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Wang T, Xia G, Li X, Gong M, Lv X. Endoplasmic reticulum stress in liver fibrosis: Mechanisms and therapeutic potential. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167695. [PMID: 39864668 DOI: 10.1016/j.bbadis.2025.167695] [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: 09/29/2024] [Revised: 01/07/2025] [Accepted: 01/22/2025] [Indexed: 01/28/2025]
Abstract
This paper reviews the important role of endoplasmic reticulum stress in the patho mechanism of liver fibrosis and its potential as a potential target for the treatment of liver fibrosis. Liver fibrosis is the result of sustained inflammation and injury to the liver due to a variety of factors, triggering excessive deposition of extracellular matrix and fibrous scar formation, which in turn leads to loss of liver function and a variety of related complications. Endoplasmic reticulum stress is one of the characteristics of chronic liver disease and is closely related to the pathological process of chronic liver disease, including alcohol-related liver disease, viral hepatitis, and liver fibrosis. The unfolded protein response is one of the important response mechanisms to endoplasmic reticulum stress. It is associated with several pathological aspects of liver fibrosis and the maintenance of endoplasmic reticulum homeostasis. Interventions targeting endoplasmic reticulum stress for the treatment of liver fibrosis have potential research and application value. An in-depth understanding of the biological basis of endoplasmic reticulum stress is also needed in the treatment of liver fibrosis, as well as the development of more effective drugs and interventions to accurately regulate the endoplasmic reticulum signaling network, to achieve the restoration and maintenance of endoplasmic reticulum homeostasis at the cellular and organ levels, and to further promote the reversal of the pathological process of liver fibrosis.
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Affiliation(s)
- Tiantian Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Guoqing Xia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xue Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Mingxu Gong
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Xiongwen Lv
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
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Khan MS, Tak J, Kim YS, Lee SG, Lee EB, Kim SG. Chronic hyperglycemia induces hepatocyte pyroptosis via Gα 12/Gα 13-associated endoplasmic reticulum stress: Effect of pharmacological intervention. Life Sci 2025; 360:123180. [PMID: 39561875 DOI: 10.1016/j.lfs.2024.123180] [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: 05/20/2024] [Revised: 07/17/2024] [Accepted: 10/22/2024] [Indexed: 11/21/2024]
Abstract
AIMS Hyperglycemia induces pathophysiological changes. Endoplasmic reticulum (ER) stress with Gα12 overexpression may promote hepatocyte death. This study investigated whether sustained hyperglycemia triggers ER stress-associated pyroptosis and fibrosis in the liver alongside an overexpression of Gα12, and examined the potential link with VEGF-A levels. MAIN METHODS Mice were subjected to a high-fat diet (60 kcal% fat) with streptozotocin (50 mg/kg body weight, three consecutive times, between 12-13th weeks). AZ2 (a functional Gα12 inhibitor) was treated at 10 mg/kg body weight (5 times/week, 3 weeks). Immunoblotting and immunohistochemistry analyses were performed. KEY FINDINGS Hepatic Gα12/Gα13 were overexpressed in the diabetic mice. The following proteins downstream from the Gα12 axis were upregulated: PGC1α, PPARα, and SIRT1. Sustained hyperglycemia promoted ER stress marker levels. Histopathological and biochemical assays showed large-sized lipid droplet accumulation, hepatocyte degeneration, and damage as blood transaminase activities increased. Moreover, the diabetic condition increased IL-1β, caspase-1, and NLRP3 levels, which were supportive of pyroptosis. Consistently, the intensities of Masson's trichrome, collagen-1A1, α-SMA, vimentin, and fibronectin all increased. VEGF-A and VEGFR2 levels also increased in the liver and/or sera. The levels of hepatic pigment epithelial-derived factor (PEDF), a physiological antagonist of VEGF-A, decreased with its reciprocal increase in serum. These events were reversed by AZ2 treatment, supporting the role of Gα12 in hyperglycemic stress in the liver. SIGNIFICANCE Chronic hyperglycemia causes hepatic pyroptosis and fibrosis related to ER stress with Gα12/Gα13 and VEGF overexpression, which may be overcome by AZ2 treatments.
