yang S, Wang Q, Li L. Longitudinal gut fungal alterations and potential fungal biomarkers for the progression of primary liver disease. SCIENCE CHINA. LIFE SCIENCES 2024; 67:1183-1198. [PMID: 38413553 DOI: 10.1007/s11427-023-2458-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 09/25/2023] [Indexed: 02/29/2024]
Abstract
Liver disease, a major health concern worldwide, is a serious and progressive disorder. Herein, we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut mycobiome. As liver disease advanced, gut integrity was disrupted, and the mycobiota was disturbed in the mouse models. The metabolites associated with hepatocellular carcinoma (HCC) differed from those associated with the cirrhotic phase as follows: levels of stercobilin and aflatoxin B1 dialcohol were reduced, while levels of triterpenoids, bafilomycin A1, and DHEA were increased in the HCC group. The abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in HCC. Based on the results from clinical human samples, the genus Candida (Ascomycota) (in humans) and the genus Kazachstania (Ascomycota) (in mice) occupied a dominant position in the HCC group, while other fungi were depleted. The increased abundance of C. albicans and depletion of S. cerevisiae may be hallmarks of the progression of liver cirrhosis to early HCC. Moreover, the administration of C. albicans and S. cerevisiae in the LC-HCC progression could accelerate or retard the progression of HCC. Therefore, gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.
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Affiliation(s)
- Shiman Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Lvwan Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yanfei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Zheyue Shu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Longxian Lv
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Yuxi Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Kefan Bi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Sisi Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Qiangqiang Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
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22
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Huang BH, Guo ZW, Lv BH, Zhao X, Li YB, Lv WL. A role for curcumin in preventing liver fibrosis in animals: a systematic review and meta-analysis. Front Pharmacol 2024; 15:1396834. [PMID: 38855740 PMCID: PMC11157132 DOI: 10.3389/fphar.2024.1396834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 04/30/2024] [Indexed: 06/11/2024] Open
Abstract
Objective This meta-analysis aimed to determine the efficacy of curcumin in preventing liver fibrosis in animal models. Methods A systematic search was conducted on studies published from establishment to November 2023 in PubMed, Web of Science, Embase, Cochrane Library, and other databases. The methodological quality was assessed using Sycle's RoB tool. An analysis of sensitivity and subgroups were performed when high heterogeneity was observed. A funnel plot was used to assess publication bias. Results This meta-analysis included 24 studies involving 440 animals with methodological quality scores ranging from 4 to 6. The results demonstrated that curcumin treatment significantly improved Aspartate aminotransferase (AST) [standard mean difference (SMD) = -3.90, 95% confidence interval (CI) (-4.96, -2.83), p < 0.01, I2 = 85.9%], Alanine aminotransferase (ALT)[SMD = - 4.40, 95% CI (-5.40, -3.40), p < 0.01, I2 = 81.2%]. Sensitivity analysis of AST and ALT confirmed the stability and reliability of the results obtained. However, the funnel plot exhibited asymmetry. Subgroup analysis based on species and animal models revealed statistically significant differences among subgroups. Furthermore, curcumin therapy improved fibrosis degree, oxidative stress level, inflammation level, and liver synthesis function in animal models of liver fibrosis. Conclusion Curcumin intervention not only mitigates liver fibrosis but also enhances liver function, while concurrently modulating inflammatory responses and antioxidant capacity in animal models. This result provided a strong basis for further large-scale animal studies as well as clinical trials in humans in the future. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024502671.
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Affiliation(s)
- Bo-Hao Huang
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate school, Beijing University of Chinese Medicine, Beijing, China
| | - Zi-Wei Guo
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bo-Han Lv
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xin Zhao
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yan-Bo Li
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wen-Liang Lv
- Department of Infection, Guang’an Men Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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23
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Shen W, Yang M, Chen H, He C, Li H, Yang X, Zhuo J, Lin Z, Hu Z, Lu D, Xu X. FGF21-mediated autophagy: Remodeling the homeostasis in response to stress in liver diseases. Genes Dis 2024; 11:101027. [PMID: 38292187 PMCID: PMC10825283 DOI: 10.1016/j.gendis.2023.05.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/23/2023] [Accepted: 05/09/2023] [Indexed: 02/01/2024] Open
Abstract
Liver diseases are worldwide problems closely associated with various stresses, such as endoplasmic reticulum stress. The exact interplay between stress and liver diseases remains unclear. Autophagy plays an essential role in maintaining homeostasis, and recent studies indicate tight crosstalk between stress and autophagy in liver diseases. Once the balance between damage and autophagy is broken, autophagy can no longer resist injury or maintain homeostasis. In recent years, FGF21 (fibroblast growth factor 21)-induced autophagy has attracted much attention. FGF21 is regarded as a stress hormone and can be up-regulated by an abundance of signaling pathways in response to stress. Also, increased FGF21 activates autophagy by a complicated signaling network in which mTOR plays a pivotal role. This review summarizes the mechanism of FGF21-mediated autophagy and its derived application in the defense of stress in liver diseases and offers a glimpse into its promising prospect in future clinical practice.
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Affiliation(s)
- Wei Shen
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Modan Yang
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Hao Chen
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Chiyu He
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Huigang Li
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Xinyu Yang
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Jianyong Zhuo
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Zuyuan Lin
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Zhihang Hu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Di Lu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
- The Institute for Organ Repair and Regenerative Medicine of Hangzhou, Hangzhou, Zhejiang 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, Zhejiang 310003, China
- National Center for Healthcare Quality Management in Liver Transplant, Hangzhou, Zhejiang 310003, China
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Li S, Ren QJ, Xie CH, Cui Y, Xu LT, Wang YD, Li S, Liang XQ, Wen B, Liang MK, Zhao XF. Taurine attenuates activation of hepatic stellate cells by inhibiting autophagy and inducing ferroptosis. World J Gastroenterol 2024; 30:2143-2154. [PMID: 38681990 PMCID: PMC11045481 DOI: 10.3748/wjg.v30.i15.2143] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/30/2024] [Accepted: 03/21/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND Liver fibrosis is a compensatory response during the tissue repair process in chronic liver injury, and finally leads to liver cirrhosis or even hepatocellular carcinoma. The pathogenesis of hepatic fibrosis is associated with the progressive accumulation of activated hepatic stellate cells (HSCs), which can transdifferentiate into myofibroblasts to produce an excess of the extracellular matrix (ECM). Myofibroblasts are the main source of the excessive ECM responsible for hepatic fibrosis. Therefore, activated hepatic stellate cells (aHSCs), the principal ECM producing cells in the injured liver, are a promising therapeutic target for the treatment of hepatic fibrosis. AIM To explore the effect of taurine on aHSC proliferation and the mechanisms involved. METHODS Human HSCs (LX-2) were randomly divided into five groups: Normal control group, platelet-derived growth factor-BB (PDGF-BB) (20 ng/mL) treated group, and low, medium, and high dosage of taurine (10 mmol/L, 50 mmol/L, and 100 mmol/L, respectively) with PDGF-BB (20 ng/mL) treated group. Cell Counting Kit-8 method was performed to evaluate the effect of taurine on the viability of aHSCs. Enzyme-linked immunosorbent assay was used to estimate the effect of taurine on the levels of reactive oxygen species (ROS), malondialdehyde, glutathione, and iron concentration. Transmission electron microscopy was applied to observe the effect of taurine on the autophagosomes and ferroptosis features in aHSCs. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to detect the effect of taurine on the expression of α-SMA, Collagen I, Fibronectin 1, LC3B, ATG5, Beclin 1, PTGS2, SLC7A11, and p62. RESULTS Taurine promoted the death of aHSCs and reduced the deposition of the ECM. Treatment with taurine could alleviate autophagy in HSCs to inhibit their activation, by decreasing autophagosome formation, downregulating LC3B and Beclin 1 protein expression, and upregulating p62 protein expression. Meanwhile, treatment with taurine triggered ferroptosis and ferritinophagy to eliminate aHSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Furthermore, bioinformatics analysis demonstrated that taurine had a direct targeting effect on nuclear receptor coactivator 4, exhibiting the best average binding affinity of -20.99 kcal/mol. CONCLUSION Taurine exerts therapeutic effects on liver fibrosis via mechanisms that involve inhibition of autophagy and trigger of ferroptosis and ferritinophagy in HSCs to eliminate aHSCs.
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Affiliation(s)
- Sen Li
- Department of Basic Science, Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Qian-Jun Ren
- Department of Basic Science, Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Can-Hao Xie
- Department of Basic Science, Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Yang Cui
- Department of Basic Science, Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Li-Tao Xu
- Department of Basic Science, Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Yi-Dan Wang
- Department of Basic Science, Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Su Li
- Department of Basic Science, Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Xing-Qiu Liang
- Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Bin Wen
- Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Ming-Kun Liang
- Traditional Chinese Medicine Specialty Office, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Fang Zhao
- Department of Science and Technology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning 541100, Guangxi Zhuang Autonomous Region, China
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Stoess C, Choi YK, Onyuru J, Friess H, Hoffman HM, Hartmann D, Feldstein AE. Cell Death in Liver Disease and Liver Surgery. Biomedicines 2024; 12:559. [PMID: 38540172 PMCID: PMC10968531 DOI: 10.3390/biomedicines12030559] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/15/2024] [Accepted: 02/17/2024] [Indexed: 01/03/2025] Open
Abstract
Cell death is crucial for maintaining tissue balance and responding to diseases. However, under pathological conditions, the surge in dying cells results in an overwhelming presence of cell debris and the release of danger signals. In the liver, this gives rise to hepatic inflammation and hepatocellular cell death, which are key factors in various liver diseases caused by viruses, toxins, metabolic issues, or autoimmune factors. Both clinical and in vivo studies strongly affirm that hepatocyte death serves as a catalyst in the progression of liver disease. This advancement is characterized by successive stages of inflammation, fibrosis, and cirrhosis, culminating in a higher risk of tumor development. In this review, we explore pivotal forms of cell death, including apoptosis, pyroptosis, and necroptosis, examining their roles in both acute and chronic liver conditions, including liver cancer. Furthermore, we discuss the significance of cell death in liver surgery and ischemia-reperfusion injury. Our objective is to illuminate the molecular mechanisms governing cell death in liver diseases, as this understanding is crucial for identifying therapeutic opportunities aimed at modulating cell death pathways.
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Affiliation(s)
- Christian Stoess
- Department of Pediatric Gastroenterology, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA; (C.S.)
- Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
| | - Yeon-Kyung Choi
- Department of Pediatric Gastroenterology, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA; (C.S.)
- Department of Internal Medicine, School of Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University, Daegu 41404, Republic of Korea
| | - Janset Onyuru
- Department of Pediatric Allergy, Immunology and Rheumatology, University of California San Diego, La Jolla, CA 92093, USA
| | - Helmut Friess
- Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
| | - Hal M. Hoffman
- Department of Pediatric Allergy, Immunology and Rheumatology, University of California San Diego, La Jolla, CA 92093, USA
| | - Daniel Hartmann
- Department of Surgery, TUM School of Medicine, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany
| | - Ariel E. Feldstein
- Department of Pediatric Gastroenterology, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA; (C.S.)
- Novo Nordisk, Global Drug Discovery, Ørestads Boulevard 108, 2300 Copenhagen, Denmark
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Xie Z, Li Y, Xiao P, Ke S. GATA3 promotes the autophagy and activation of hepatic stellate cell in hepatic fibrosis via regulating miR-370/HMGB1 pathway. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:219-229. [PMID: 37207965 DOI: 10.1016/j.gastrohep.2023.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 04/16/2023] [Accepted: 05/10/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND Hepatic fibrosis (HF) is a common result of the repair process of various chronic liver diseases. Hepatic stellate cells (HSCs) activation is the central link in the occurrence of HF. METHODS ELISA and histological analysis were performed to detect the pathological changes of liver tissues. In vitro, HSCs were treated with TGF-β1 as HF cell model. Combination of GATA-binding protein 3 (GATA3) and miR-370 gene promoter was ensured by ChIP and luciferase reporter assay. Autophagy was monitored by observing the GFP-LC3 puncta formation. The interaction between miR-370 and high mobility group box 1 protein (HMGB1) was verified by luciferase reporter assay. RESULTS CCl4-induced HF mice exhibited an increase of ALT and AST, and severe damage and fibrosis of liver tissues. GATA3 and HMGB1 were up-regulated, and miR-370 was down-regulated in CCl4-induced HF mice and activated HSCs. GATA3 enhanced expression of the autophagy-related proteins and activation markers in the activated HSCs. Inhibition of autophagy partly reversed GATA3-induced activation of HSCs and the promotion of GATA3 to hepatic fibrosis. Moreover, GATA3 suppressed miR-370 expression via binding with its promotor, and enhanced HMGB1 expression in HSCs. Increasing of miR-370 inhibited HMGB1 expression by directly targeting its mRNA 3'-UTR. The promotion of GATA3 to TGF-β1-induced HSCs autophagy and activation was abrogated by miR-370 up-regulation or HMGB1 knockdown. CONCLUSIONS This work demonstrates that GATA3 promotes autophagy and activation of HSCs by regulating miR-370/HMGB1 signaling pathway, which contributes to accelerate HF. Thus, this work suggests that GATA3 may be a potential target for prevention and treatment of HF.
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Affiliation(s)
- Zhengyuan Xie
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
| | - Yangyang Li
- Medical College of Nanchang University, Nanchang 330006, China
| | - Peiguang Xiao
- Medical College of Nanchang University, Nanchang 330006, China
| | - Shanmiao Ke
- Medical College of Nanchang University, Nanchang 330006, China
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Sun YD, Zhang H, Li YM, Han JJ. Abnormal metabolism in hepatic stellate cells: Pandora's box of MAFLD related hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2024; 1879:189086. [PMID: 38342420 DOI: 10.1016/j.bbcan.2024.189086] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/25/2023] [Accepted: 02/06/2024] [Indexed: 02/13/2024]
Abstract
Metabolic associated fatty liver disease (MAFLD) is a significant risk factor for the development of hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs), as key mediators in liver injury response, are believed to play a crucial role in the repair process of liver injury. However, in MAFLD patients, the normal metabolic and immunoregulatory mechanisms of HSCs become disrupted, leading to disturbances in the local microenvironment. Abnormally activated HSCs are heavily involved in the initiation and progression of HCC. The metabolic disorders and abnormal activation of HSCs not only initiate liver fibrosis but also contribute to carcinogenesis. In this review, we provide an overview of recent research progress on the relationship between the abnormal metabolism of HSCs and the local immune system in the liver, elucidating the mechanisms of immune imbalance caused by abnormally activated HSCs in MAFLD patients. Based on this understanding, we discuss the potential and challenges of metabolic-based and immunology-based mechanisms in the treatment of MAFLD-related HCC, with a specific focus on the role of HSCs in HCC progression and their potential as targets for anti-cancer therapy. This review aims to enhance researchers' understanding of the importance of HSCs in maintaining normal liver function and highlights the significance of HSCs in the progression of MAFLD-related HCC.
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Affiliation(s)
- Yuan-Dong Sun
- Department of Interventional Radiology, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University, Shandong Academy of Medical Sciences, China
| | - Hao Zhang
- Department of Interventional Radiology, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University, Shandong Academy of Medical Sciences, China
| | - Yuan-Min Li
- NHC Key Laboratory of Transplant Engineering and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, China
| | - Jian-Jun Han
- Department of Interventional Radiology, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University, Shandong Academy of Medical Sciences, China.