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Affiliation(s)
- Muhammad Sohaib Khan
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do 10326, Republic of Korea
| | - Jihoon Tak
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do 10326, Republic of Korea
| | - Yun Seok Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sang Gil Lee
- Center of Research and Development, A Pharma Inc, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Eun Byul Lee
- Center of Research and Development, A Pharma Inc, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do 10326, Republic of Korea.
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Esmaeilian Y, Oktem O. Real-Time Visualization of Cholesterol Trafficking in Human Granulosa Cells Using Confocal Live Cell Microscopy as a Tool to Study the Novel Role of Autophagy in Sex Steroid Synthesis. Methods Mol Biol 2025; 2879:139-150. [PMID: 38411890 DOI: 10.1007/7651_2024_521] [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] [Indexed: 02/28/2024]
Abstract
Autophagy is an evolutionarily conserved process that aims to maintain the energy homeostasis of the cell by recycling long-lived proteins and organelles. We have very recently demonstrated that lipophagy, a special form of autophagy, mediates the association of the lipid droplets (LDs) with lysosomes to deliver the lipid cargo within the LDs to lysosomes for degradation in order to release free cholesterol required for steroid synthesis in human ovary and testis. In this chapter, we describe live cell confocal microscopy technique that allows us to monitor real-time cholesterol trafficking and the association of cholesterol-laden LDs with lysosome (lipophagy) in human granulosa cells.
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Affiliation(s)
- Yashar Esmaeilian
- Research Center for Translational Medicine, Koç University, Istanbul, Turkey
| | - Ozgur Oktem
- Research Center for Translational Medicine, Koç University, Istanbul, Turkey.
- The Graduate School of Health Sciences, Koç University, Istanbul, Turkey.
- Department of Obstetrics and Gynecology, School of Medicine, Koç University, Istanbul, Turkey.
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Wei H, Bi Y, Liao C, Huang Y, Lian Y. Plasma microRNA-15a/16-1 serves as a non-invasive indicator of liver fibrosis severity in individuals with chronic hepatitis B. Noncoding RNA Res 2024; 9:1342-1350. [PMID: 39247146 PMCID: PMC11380177 DOI: 10.1016/j.ncrna.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/05/2024] [Accepted: 08/14/2024] [Indexed: 09/10/2024] Open
Abstract
Background The lack of effective non-invasive diagnostic methods for liver fibrosis hinders timely treatment for chronic hepatitis B (CHB) patients, leading to the progression of advanced liver disease. Circulating microRNAs offer a non-invasive approach to fibrosis assessment. MicroRNA-15a/16-1 (miR-15a/16) was reported to be implicated in fibrosis development, but the role of plasma miR-15a/16 in liver fibrosis assessment remains poorly understood. This study explored the importance of plasma miR-15a/16 in assessing liver fibrosis severity of CHB patients. Methods Quantitative PCR was utilized to measure the levels of plasma miR-15a/16 in 435 patients with CHB and 74 healthy controls. We assessed the correlation between plasma miR-15a/16 levels and liver fibrosis and cirrhosis using Pearson correlation coefficients, multivariate linear and logistic regression models, and smooth curve fitting. Utilizing the receiver operating characteristic (ROC) curve, we examined the diagnostic potential of plasma miR-15a/16 in severe fibrosis and cirrhosis. Results Plasma levels of miR-15a/16 in patients with CHB were significantly reduced compared to those in healthy controls. In the CHB cohort, levels were notably decreased in individuals with severe fibrosis or cirrhosis compared to those without severe fibrosis or cirrhosis. Plasma miR-15a/16 levels exhibited a negative relationship with the severity of liver fibrosis, gradually decreasing as the histological fibrosis stage progressed from S0 to S4. Reduced levels of plasma miR-15a/16 were linked to an elevated risk of severe liver fibrosis (miR-15a: odds ratio [OR] = 0.243; 95 % confidence interval [CI]: 0.138, 0.427; miR-16: OR = 0.201; 95 % CI: 0.097, 0.417) and cirrhosis (miR-15a: OR = 0.153; 95 % CI: 0.079, 0.298; miR-16: OR = 0.064; 95 % CI: 0.025, 0.162). MiR-15a achieved an area under the ROC curve of 0.886 and 0.832 for detecting moderate-to-severe fibrosis (S2-S4) and cirrhosis, respectively. MiR-16 demonstrated similar diagnostic values. Conclusion Plasma miR-15a/16 levels were negatively correlated with the severity of liver fibrosis in CHB patients and could serve as a new non-invasive indicator in evaluating liver fibrosis.