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Huang Y, Luo W, Yang Z, Lan T, Wei X, Wu H. Machine learning and experimental validation identified autophagy signature in hepatic fibrosis. Front Immunol 2024; 15:1337105. [PMID: 38481992 PMCID: PMC10933073 DOI: 10.3389/fimmu.2024.1337105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 02/14/2024] [Indexed: 04/10/2024] Open
Abstract
Background The molecular mechanisms of hepatic fibrosis (HF), closely related to autophagy, remain unclear. This study aimed to investigate autophagy characteristics in HF. Methods Gene expression profiles (GSE6764, GSE49541 and GSE84044) were downloaded, normalized, and merged. Autophagy-related differentially expressed genes (ARDEGs) were determined using the limma R package and the Wilcoxon rank sum test and then analyzed by GO, KEGG, GSEA and GSVA. The infiltration of immune cells, molecular subtypes and immune types of healthy control (HC) and HF were analyzed. Machine learning was carried out with two methods, by which, core genes were obtained. Models of liver fibrosis in vivo and in vitro were constructed to verify the expression of core genes and corresponding immune cells. Results A total of 69 ARDEGs were identified. Series functional cluster analysis showed that ARDEGs were significantly enriched in autophagy and immunity. Activated CD4 T cells, CD56bright natural killer cells, CD56dim natural killer cells, eosinophils, macrophages, mast cells, neutrophils, and type 17 T helper (Th17) cells showed significant differences in infiltration between HC and HF groups. Among ARDEGs, three core genes were identified, that were ATG5, RB1CC1, and PARK2. Considerable changes in the infiltration of immune cells were observed at different expression levels of the three core genes, among which the expression of RB1CC1 was significantly associated with the infiltration of macrophage, Th17 cell, natural killer cell and CD56dim natural killer cell. In the mouse liver fibrosis experiment, ATG5, RB1CC1, and PARK2 were at higher levels in HF group than those in HC group. Compared with HC group, HF group showed low positive area in F4/80, IL-17 and CD56, indicating decreased expression of macrophage, Th17 cell, natural killer cell and CD56dim natural killer cell. Meanwhile, knocking down RB1CC1 was found to inhibit the activation of hepatic stellate cells and alleviate liver fibrosis. Conclusion ATG5, RB1CC1, and PARK2 are promising autophagy-related therapeutic biomarkers for HF. This is the first study to identify RB1CC1 in HF, which may promote the progression of liver fibrosis by regulating macrophage, Th17 cell, natural killer cell and CD56dim natural killer cell.
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Affiliation(s)
- Yushen Huang
- Department of Pharmacy, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
| | - Wen Luo
- Department of Gastrointestinal Surgery, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
| | - Zhijie Yang
- Department of Pharmacy, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
| | - Tian Lan
- Department of Pharmacy, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
| | - Xiaomou Wei
- Department of Scientific Research, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
| | - Hongwen Wu
- Department of Pharmacy, Liuzhou Workers Hospital, Liuzhou, Guangxi, China
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Ren Q, Sun Q, Fu J. Dysfunction of autophagy in high-fat diet-induced non-alcoholic fatty liver disease. Autophagy 2024; 20:221-241. [PMID: 37700498 PMCID: PMC10813589 DOI: 10.1080/15548627.2023.2254191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 08/24/2023] [Indexed: 09/14/2023] Open
Abstract
ABBREVIATIONS ACOX1: acyl-CoA oxidase 1; ADH5: alcohol dehydrogenase 5 (class III), chi polypeptide; ADIPOQ: adiponectin, C1Q and collagen domain containing; ATG: autophagy related; BECN1: beclin 1; CRTC2: CREB regulated transcription coactivator 2; ER: endoplasmic reticulum; F2RL1: F2R like trypsin receptor 1; FA: fatty acid; FOXO1: forkhead box O1; GLP1R: glucagon like peptide 1 receptor; GRK2: G protein-coupled receptor kinase 2; GTPase: guanosine triphosphatase; HFD: high-fat diet; HSCs: hepatic stellate cells; HTRA2: HtrA serine peptidase 2; IRGM: immunity related GTPase M; KD: knockdown; KDM6B: lysine demethylase 6B; KO: knockout; LAMP2: lysosomal associated membrane protein 2; LAP: LC3-associated phagocytosis; LDs: lipid droplets; Li KO: liver-specific knockout; LSECs: liver sinusoidal endothelial cells; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K5: mitogen-activated protein kinase kinase kinase 5; MED1: mediator complex subunit 1; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; NFE2L2: NFE2 like bZIP transcription factor 2; NOS3: nitric oxide synthase 3; NR1H3: nuclear receptor subfamily 1 group H member 3; OA: oleic acid; OE: overexpression; OSBPL8: oxysterol binding protein like 8; PA: palmitic acid; RUBCNL: rubicon like autophagy enhancer; PLIN2: perilipin 2; PLIN3: perilipin 3; PPARA: peroxisome proliferator activated receptor alpha; PRKAA2/AMPK: protein kinase AMP-activated catalytic subunit alpha 2; RAB: member RAS oncogene family; RPTOR: regulatory associated protein of MTOR complex 1; SCD: stearoyl-CoA desaturase; SIRT1: sirtuin 1; SIRT3: sirtuin 3; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1;SREBF2: sterol regulatory element binding transcription factor 2; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; TAGs: triacylglycerols; TFEB: transcription factor EB; TP53/p53: tumor protein p53; ULK1: unc-51 like autophagy activating kinase 1; VMP1: vacuole membrane protein 1.
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Affiliation(s)
- Qiannan Ren
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Qiming Sun
- International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
- Department of Biochemistry, and Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junfen Fu
- Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
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Peng ML, Zhang LJ, Luo Y, Xu SY, Long XM, Ao JL, Liao SG, Zhu QF, He X, Xu GB. Phomopsterone B Alleviates Liver Fibrosis through mTOR-Mediated Autophagy and Apoptosis Pathway. Molecules 2024; 29:417. [PMID: 38257331 PMCID: PMC10820960 DOI: 10.3390/molecules29020417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Liver fibrosis is the initial pathological process of many chronic liver diseases. Targeting hepatic stellate cell (HSC) activation is an available strategy for the therapy of liver fibrosis. We aimed to explore the anti-liver fibrosis activity and potential mechanism of phomopsterone B (PB) in human HSCs. The results showed that PB effectively attenuated the proliferation of TGF-β1-stimulated LX-2 cells in a concentration-dependent manner at doses of 1, 2, and 4 μM. Quantitative real-time PCR and Western blot assays displayed that PB significantly reduced the expression levels of α-SMA and collagen I/III. AO/EB and Hoechst33342 staining and flow cytometry assays exhibited that PB promoted the cells' apoptosis. Meanwhile, PB diminished the number of autophagic vesicles and vacuolated structures, and the LC3B fluorescent spots indicated that PB could effectively inhibit the accretion of autophagosomes in LX-2 cells. Moreover, rapamycin and MHY1485 were utilized to further investigate the effect of mTOR in autophagy and apoptosis. The results demonstrated that PB regulated autophagy and apoptosis via the mTOR-dependent pathway in LX-2 cells. In summary, this is the first evidence that PB effectively alleviates liver fibrosis in TGF-β1-stimulated LX-2 cells, and PB may be a promising candidate for the prevention of liver fibrosis.
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Affiliation(s)
- Mei-Lin Peng
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
- University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province, Guian New District, Guiyang 550025, China
- Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, China
| | - Li-Jie Zhang
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
| | - Yan Luo
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
| | - Shi-Ying Xu
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
| | - Xing-Mei Long
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
| | - Jun-Li Ao
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
- Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, China
| | - Shang-Gao Liao
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
- University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province, Guian New District, Guiyang 550025, China
- Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, China
| | - Qin-Feng Zhu
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
- University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province, Guian New District, Guiyang 550025, China
| | - Xun He
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
- University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province, Guian New District, Guiyang 550025, China
| | - Guo-Bo Xu
- State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guian New District, Guiyang 550004, China; (M.-L.P.); (L.-J.Z.); (Y.L.); (S.-Y.X.); (X.-M.L.); (J.-L.A.); (S.-G.L.); (Q.-F.Z.)
- University Engineering Research Center for the Prevention and Treatment of Chronic Diseases by Authentic Medicinal Materials in Guizhou Province, Guian New District, Guiyang 550025, China
- Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, China
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Jiang Y, Hou L, Dou J, Xuan M, Cui Z, Lian L, Nan J, Wu Y. Sesamol as a potential candidate for the treatment of hepatic fibrosis, based on its regulation of FXR/LXR axis-mediated inhibition of autophagy through crosstalk between hepatic cells and macrophage. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 123:155145. [PMID: 37976698 DOI: 10.1016/j.phymed.2023.155145] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 10/01/2023] [Accepted: 10/12/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Sesamol (SEM), a natural lignan compound isolated from sesame, has strong anti-oxidant property, regulating lipid metabolism, decreasing cholesterol and hepatoprotection. However, its anti-hepatic fibrosis effect and mechanisms have not been comprehensively elucidated. HYPOTHESIS/PURPOSE This study aims to investigate the anti-hepatic fibrosis of SEM and its underlying mechanisms. METHOD C57BL/6 mice with hepatic fibrosis were induced by TAA, then administrated with SEM or curcumin, respectively. HSCs were stimulated by TGF-β or conditioned medium, and then cultured with SEM, GW4064, GW3965, Rapamycin (RA) or 3-methyladenine (3-MA), respectively. Mice with hepatic fibrosis also were administrated with SEM, RA or 3-MA to estimate the effect of SEM on autophagy. RESULTS In vitro, SEM significantly inhibited extracellular matrix deposition, P2 × 7r-NLRP3, and inflammatory cytokines. SEM increased FXR and LXRα/β expressions and decreased MAPLC3α/β and P62 expressions, functioning as 3-MA (autophagy inhibitor). In vivo, SEM reduced serum transaminase, histopathology changes, fibrogenesis, autophagy markers and inflammatory cytokines caused by TAA. LX-2 were activated with conditioned medium from LPS-primed THP-1, which resulted in significant enhance of autophagy markers and inflammatory cytokines and decrease of FXR and LXRα/β expressions. SEM could reverse above these changes and function as 3-MA, GW4064, or GW3965. Deficiency of FXR or LXR attenuated the regulation of SEM on α-SMA, MAPLC3α/β, P62 and IL-1β in activated LX-2. In activated THP-1, deficiency of FXR could decrease the expression of LXR, and vice versa. Deficiency of FXR or LXR in activated MΦ decreased the expressions of FXR and LXR in activated LX-2. Deficiency FXR or LXR in activated MΦ also attenuated the regulation of SEM on α-SMA, MAPLC3α/β, P62, caspase-1 and IL-1β. In vivo, SEM significantly reversed hepatic fibrosis via FXR/LXR and autophagy. CONCLUSION SEM could regulate hepatic fibrosis by inhibiting fibrogenesis, autophagy and inflammation. FXR/LXR axis-mediated inhibition of autophagy contributed to the regulation of SEM against hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. SEM might be a prospective therapeutic candidate, and its mechanism would be a new direction or strategy for hepatic fibrosis treatment.
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Affiliation(s)
- YuChen Jiang
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - LiShuang Hou
- Air Force Medical University, Xi'an 710032, China
| | - JiaYi Dou
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - MeiYan Xuan
- School of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan
| | - ZhenYu Cui
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - LiHua Lian
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - JiXing Nan
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
| | - YanLing Wu
- Key Laboratory of Natural Medicines of the Changbai Mountain (Yanbian University), Ministry of Education, Key Laboratory for Traditional Chinese Korean Medicine Research (Yanbian University), State Ethnic Affairs, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China.
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Raza S, Rajak S, Singh R, Zhou J, Sinha RA, Goel A. Cell-type specific role of autophagy in the liver and its implications in non-alcoholic fatty liver disease. World J Hepatol 2023; 15:1272-1283. [PMID: 38192406 PMCID: PMC7615497 DOI: 10.4254/wjh.v15.i12.1272] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/07/2023] [Accepted: 12/08/2023] [Indexed: 12/25/2023] Open
Abstract
Autophagy, a cellular degradative process, has emerged as a key regulator of cellular energy production and stress mitigation. Dysregulated autophagy is a common phenomenon observed in several human diseases, and its restoration offers curative advantage. Non-alcoholic fatty liver disease (NAFLD), more recently renamed metabolic dysfunction-associated steatotic liver disease, is a major metabolic liver disease affecting almost 30% of the world population. Unfortunately, NAFLD has no pharmacological therapies available to date. Autophagy regulates several hepatic processes including lipid metabolism, inflammation, cellular integrity and cellular plasticity in both parenchymal (hepatocytes) and non-parenchymal cells (Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells) with a profound impact on NAFLD progression. Understanding cell type-specific autophagy in the liver is essential in order to develop targeted treatments for liver diseases such as NAFLD. Modulating autophagy in specific cell types can have varying effects on liver function and pathology, making it a promising area of research for liver-related disorders. This review aims to summarize our present understanding of cell-type specific effects of autophagy and their implications in developing autophagy centric therapies for NAFLD.
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Affiliation(s)
- Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India
| | - Rajani Singh
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India
| | - Jin Zhou
- CVMD, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Rohit A Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India
| | - Amit Goel
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India.
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Le TV, Truong NH, Holterman AXL. Autophagy modulates physiologic and adaptive response in the liver. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:304-320. [PMID: 39958781 PMCID: PMC11792069 DOI: 10.1016/j.livres.2023.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/20/2023] [Accepted: 11/14/2023] [Indexed: 01/03/2025]
Abstract
Autophagy is a physiological process that is ubiquitous and essential to the disposal or recycling of damaged cellular organelles and misfolded proteins to maintain organ homeostasis and survival. Its importance in the regulation of liver function in normal and pathological conditions is increasingly recognized. This review summarizes how autophagy regulates epithelial cell- and non-epithelial cell-specific function in the liver and how it differentially participates in hepatic homeostasis, hepatic injury response to stress-induced liver damage such as cholestasis, sepsis, non-alcoholic and alcohol-associated liver disease, viral hepatitis, hepatic fibrosis, hepatocellular and cholangiocellular carcinoma, and aging. Autophagy-based interventional studies for liver diseases that are currently registered in clinicatrials.gov are summarized. Given the broad and multidirectional autophagy response in the liver, a more refined understanding of the liver cell-specific autophagy activities in a context-dependent manner is necessary.
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Affiliation(s)
- Trinh Van Le
- Laboratory of Stem Cell Research and Application, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Nhung Hai Truong
- Faculty of Biology and Biotechnology, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
| | - Ai Xuan L. Holterman
- Department of Pediatrics and Surgery, University of Illinois College of Medicine, Chicago and Peoria, IL, USA
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Aghajanzadeh T, Talkhabi M, Zali MR, Hatami B, Baghaei K. Diagnostic potential and pathogenic performance of circulating miR-146b, miR-194, and miR-214 in liver fibrosis. Noncoding RNA Res 2023; 8:471-480. [PMID: 37434946 PMCID: PMC10331815 DOI: 10.1016/j.ncrna.2023.06.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/17/2023] [Accepted: 06/25/2023] [Indexed: 07/13/2023] Open
Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins. Due to the lack of an accurate test for an early diagnosis of liver fibrosis and the invasiveness of the liver biopsy procedure, there is an urgent need for effective non-invasive biomarkers for screening the patients. we aimed to evaluate the diagnostic performance of circulating miRNAs (miR-146b, -194, -214) and their related mechanisms in the pathogenesis of liver fibrosis. The expression levels of miR-146b, -194, and -214 were quantified in whole blood samples from NAFLD patients using real-time PCR. The competing endogenous RNA (ceRNA) network was constructed and a gene set enrichment analysis (GSEA) was performed for HSC activation-related genes. Also, the transcription factor (TF)-miR co-regulatory network and the survival plot for three miRNAs and core genes were illustrated. The qPCR results showed that the relative expression of miR-146b and miR-214 significantly increased in NAFLD patients, while miR-194 showed significant down-regulation. The ceRNA network analysis implicated NEAT1 and XIST as sponge candidates for these miRNAs. The GSEA results identified 15 core genes involved in HSC activation, primarily enriched in NF-κB activation and autophagy pathways. STAT3, TCF3, RELA, and RUNX1 were considered potential transcription factors connected to miRNAs in the TF-miR network. Our study elucidated three candidate circulating miRNAs differentially expressed in NAFLD that could serve as a promising non-invasive diagnostic tool for early detection strategies. Also, NF-κB activation, autophagy, and negative regulation of the apoptotic process are the main potential underlying mechanisms regulated by these miRNAs in liver fibrosis pathogenesis.