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Affiliation(s)
- Huan Wei
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanhua Bi
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Chunhong Liao
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuehua Huang
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yifan Lian
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Lee JH, Seo KH, Yang JH, Cho SS, Kim NY, Kim JH, Kim KM, Ki SH. CCCP induces hepatic stellate cell activation and liver fibrogenesis via mitochondrial and lysosomal dysfunction. Free Radic Biol Med 2024; 225:181-192. [PMID: 39370054 DOI: 10.1016/j.freeradbiomed.2024.10.259] [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: 08/11/2024] [Revised: 09/23/2024] [Accepted: 10/02/2024] [Indexed: 10/08/2024]
Abstract
Hepatic stellate cells (HSCs) are primary cells for development and progression of liver fibrosis. Mitophagy is an essential lysosomal process for mitochondrial homeostasis, which can be activated by carbonyl cyanide m-chlorophenyl hydrazone (CCCP), a representative mitochondrial uncoupler. However, little information is available on the role of CCCP-mediated mitophagy in HSC activation and liver fibrogenesis. In this study, we showed that CCCP treatment in HSCs caused mitochondrial dysfunction proved by decreased mitochondrial membrane potential, mitochondrial DNA, and ATP contents and increased mitochondrial ROS. Moreover, CCCP induced mitophagy and impaired mitophagy flux at the later stage. This blockade of mitophagic flux effect was mediated by suppression of lysosomal activity; CCCP decreased expression of lysosomal markers and cathepsin B activity, and increased lysosomal pH. Intriguingly, CCCP treatment in LX-2 cells or primary HSCs elevated plasminogen activator inhibitor-1 (PAI-1), a typical fibrogenic marker of HSCs which was attenuated by mitochondrial division inhibitor 1, a mitophagy inhibitor. The up-regulation of PAI-1 by CCCP was not due to altered transcriptional activity but lysosomal dysfunction. In vivo acute or sub-chronic treatment of CCCP to mice induced mitophagy and fibrogenesis of liver. Hepatic fibrogenic marker (PAI-1) was incremented with mitophagy markers (parkin and PTEN-induced putative kinase 1) in the livers of CCCP injected mice. Furthermore, we found that 5-aminoimidazole-4-carboxyamide ribonucleoside reversed CCCP-mediated mitophagy and subsequent HSC activation. To conclude, CCCP facilitated HSC activation and hepatic fibrogenesis via mitochondrial dysfunction and lysosomal blockade, implying that attenuation of CCCP-related signaling molecules may contribute to treat liver fibrosis.
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Affiliation(s)
- Ji Hyun Lee
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju, 61452, South Korea
| | - Kyu Hwa Seo
- General for Narcotics Safety Planning, Pharmaceutical Safety Bureau, Ministry of Food and Drug Safety (MFDS), Cheongju, South Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, South Korea
| | - Sam Seok Cho
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju, 61452, South Korea; Non-Clinical Evaluation Center, Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Chonbuk, South Korea
| | - Na Yeon Kim
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju, 61452, South Korea
| | - Ji Hye Kim
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju, 61452, South Korea
| | - Kyu Min Kim
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju, 61452, South Korea; Institute of Well-Aging Medicare & Chosun University LAMP Project Group, Chosun University, Gwangju, 61452, South Korea; Department of Integrative Biological Sciences & BK21 FOUR Educational Research Group for Age-associated Disorder Control Technology, Chosun University, Gwangju, 61452, South Korea.
| | - Sung Hwan Ki
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju, 61452, South Korea.
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Baek JS, Lee JH, Kim JH, Cho SS, Kim YS, Yang JH, Shin EJ, Kang HG, Kim SJ, Ahn SG, Park EY, Baek DJ, Yim SK, Kang KW, Ki SH, Kim KM. An inducible sphingosine kinase 1 in hepatic stellate cells potentiates liver fibrosis. Biochem Pharmacol 2024; 229:116520. [PMID: 39236934 DOI: 10.1016/j.bcp.2024.116520] [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: 12/06/2023] [Revised: 08/19/2024] [Accepted: 09/02/2024] [Indexed: 09/07/2024]
Abstract
Hepatic stellate cells (HSCs) play a role in hepatic fibrosis and sphingosine kinase (SphK) is involved in biological processes. As studies on the regulatory mechanisms and functions of SphK in HSCs during liver fibrosis are currently limited, this study aimed to elucidate the regulatory mechanism and connected pathways of SphK upon HSC activation. The expression of SphK1 was higher in HSCs than in hepatocytes, and upregulated in activated primary HSCs. SphK1 was also increased in liver homogenates of carbon tetrachloride-treated or bile duct ligated mice and in transforming growth factor-β (TGF-β)-treated LX-2 cells. TGF-β-mediated SphK1 induction was due to Smad3 signaling in LX-2 cells. SphK1 modulation altered the expression of liver fibrogenesis-related genes. This SphK1-mediated profibrogenic effect was dependent on SphK1/sphingosine-1-phosphate/sphingosine-1-phosphate receptor signaling through ERK. Epigallocatechin gallate blocked TGF-β-induced SphK1 expression and hepatic fibrogenesis by attenuating Smad and MAPK activation. SphK1 induced by TGF-β facilitates HSC activation and liver fibrogenesis, which is reversed by epigallocatechin gallate. Accordingly, SphK1 and related signal transduction may be utilized to treat liver fibrosis.
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Affiliation(s)
- Jin Sol Baek
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea
| | - Ji Hyun Lee
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea
| | - Ji Hye Kim
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea
| | - Sam Seok Cho
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea; Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju 61452, Republic of Korea
| | - Yun Seok Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Pharmacy, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do 58245, Republic of Korea
| | - Eun Jin Shin
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Department of Integrative Biological Sciences & BK21 FOUR Educational Research Group for Age-associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea; Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju 61452, Republic of Korea
| | - Hyeon-Gu Kang
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Department of Integrative Biological Sciences & BK21 FOUR Educational Research Group for Age-associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea
| | - Seok-Jun Kim
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Department of Integrative Biological Sciences & BK21 FOUR Educational Research Group for Age-associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea; Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju 61452, Republic of Korea
| | - Sang-Gun Ahn
- Department of Pathology, School of Dentistry, Chosun University, Gwangju 61452, Republic of Korea
| | - Eun Young Park
- College of Pharmacy, Mokpo National University, Muan-gun, Jeollanam-do 58554, Republic of Korea
| | - Dong Jae Baek
- College of Pharmacy, Mokpo National University, Muan-gun, Jeollanam-do 58554, Republic of Korea
| | - Sung-Kun Yim
- Marine Biotechnology Research Center, Jeonnam Bioindustry Foundation, 21-7, Nonggongdanji 4Gil, Wando-eup, Wando-gun, Jeollanam-do 59108, Republic of Korea
| | - Keon Wook Kang
- Department of Pharmacy, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Sung Hwan Ki
- MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju 61452, South Korea
| | - Kyu Min Kim
- Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju 61452, Republic of Korea; Department of Integrative Biological Sciences & BK21 FOUR Educational Research Group for Age-associated Disorder Control Technology, Chosun University, Gwangju 61452, Republic of Korea; Institute of Well-Aging Medicare & Chosun University G-LAMP Project Group, Chosun University, Gwangju 61452, Republic of Korea.