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Affiliation(s)
- Taha Aghajanzadeh
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Talkhabi
- Department of Animal Sciences and Marine Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Shu Y, He Y, Ye G, Liu X, Huang J, Zhang Q, Tian D, Wang T, Shu J. Curcumin inhibits the activity and induces apoptosis of activated hepatic stellate cell by suppressing autophagy. J Cell Biochem 2023; 124:1764-1778. [PMID: 37909649 DOI: 10.1002/jcb.30487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 09/09/2023] [Accepted: 09/25/2023] [Indexed: 11/03/2023]
Abstract
Curcumin, a kind of natural compound, has been previously proven to inhibit the autophagy in hepatic stellate cells (HSCs) and induce their apoptosis. However, it is not clear whether the enhanced apoptosis of activated HSCs (aHSCs) caused by curcumin depends on autophagy inhibition. We aim to verify this hypothesis and explore the potential mechanisms in this study. Immortalized human HSC line LX-2 was used as an experimental specimen and pretreated with transforming growth factor β1(TGF-β1) for 24 h to activate it before drug application. The levels of autophagy, apoptosis, cell activity, lipid metabolism, and the activity of the PI3K/Akt/mTOR signal pathway were evaluated by multiple methods, such as Western blotting, mcherry-EGFP-LC3B adenoviruses transfection, immunofluorescence, Nile Red staining, flow cytometry among others. Our results showed that rapamycin, an autophagy activator, could partly offset the effects of curcumin on autophagy and apoptosis of LX-2 cells, while 3-Methyladenine (3-MA), an autophagy inhibitor, could enhance these effects. Furthermore, curcumin could promote the activity of the PI3K/Akt/mTOR signal pathway in LX-2 cells, while PI3K inhibitor could partly offset this effect and increase the autophagy level. Overall, we demonstrated that curcumin could inhibit the activity and promote LX-2 cells apoptosis by suppressing autophagy by activating the PI3K/Akt/mTOR signal pathway. In addition, lipid recovery and energy deprivation due to autophagy inhibition may be the exact mechanism by which curcumin attenuates the pro-fibrotic activity of LX-2.
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Affiliation(s)
- Yongxiang Shu
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Yajun He
- Department of Clinical laboratory, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Guorong Ye
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Xuyou Liu
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Jiahuang Huang
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Qinghui Zhang
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Da Tian
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Tengyan Wang
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
| | - Jianchang Shu
- Department of Gastroenterology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, China
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Zhang YW, Hou LS, Xing JH, Zhang TR, Zhou SY, Zhang BL. Two-Membrane Hybrid Nanobiomimetic Delivery System for Targeted Autophagy Inhibition of Activated Hepatic Stellate Cells To Synergistically Treat Liver Fibrosis. ACS APPLIED MATERIALS & INTERFACES 2023. [PMID: 37899504 DOI: 10.1021/acsami.3c11046] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
Liver fibrosis is one of the most common and highly prevalent chronic liver diseases caused by multiple pathogenic factors, and there is still no effective therapeutic drugs up to now. The activated hepatic stellate cells (aHSCs) are the main executor in liver fibrosis, and the autophagy plays a key role in the proliferation and differentiation of aHSCs, which promotes the development of liver fibrosis. However, autophagy has the opposite effect on the different kinds of liver cells in the development of liver fibrosis, and the clinical treatment has been limited by the poor selectivity and inefficient drug delivery to aHSCs. Therefore, in this study, a liposome (Lip) and exosome (Exo) two-membrane hybrid nanobiomimetic delivery system HCQ@VA-Lip-Exo was designed, which was modified by vitamin A (VA) to target the aHSCs and carried the autophagy inhibitor hydroxychloroquine (HCQ). The experimental results in vitro and in vivo revealed that the constructed aHSC-targeted hybrid delivery system HCQ@VA-Lip-Exo combined with the benefits of HCQ and exosomes derived from bone marrow mesenchymal stem cells. HCQ@VA-Lip-Exo had good aHSC-targeted delivery ability, effective autophagy inhibition, and synergistical anti-liver fibrosis performance, thus reducing the production and deposition of the extracellular matrix to inhibit the liver fibrosis. This combined strategy provided a potential idea for the construction and clinical application of a two-membrane hybrid delivery system as an effective targeted therapy of liver fibrosis.
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Affiliation(s)
- Yao-Wen Zhang
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China
| | - Li-Shuang Hou
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China
| | - Jie-Hua Xing
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China
| | - Tang-Rui Zhang
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China
| | - Si-Yuan Zhou
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China
- Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China
| | - Bang-Le Zhang
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China
- Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China
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37
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Geng Y, Wang J, Serna-Salas SA, Villanueva AH, Buist-Homan M, Arrese M, Olinga P, Blokzijl H, Moshage H. Hepatic stellate cells induce an inflammatory phenotype in Kupffer cells via the release of extracellular vesicles. J Cell Physiol 2023; 238:2293-2303. [PMID: 37555553 DOI: 10.1002/jcp.31086] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/15/2023] [Accepted: 07/12/2023] [Indexed: 08/10/2023]
Abstract
Liver fibrosis is the response of the liver to chronic liver inflammation. The communication between the resident liver macrophages (Kupffer cells [KCs]) and hepatic stellate cells (HSCs) has been mainly viewed as one-directional: from KCs to HSCs with KCs promoting fibrogenesis. However, recent studies indicated that HSCs may function as a hub of intercellular communications. Therefore, the aim of the present study was to investigate the role of HSCs on the inflammatory phenotype of KCs. Primary rat HSCs and KCs were isolated from male Wistar rats. HSCs-derived conditioned medium (CM) was harvested from different time intervals (Day 0-2: CM-D2 and Day 5-7: CM-D7) during the activation of HSCs. Extracellular vesicles (EVs) were isolated from CM by ultracentrifugation and evaluated by nanoparticle tracking analysis and western blot analysis. M1 and M2 markers of inflammation were measured by quantitative PCR and macrophage function by assessing phagocytic capacity. CM-D2 significantly induced the inflammatory phenotype in KCs, but not CM-D7. Neither CM-D2 nor CM-D7 affected the phagocytosis of KCs. Importantly, the proinflammatory effect of HSCs-derived CM is mediated via EVs released from HSCs since EVs isolated from CM mimicked the effect of CM, whereas EV-depleted CM lost its ability to induce a proinflammatory phenotype in KCs. In addition, when the activation of HSCs was inhibited, HSCs produced less EVs. Furthermore, the proinflammatory effects of CM and EVs are related to activating Toll-like receptor 4 (TLR4) in KCs. In conclusion, HSCs at an early stage of activation induce a proinflammatory phenotype in KCs via the release of EVs. This effect is absent in CM derived from HSCs at a later stage of activation and is dependent on the activation of TLR4 signaling pathway.
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Affiliation(s)
- Yana Geng
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Junyu Wang
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Sandra Alejandra Serna-Salas
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alejandra Hernández Villanueva
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Marco Arrese
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Hans Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Zhang Y, Zhang Y, Chen T, Lin Y, Gong J, Xu Q, Wang J, Li J, Meng Y, Li Y, Li X. Caveolin-1 depletion attenuates hepatic fibrosis via promoting SQSTM1-mediated PFKL degradation in HSCs. Free Radic Biol Med 2023; 204:95-107. [PMID: 37116593 DOI: 10.1016/j.freeradbiomed.2023.04.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 04/30/2023]
Abstract
The key glycolytic enzyme phosphofructokinase (PFK) is responsible for maintaining glycolytic stability and an important energy source for activating hepatic stellate cells (HSCs). However, its regulation in activated HSCs remains unclear. Caveolin-1 (Cav1), a major constituent of caveolae, has emerged as a key target for triggering glycolysis. However, the relationship between Cav1 and glycolysis during HSC activation is not well established. In this study, Cav1 was upregulated in mouse and human fibrotic liver tissues. We concluded that HSC-specific Cav1 knockdown markedly alleviates liver injury and fibrosis. Mechanistically, Cav1 was elevated during primary mouse HSC activation, competing with SQSTM1 for the regulatory subunit of PFK liver type and inhibiting the SQSTM1-mediated autophagy-independent lysosomal degradation pathway to sustain HSC activation. We also identified the heptapeptide alamandine as a promising therapeutic agent that downregulates Cav1 protein levels via proteasomal degradation and may impair glycolysis. Our study provides evidence of the crucial role and mechanism of Cav1 in the glucose metabolic network in HSCs and highlights Cav1 as a critical therapeutic target for the treatment of liver fibrosis.
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Affiliation(s)
- Yan Zhang
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Yijie Zhang
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Tingting Chen
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Ying Lin
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Jiacheng Gong
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Qihan Xu
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Jun Wang
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Jierui Li
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China; Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
| | - Ying Meng
- Department of Respiratory Diseases, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
| | - Yang Li
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
| | - Xu Li
- Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China.