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Zhang X, Yang Z, Fu C, Yao R, Li H, Peng F, Li N. Emerging roles of liquid-liquid phase separation in liver innate immunity. Cell Commun Signal 2024; 22:430. [PMID: 39227829 PMCID: PMC11373118 DOI: 10.1186/s12964-024-01787-4] [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: 05/23/2024] [Accepted: 08/11/2024] [Indexed: 09/05/2024] Open
Abstract
Biomolecular condensates formed by liquid-liquid phase separation (LLPS) have become an extensive mechanism of macromolecular metabolism and biochemical reactions in cells. Large molecules like proteins and nucleic acids will spontaneously aggregate and assemble into droplet-like structures driven by LLPS when the physical and chemical properties of cells are altered. LLPS provides a mature molecular platform for innate immune response, which tightly regulates key signaling in liver immune response spatially and physically, including DNA and RNA sensing pathways, inflammasome activation, and autophagy. Take this, LLPS plays a promoting or protecting role in a range of liver diseases, such as viral hepatitis, non-alcoholic fatty liver disease, liver fibrosis, hepatic ischemia-reperfusion injury, autoimmune liver disease, and liver cancer. This review systematically describes the whole landscape of LLPS in liver innate immunity. It will help us to guide a better-personalized approach to LLPS-targeted immunotherapy for liver diseases.
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Affiliation(s)
- Xinying Zhang
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
- NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
- Clinical Laboratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 87 Xiangya Road, Hunan Province, China
| | - Ziyue Yang
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
- NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
| | - Chunmeng Fu
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
- NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
| | - Run Yao
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
- Clinical Laboratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
| | - Huan Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
- Clinical Laboratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China
| | - Fang Peng
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China.
- NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China.
| | - Ning Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China.
- Clinical Laboratory, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China.
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Gao R, Mao J. Noncoding RNA-Mediated Epigenetic Regulation in Hepatic Stellate Cells of Liver Fibrosis. Noncoding RNA 2024; 10:44. [PMID: 39195573 DOI: 10.3390/ncrna10040044] [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: 05/22/2024] [Revised: 07/09/2024] [Accepted: 08/01/2024] [Indexed: 08/29/2024] Open
Abstract
Liver fibrosis is a significant contributor to liver-related disease mortality on a global scale. Despite this, there remains a dearth of effective therapeutic interventions capable of reversing this condition. Consequently, it is imperative that we gain a comprehensive understanding of the underlying mechanisms driving liver fibrosis. In this regard, the activation of hepatic stellate cells (HSCs) is recognized as a pivotal factor in the development and progression of liver fibrosis. The role of noncoding RNAs (ncRNAs) in epigenetic regulation of HSCs transdifferentiation into myofibroblasts has been established, providing new insights into gene expression changes during HSCs activation. NcRNAs play a crucial role in mediating the epigenetics of HSCs, serving as novel regulators in the pathogenesis of liver fibrosis. As research on epigenetics expands, the connection between ncRNAs involved in HSCs activation and epigenetic mechanisms becomes more evident. These changes in gene regulation have attracted considerable attention from researchers in the field. Furthermore, epigenetics has contributed valuable insights to drug discovery and the identification of therapeutic targets for individuals suffering from liver fibrosis and cirrhosis. As such, this review offers a thorough discussion on the role of ncRNAs in the HSCs activation of liver fibrosis.
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Affiliation(s)
- Ruoyu Gao
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
| | - Jingwei Mao
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China
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McDuffie EL, Panettieri RA, Scott CP. G 12/13 signaling in asthma. Respir Res 2024; 25:295. [PMID: 39095798 PMCID: PMC11297630 DOI: 10.1186/s12931-024-02920-0] [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: 06/14/2024] [Accepted: 07/19/2024] [Indexed: 08/04/2024] Open
Abstract
Shortening of airway smooth muscle and bronchoconstriction are pathognomonic for asthma. Airway shortening occurs through calcium-dependent activation of myosin light chain kinase, and RhoA-dependent calcium sensitization, which inhibits myosin light chain phosphatase. The mechanism through which pro-contractile stimuli activate calcium sensitization is poorly understood. Our review of the literature suggests that pro-contractile G protein coupled receptors likely signal through G12/13 to activate RhoA and mediate calcium sensitization. This hypothesis is consistent with the effects of pro-contractile agonists on RhoA and Rho kinase activation, actin polymerization and myosin light chain phosphorylation. Recognizing the likely role of G12/13 signaling in the pathophysiology of asthma rationalizes the effects of pro-contractile stimuli on airway hyperresponsiveness, immune activation and airway remodeling, and suggests new approaches for asthma treatment.
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Affiliation(s)
- Elizabeth L McDuffie
- Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Reynold A Panettieri
- Rutgers Institute for Translational Medicine and Science, Child Health Institute, Rutgers University, New Brunswick, NJ, USA
| | - Charles P Scott
- Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
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Zhang T, Zhang J, Yang G, Hu J, Wang H, Jiang R, Yao G. Long non-coding RNA PWRN1 affects ovarian follicular development by regulating the function of granulosa cells. Reprod Biomed Online 2024; 48:103697. [PMID: 38430661 DOI: 10.1016/j.rbmo.2023.103697] [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: 05/31/2023] [Revised: 10/25/2023] [Accepted: 10/29/2023] [Indexed: 03/05/2024]
Abstract
RESEARCH QUESTION What is the role of Prader-Willi region non-protein coding RNA 1 (PWRN1) in ovarian follicular development and its molecular mechanism? DESIGN The expression and localization of PWRN1 were detected in granulosa cells from patients with different ovarian functions, and the effect of interfering with PWRN1 expression on cell function was detected by culturing granulosa cells in vitro. Furthermore, the effects of interfering with PWRN1 expression on ovarian function of female mice were explored through in-vitro and in-vivo experiments. RESULTS The expression of PWRN1 was significantly lower in granulosa cells derived from patients with diminished ovarian reserve (DOR) compared with patients with normal ovarian function. By in-vitro culturing of primary granulosa cells or the KGN cell line, the results showed that the downregulation of PWRN1 promoted granulosa cell apoptosis, caused cell cycle arrested in S-phase, generated high levels of autophagy and led to significant decrease in steroidogenic capacity, including inhibition of oestradiol and progesterone production. In addition, SIRT1 overexpression could partially reverse the inhibitory effect of PWRN1 downregulation on cell proliferation. The results of in-vitro culturing of newborn mouse ovary showed that the downregulation of PWRN1 could slow down the early follicular development. Further, by injecting AAV-sh-PWRN1 in mouse ovarian bursa, the oestrous cycle of mouse was affected, and the number of oocytes retrieved after ovulation induction and embryos implanted after mating was significantly reduced. CONCLUSION This study systematically elucidated the novel mechanism by which lncRNA PWRN1 participates in the regulation of granulosa cell function and follicular development.
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Affiliation(s)
- Tongwei Zhang
- Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Junya Zhang
- Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guang Yang
- Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingyi Hu
- Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huihui Wang
- Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ran Jiang
- Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guidong Yao
- Center for Reproductive Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Henan Key Laboratory of Reproduction and Genetics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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11
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He T, Zou J, Sun K, Yang J. Global research status and frontiers on autophagy in hepatocellular carcinoma: a comprehensive bibliometric and visualized analysis. Int J Surg 2024; 110:2788-2802. [PMID: 38376850 PMCID: PMC11093451 DOI: 10.1097/js9.0000000000001202] [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: 11/08/2023] [Accepted: 02/04/2024] [Indexed: 02/21/2024]
Abstract
BACKGROUND An extensive body of research has explored the role of autophagy in hepatocellular carcinoma (HCC), revealing its critical involvement in the disease's pathogenesis, progression, and therapeutic targeting. However, there is a discernible deficit in quantitative, analytical studies concerning autophagy in the context of HCC. Accordingly, this investigation endeavored to meticulously assess the evolution of autophagy research, employing bibliometric citation analysis to offer a comprehensive evaluation of the findings in this field. METHODS The authors conducted a literature search on 2 August 2023, to extract relevant publications spanning from 2013 to 2022, indexed in the Science Citation Index-Expanded (SCIE) of the Web of Science Core Collection (WOSCC). Subsequently, the authors performed a bibliometric assessment of the compiled documents using visualization tools such as CiteSpace and VOSviewer. RESULTS The search yielded 734 publications penned by 4699 authors, encompassing contributions from 41 countries and 909 institutions, disseminated across 272 journals, and comprising 26 295 co-cited references from 2667 journals. Notably, China led in publication volume with 264 articles (amounting to 35.9%) and exhibited the most robust collaboration with the United States. The mechanisms underlying autophagy's influence on the emergence and advancement of HCC, as well as the implicated proteins and genes, have garnered significant attention. In recent years, investigations of targeting autophagy and the resistance to sorafenib have surfaced as pivotal themes and emerging frontiers in this domain. CONCLUSIONS This study rigorously collated and distilled the prevailing research narratives and novel insights on autophagy in HCC. The resultant synthesis provides a substantive foundation for medical professionals and researchers, as well as pivotal implications for future investigative endeavors in this arena.