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Tao H, Liu Q, Zeng A, Song L. Unlocking the potential of Mesenchymal stem cells in liver Fibrosis: Insights into the impact of autophagy and aging. Int Immunopharmacol 2023; 121:110497. [PMID: 37329808 DOI: 10.1016/j.intimp.2023.110497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/30/2023] [Accepted: 06/11/2023] [Indexed: 06/19/2023]
Abstract
Liver fibrosis is a chronic liver disease characterized by extracellular matrix protein accumulation, potentially leading to cirrhosis or hepatocellular carcinoma. Liver cell damage, inflammatory responses, and apoptosis due to various reasons induce liver fibrosis. Although several treatments, such as antiviral drugs and immunosuppressive therapies, are available for liver fibrosis, they only provide limited efficacy. Mesenchymal stem cells (MSCs) have become a promising therapeutic option for liver fibrosis, because they can modulate the immune response, promote liver regeneration, and inhibit the activation of hepatic stellate cells that contribute to disease development. Recent studies have suggested that the mechanisms through which MSCs gain their antifibrotic properties involve autophagy and senescence. Autophagy, a vital cellular self-degradation process, is critical for maintaining homeostasis and protecting against nutritional, metabolic, and infection-mediated stress. The therapeutic effects of MSCs depend on appropriate autophagy levels, which can improve the fibrotic process. Nonetheless, aging-related autophagic damage is associated with a decline in MSC number and function, which play a crucial role in liver fibrosis development. This review summarizes the recent advancements in the understanding of autophagy and senescence in MSC-based liver fibrosis treatment, presenting the key findings from relevant studies.
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Affiliation(s)
- Hongxia Tao
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Qianglin Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan 610041, PR China.
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China.
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40
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Yenilmez B, Harney S, DiMarzio C, Kelly M, Min K, Echeverria D, Bramato BM, Jackson SO, Reddig K, Kim JK, Khvorova A, Czech MP. Dual targeting of hepatocyte DGAT2 and stellate cell FASN alleviates nonalcoholic steatohepatitis in mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.05.547848. [PMID: 37461560 PMCID: PMC10350091 DOI: 10.1101/2023.07.05.547848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is a malady of multiple cell types associated with hepatocyte triglyceride (TG) accumulation, macrophage inflammation, and stellate cell-induced fibrosis, with no approved therapeutics yet available. Here, we report that stellate cell fatty acid synthase (FASN) in de novo lipogenesis drives the autophagic flux that is required for stellate cell activation and fibrotic collagen production. Further, we employ a dual targeting approach to NASH that selectively depletes collagen through selective stellate cell knockout of FASN (using AAV9-LRAT Cre in FASNfl/fl mice), while lowering hepatocyte triglyceride by depleting DGAT2 with a GalNac-conjugated, fully chemically modified siRNA. DGAT2 silencing in hepatocytes alone or in combination with stellate cell FASNKO reduced liver TG accumulation in a choline-deficient NASH mouse model, while FASNKO in hepatocytes alone (using AAV8-TBG Cre in FASNfl/fl mice) did not. Neither hepatocyte DGAT2 silencing alone nor FASNKO in stellate cells alone decreased fibrosis (total collagen), while loss of both DGAT2 plus FASN caused a highly significant attenuation of NASH. These data establish proof of concept that dual targeting of DGAT2 plus FASN alleviates NASH progression in mice far greater than targeting either gene product alone.
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Affiliation(s)
- Batuhan Yenilmez
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Shauna Harney
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Chloe DiMarzio
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Mark Kelly
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Kyounghee Min
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Dimas Echeverria
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Brianna M. Bramato
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Samuel O. Jackson
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Keith Reddig
- Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Jason K. Kim
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Anastasia Khvorova
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Michael P. Czech
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
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Wang Y, Xiong L, Dong Z, Ran K, Bai W, Mo Z, Huang K, Ye Y, Tao Y, Yin S, Li M, He Q. Autophagy-Interfering Nanoboat Drifting along CD44-Golgi-ER Flow as RNAi Therapeutics for Hepatic Fibrosis. ACS APPLIED MATERIALS & INTERFACES 2023. [PMID: 37290012 DOI: 10.1021/acsami.3c03416] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The upregulated autophagy fuels the activation of hepatic stellate cells (HSCs) to promote hepatic fibrosis. However, the lack of specific inhibitors targeting autophagy and high requirements for cell targeting impede the application of antifibrotic therapy that targets autophagy. RNA interference (RNAi)-based short interfering RNA (siRNA) provides an approach to specifically inhibit autophagy. The therapeutic potential of siRNA, however, is far from being exploited due to the lack of safe and effective delivery vehicles. The cytoplasmic delivery of siRNA is essential for RNAi, and the intracellular trafficking pathway of vehicles determines the fate of siRNA. Unfortunately, the lysosomal degradation pathway, the intracellular fate of most gene vehicles, impedes RNAi efficiency. Inspired by the trafficking pathway of some viruses infecting cells, KDEL-grafted chondroitin sulfate (CK) was designed to alter the intracellular delivery fate of siRNA. The well-designed CD44-Golgi-ER trafficking pathway of CK was realized by triple cascade targeting including (1) CD44 targeting mediated by chondroitin sulfate, (2) Golgi apparatus targeting mediated by the caveolin-mediated endocytic pathway, and (3) endoplasmic reticulum (ER) targeting mediated by coat protein I (COP I) vesicles. CK was adsorbed on the complex of cationic liposomes (Lip) encapsulating siRNA targeting autophagy-related gene 7 (siATG7) to afford Lip/siATG7/CK. Lip/siATG7/CK functions as a drifting boat that follows the CD44-Golgi-ER flow and travels downstream to its destination (ER), bypassing the lysosomal degradation pathway and endowing HSCs with excellent RNAi efficiency. The efficient downregulation of ATG7 leads to an excellent antifibrotic effect both in vitro and in vivo.
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Affiliation(s)
- Yashi Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Lin Xiong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Ziyan Dong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Kaixin Ran
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Wenjing Bai
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Ziyi Mo
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Kexin Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Yunxia Ye
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Yuan Tao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Sheng Yin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Man Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
| | - Qin He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Med-X Center for Materials, Sichuan University, Chengdu 610041, People's Republic of China
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42
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Li ZB, Jiang L, Ni JD, Xu YH, Liu F, Liu WM, Wang SG, Liu ZQ, Wang CY. Salvianolic acid B suppresses hepatic fibrosis by inhibiting ceramide glucosyltransferase in hepatic stellate cells. Acta Pharmacol Sin 2023; 44:1191-1205. [PMID: 36627345 PMCID: PMC10203340 DOI: 10.1038/s41401-022-01044-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 12/14/2022] [Indexed: 01/11/2023]
Abstract
UDP-glucose ceramide glucosyltransferase (UGCG) is the first key enzyme in glycosphingolipid (GSL) metabolism that produces glucosylceramide (GlcCer). Increased UGCG synthesis is associated with cell proliferation, invasion and multidrug resistance in human cancers. In this study we investigated the role of UGCG in the pathogenesis of hepatic fibrosis. We first found that UGCG was over-expressed in fibrotic livers and activated hepatic stellate cells (HSCs). In human HSC-LX2 cells, inhibition of UGCG with PDMP or knockdown of UGCG suppressed the expression of the biomarkers of HSC activation (α-SMA and collagen I). Furthermore, pretreatment with PDMP (40 μM) impaired lysosomal homeostasis and blocked the process of autophagy, leading to activation of retinoic acid signaling pathway and accumulation of lipid droplets. After exploring the structure and key catalytic residues of UGCG in the activation of HSCs, we conducted virtual screening, molecular interaction and molecular docking experiments, and demonstrated salvianolic acid B (SAB) from the traditional Chinese medicine Salvia miltiorrhiza as an UGCG inhibitor with an IC50 value of 159 μM. In CCl4-induced mouse liver fibrosis, intraperitoneal administration of SAB (30 mg · kg-1 · d-1, for 4 weeks) significantly alleviated hepatic fibrogenesis by inhibiting the activation of HSCs and collagen deposition. In addition, SAB displayed better anti-inflammatory effects in CCl4-induced liver fibrosis. These results suggest that UGCG may represent a therapeutic target for liver fibrosis; SAB could act as an inhibitor of UGCG, which is expected to be a candidate drug for the treatment of liver fibrosis.
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Affiliation(s)
- Zi-Bo Li
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Lin Jiang
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Jia-Dong Ni
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Yuan-Hang Xu
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Fang Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Wen-Ming Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Shao-Gui Wang
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| | - Zhong-Qiu Liu
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| | - Cai-Yan Wang
- Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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Yum YJ, Yoo J, Bang K, Jun JE, Jeong IK, Ahn KJ, Chung HY, Hwang YC. Peroxisome proliferator-activated receptor γ activation ameliorates liver fibrosis-differential action of transcription factor EB and autophagy on hepatocytes and stellate cells. Hepatol Commun 2023; 7:e0154. [PMID: 37204406 PMCID: PMC10538880 DOI: 10.1097/hc9.0000000000000154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/07/2023] [Indexed: 05/20/2023] Open
Abstract
BACKGROUND Peroxisome proliferator-activated receptor γ (PPARγ) activation suppresses HSC activation and liver fibrosis. Moreover, autophagy is implicated in hepatic lipid metabolism. Here, we determined whether PPARγ activation ameliorates HSC activation by downregulating transcription factor EB (TFEB)-mediated autophagy. METHODS AND RESULTS Atg7 or Tfeb knockdown in human HSC line LX-2 cells downregulated the expression of fibrogenic markers including α smooth muscle actin, glial fibrillary acidic protein, and collagen type 1. Conversely, Atg7 or Tfeb overexpression upregulated fibrogenic marker expression. Rosiglitazone (RGZ)-mediated PPARγ activation and/or overexpression in LX-2 cells and primary HSCs decreased autophagy, as indicated by LC3B conversion, total and nuclear-TFEB contents, mRFP-LC3 and BODIPY 493/503 colocalization, and GFP-LC3 and LysoTracker colocalization. RGZ treatment decreased liver fat content, liver enzyme levels, and fibrogenic marker expression in high-fat high-cholesterol diet-fed mice. Electron microscopy showed that RGZ treatment restored the high-fat high-cholesterol diet-mediated lipid droplet decrease and autophagic vesicle induction in primary HSCs and liver tissues. However, TFEB overexpression in LX-2 cells offset the aforementioned effects of RGZ on autophagic flux, lipid droplets, and fibrogenic marker expression. CONCLUSIONS Activation of PPARγ with RGZ ameliorated liver fibrosis and downregulation of TFEB and autophagy in HSCs may be important for the antifibrotic effects of PPARγ activation.
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Kitsugi K, Noritake H, Matsumoto M, Hanaoka T, Umemura M, Yamashita M, Takatori S, Ito J, Ohta K, Chida T, Suda T, Kawata K. Simvastatin inhibits hepatic stellate cells activation by regulating the ferroptosis signaling pathway. Biochim Biophys Acta Mol Basis Dis 2023:166750. [PMID: 37268254 DOI: 10.1016/j.bbadis.2023.166750] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 05/03/2023] [Accepted: 05/04/2023] [Indexed: 06/04/2023]
Abstract
BACKGROUND & AIMS Ferroptosis is a form of regulated cell death and its promotion in hepatic stellate cells (HSCs) attenuates liver fibrosis. Statins, which are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may induce ferroptosis via the downregulation of glutathione peroxidase 4 (GPX4) by inhibiting the mevalonate pathway. However, little evidence is available regarding the association between statins and ferroptosis. Therefore, we investigated the association between statins and ferroptosis in HSCs. METHODS Two human HSC cell lines, LX-2 and TWNT-1, were treated with simvastatin, an HMG-CoA reductase inhibitor. Mevalonic acid (MVA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were used to determine the involvement of the mevalonate pathway. We performed a detailed analysis of the ferroptosis signaling pathway. We also investigated human liver tissue samples from patients with nonalcoholic steatohepatitis to clarify the effect of statins on GPX4 expression. RESULTS Simvastatin reduced cell mortality and inhibited HSCs activation, accompanied by iron accumulation, oxidative stress, lipid peroxidation, and reduced GPX4 protein expression. These results indicate that simvastatin inhibits HSCs activation by promoting ferroptosis. Furthermore, treatment with MVA, FPP, or GGPP attenuated simvastatin-induced ferroptosis. These results suggest that simvastatin promotes ferroptosis in HSCs by inhibiting the mevalonate pathway. In human liver tissue samples, statins downregulated the expression of GPX4 in HSCs without affecting hepatocytes. CONCLUSIONS Simvastatin inhibits the activation of HSCs by regulating the ferroptosis signaling pathway.
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Affiliation(s)
- Kensuke Kitsugi
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
| | - Hidenao Noritake
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Moe Matsumoto
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Tomohiko Hanaoka
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Masahiro Umemura
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Maho Yamashita
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Shingo Takatori
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Jun Ito
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuyoshi Ohta
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takeshi Chida
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Takafumi Suda
- Division of Respiratory Medicine, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kazuhito Kawata
- Division of Hepatology, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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Brichkina A, Polo P, Sharma SD, Visestamkul N, Lauth M. A Quick Guide to CAF Subtypes in Pancreatic Cancer. Cancers (Basel) 2023; 15:cancers15092614. [PMID: 37174079 PMCID: PMC10177377 DOI: 10.3390/cancers15092614] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/21/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic cancer represents one of the most desmoplastic malignancies and is characterized by an extensive deposition of extracellular matrix. The latter is provided by activated cancer-associated fibroblasts (CAFs), which are abundant cells in the pancreatic tumor microenvironment. Many recent studies have made it clear that CAFs are not a singular cellular entity but represent a multitude of potentially dynamic subgroups that affect tumor biology at several levels. As mentioned before, CAFs significantly contribute to the fibrotic reaction and the biomechanical properties of the tumor, but they can also modulate the local immune environment and the response to targeted, chemo or radiotherapy. As the number of known and emerging CAF subgroups is steadily increasing, it is becoming increasingly difficult to keep up with these developments and to clearly discriminate the cellular subsets identified so far. This review aims to provide a helpful overview that enables readers to quickly familiarize themselves with field of CAF heterogeneity and to grasp the phenotypic, functional and therapeutic distinctions of the various stromal subpopulations.
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Affiliation(s)
- Anna Brichkina
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
| | - Pierfrancesco Polo
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
| | - Shrey Dharamvir Sharma
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
| | - Nico Visestamkul
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
| | - Matthias Lauth
- Center for Tumor and Immune Biology, Clinics for Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Hans-Meerwein-Str. 3, 35043 Marburg, Germany
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Tan Y, Li C, Zhou J, Deng F, Liu Y. Berberine attenuates liver fibrosis by autophagy inhibition triggering apoptosis via the miR-30a-5p/ATG5 axis. Exp Cell Res 2023; 427:113600. [PMID: 37062521 DOI: 10.1016/j.yexcr.2023.113600] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 03/03/2023] [Accepted: 04/09/2023] [Indexed: 04/18/2023]
Abstract
Berberine (BBR) is an effective drug against liver fibrosis (LF). Autophagy is involved in the pathogenesis of LF; however, the mechanism linking BBR to autophagy in LF remains unresolved. To explore the underlying mechanism, we assessed the effects of BBR on autophagy and apoptosis of activated hepatic stellate cells (HSCs) in vitro and in a murine model of fibrosis. The decreased expression of the autophagy activation marker ATG5, autophagosome formation, and autophagy flux in the HSC model confirmed that BBR inhibited autophagy in activated HSCs and in mice with liver fibrosis. Moreover, ATG5 was necessary for inducing autophagy and HSC activation. BBR suppressed ATG5 expression by upregulating miR-30a-5p expression, which affected the stability of ATG5 mRNA by binding to its 3'-untranslated region, an effect that was attenuated by treatment with a miR-30a-5p inhibitor. BBR also markedly induced HSC apoptosis, as indicated by the upregulated expression of the pro-apoptosis markers p53, BAX, and cleaved PARP and the downregulated expression of the anti-apoptosis marker BCL-2, effects that were reversed by ATG5 overexpression. In vivo, BBR improved mouse LF by decreasing collagen deposition, inflammatory cell infiltration, and expression of fibrosis markers hydroxyproline, α-smooth muscle actin, and collagen type 1-A1 and the autophagy marker LC3. BBR had a protective effect on mouse fibrotic livers and reduced serum aspartate aminotransferase and alanine aminotransferase levels. Collectively, these results reveal a novel mechanism of BBR-induced autophagy inhibition triggering apoptosis in HSCs, providing a reliable experimental and theoretical basis for developing BBR-based candidate drugs for LF.
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Affiliation(s)
- Yuehao Tan
- Sichuan Nursing Vocational College, Chengdu, 610100, China
| | - Can Li
- Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China
| | - Jiali Zhou
- Sichuan Nursing Vocational College, Chengdu, 610100, China
| | - Fengmei Deng
- School of Basic Medical Science, Chengdu Medical College, Chengdu, 610500, China.
| | - Yilun Liu
- Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China; People's Hospital of Mingshan District, Ya'an, Sichuan, 625100, China.
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Tacke F, Puengel T, Loomba R, Friedman SL. An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH. J Hepatol 2023:S0168-8278(23)00218-0. [PMID: 37061196 DOI: 10.1016/j.jhep.2023.03.038] [Citation(s) in RCA: 142] [Impact Index Per Article: 71.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/08/2023] [Accepted: 03/29/2023] [Indexed: 04/17/2023]
Abstract
Successful development of treatments for non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH) has been challenging. Because NASH and fibrosis lead to NAFLD progression towards cirrhosis and to clinical outcomes, approaches have either sought to attenuate metabolic dysregulation and cell injury, or directly target the inflammation and fibrosis that ensue. Targets for reducing the activation of inflammatory cascades include nuclear receptor agonists (thyroid hormone receptor-beta, e.g. resmetirom, peroxisome proliferator-activated receptor [PPAR], e.g. lanifibranor, farnesoid X receptor [FXR], e.g. obeticholic acid), modulators of lipotoxicity (e.g. aramchol, acetyl-CoA carboxylase inhibitors) or modification of genetic variants (e.g. PNPLA3 gene silencing). Extrahepatic inflammatory signals from circulation, adipose tissue or gut are targets of hormonal agonists (e.g. glucagon-like peptide-1 [GLP-1] like semaglutide, fibroblast growth factor [FGF]-19 or FGF21), microbiota or lifestyle (weight loss, diet, exercise) interventions. Stress signals and hepatocyte death activate immune responses engaging innate (macrophages, lymphocytes) and adaptive (auto-aggressive T-cells) mechanisms. Therapies seek to blunt immune cell activation, recruitment (chemokine receptor inhibitors) and responses (e.g. galectin 3 inhibition, anti-platelet drugs). The disease-driving pathways of NASH converge to elicit fibrosis, which is reversible. The activation of hepatic stellate cells (HSC) into matrix-producing myofibroblasts can be inhibited by antagonizing soluble factors (e.g. integrins, cytokines), cellular crosstalk (e.g. with macrophages), and agonizing nuclear receptor signaling (e.g. FXR or PPAR agonists). In advanced fibrosis, cell therapy with restorative macrophages or reprogrammed T-cells (e.g., CAR T) may accelerate repair through HSC deactivation or killing, or by enhancing matrix degradation. Heterogeneity of disease - either due to genetics or divergent disease drivers - is an obstacle to defining effective drugs for all patients with NASH that will be incrementally overcome.
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Affiliation(s)
- Frank Tacke
- Department of Hepatology & Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
| | - Tobias Puengel
- Department of Hepatology & Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health, Berlin, Germany
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, San Diego, CA, United States.
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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Abeliovich H, Debnath J, Ding WX, Jackson WT, Kim DH, Klionsky DJ, Ktistakis N, Margeta M, Münz C, Petersen M, Sadoshima J, Vergne I. Where is the field of autophagy research heading? Autophagy 2023; 19:1049-1054. [PMID: 36628432 PMCID: PMC10012950 DOI: 10.1080/15548627.2023.2166301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
In this editors' corner, the section editors were asked to indicate where they see the autophagy field heading and to suggest what they consider to be key unanswered questions in their specialty area.
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Affiliation(s)
- Hagai Abeliovich
- Department of Biochemistry, Food Science and Nutrition, Hebrew University of Jerusalem, Rehovot, Israel
| | - Jayanta Debnath
- Department of Pathology, USCF School of Medicine, San Francisco, CA, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - William T. Jackson
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Do-Hyung Kim
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minn, USA
| | | | | | - Marta Margeta
- Department of Pathology, USCF School of Medicine, San Francisco, CA, USA
| | - Christian Münz
- Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland
| | - Morten Petersen
- Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Isabelle Vergne
- Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, University of Toulouse III-Paul Sabatier, Toulouse, France
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Le TV, Phan-Thi HT, Huynh-Thi MX, Dang TM, Holterman AXL, Grassi G, Nguyen-Luu TU, Truong NH. Autophagy Inhibitor Chloroquine Downmodulates Hepatic Stellate Cell Activation and Liver Damage in Bile-Duct-Ligated Mice. Cells 2023; 12:1025. [PMID: 37048098 PMCID: PMC10092998 DOI: 10.3390/cells12071025] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/15/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
Hepatic stellate cell (HSC) activation via the autophagy pathway is a critical factor in liver fibrogenesis. This study tests the hypothesis that chloroquine (CQ) treatment can prevent autophagy and HSC activation in vitro and in vivo in bile-duct-ligated (BDL) mice. Sham-operated and BDL mice were treated with either PBS or CQ in two 60 mg/kg doses the day (D) before and after surgery. On day 2 (2D), HSCs were isolated, and their biological activities were evaluated by measuring intracellular lipid content, α-sma/collagen, and expression of autophagy lc3, sqstm1/p62 markers. The treatment efficacy on liver function was evaluated with serum albumin, transaminases (AST/ALT), and hepatic histology. Primary HSCs were treated in vitro for 24 h with CQ at 0, 2.5, 5, 10, 30, and 50 µM. Autophagy and HSC activation were assessed after 2D of treatment. CQ treatment improved serum AST/ALT, albumin, and bile duct proliferation in 2D BDL mice. This is associated with a suppression of HSC activation, shown by higher HSC lipid content and collagen I staining, along with the blockage of HSC autophagy indicated by an increase in p62 level and reduction in lc3 staining. CQ 5 µM inhibited autophagy in primary HSCs in vitro by increasing p62 and lc3 accumulation, thereby suppressing their in vitro activation. The autophagy inhibitor CQ reduced HSC activation in vitro and in vivo. CQ improved liver function and reduced liver injury in BDL mice.
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Affiliation(s)
- Trinh Van Le
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - Hong-Thuy Phan-Thi
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - My-Xuan Huynh-Thi
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - Thanh Minh Dang
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - Ai Xuan Le Holterman
- Department of Pediatrics and Surgery, University of Illinois College of Medicine, Chicago, IL 60607, USA
| | - Gabriele Grassi
- Department of Life Sciences, University Hospital of Cattinara, University of Trieste, 34100 Trieste, Italy
| | - Thao-Uyen Nguyen-Luu
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.V.L.)
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
| | - Nhung Hai Truong
- Viet Nam National University, Ho Chi Minh City 700000, Vietnam
- Faculty of Biology and Biotechnology, University of Science, Ho Chi Minh City 700000, Vietnam
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Wu Y, Tan HWS, Lin JY, Shen HM, Wang H, Lu G. Molecular mechanisms of autophagy and implications in liver diseases. LIVER RESEARCH 2023; 7:56-70. [PMID: 39959698 PMCID: PMC11792062 DOI: 10.1016/j.livres.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/03/2022] [Accepted: 02/15/2023] [Indexed: 02/22/2023]
Abstract
Autophagy is a highly conserved process in which cytosolic contents are degraded by the lysosome, which plays an important role in energy and nutrient balance, and protein or organelle quality control. The liver is the most important organ for metabolism. Studies to date have revealed a significant role of autophagy in the maintenance of liver homeostasis under basal and stressed conditions, and the impairment of autophagy has been closely linked to various liver diseases. Therefore, a comprehensive understanding of the roles of autophagy in liver diseases may help in the development of therapeutic strategies via targeting autophagy. In this review, we will summarize the latest understanding of the molecular mechanisms of autophagy and systematically discuss its implications in various liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, viral hepatitis, hepatocellular carcinoma, and acetaminophen-induced liver injury.
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Affiliation(s)
- Yuankai Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hayden Weng Siong Tan
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jin-Yi Lin
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Han-Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
| | - Haihe Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guang Lu
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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