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Affiliation(s)
- Tao He
- Department of Hepatobiliary Surgery
| | - Jieyu Zou
- Department of Oncology, Chengdu Second People’s Hospital, Chengdu, Sichuan, People’s Republic of China
| | - Ke Sun
- Department of Hepatobiliary Surgery
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12
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Tak J, An Q, Lee SG, Lee CH, Kim SG. Gα12 and endoplasmic reticulum stress-mediated pyroptosis in a single cycle of dextran sulfate-induced mouse colitis. Sci Rep 2024; 14:6335. [PMID: 38491049 PMCID: PMC10943197 DOI: 10.1038/s41598-024-56685-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: 12/10/2023] [Accepted: 03/09/2024] [Indexed: 03/18/2024] Open
Abstract
Inflammatory bowel disease (IBD) pathogenesis involves complex inflammatory events and cell death. Although IBD involves mainly necrosis in the digestive tract, pyroptosis has also been recognized. Nonetheless, the underlying basis is elusive. Gα12/13 overexpression may affect endoplasmic reticulum (ER) stress. This study examined how Gα12/13 and ER stress affect pyroptosis using dextran sulfate sodium (DSS)-induced colitis models. Gα12/13 levels were increased in the distal and proximal colons of mice exposed to a single cycle of DSS, as accompanied by increases of IRE1α, ATF6, and p-PERK. Moreover, Il-6, Il-1β, Ym1, and Arg1 mRNA levels were increased with caspase-1 and IL-1β activation, supportive of pyroptosis. In the distal colon, RIPK1/3 levels were enhanced to a greater degree, confirming necroptosis. By contrast, the mice subjected to three cycles of DSS treatments showed decreases of Gα12/13, as accompanied by IRE1α and ATF6 suppression, but increases of RIPK1/3 and c-Cas3. AZ2 treatment, which inhibited Gα12, has an anti-pyroptotic effect against a single cycle of colitis. These results show that a single cycle of DSS-induced colitis may cause ER stress-induced pyroptosis as mediated by Gα12 overexpression in addition to necroptosis, but three cycles model induces only necroptosis, and that AZ2 may have an anti-pyroptotic effect.
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Affiliation(s)
- Jihoon Tak
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Quanxi An
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Sang Gil Lee
- Research and Development Institute, A Pharma Inc, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Gyeonggi-do, 10326, Republic of Korea.
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13
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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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14
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Nishiyama K. The role of P2Y 6 receptor in the pathogenesis of cardiovascular and inflammatory diseases. J Pharmacol Sci 2024; 154:108-112. [PMID: 38246724 DOI: 10.1016/j.jphs.2024.01.003] [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: 11/13/2023] [Revised: 12/20/2023] [Accepted: 01/05/2024] [Indexed: 01/23/2024] Open
Abstract
The purinergic receptor P2Y6 receptor (P2Y6R) is a member of the G protein-coupled receptors (GPCR) family. P2Y6R is widely expressed in various cell types and plays a critical role in physiological processes, where it is activated by extracellular uridine diphosphate (UDP) and mobilizes Ca2+ via the Gαq/11 protein pathway. We have recently discovered the pathophysiological role of P2Y6R in cardiovascular and inflammatory diseases, including inflammatory bowel disease and non-alcoholic fatty liver disease. Furthermore, we uncovered the redox-dependent internalization of P2Y6R. In this review, we provide a comprehensive overview of the pathophysiological activity of P2Y6R in cardiovascular and inflammatory diseases. Additionally, we discuss the concept of atypical internalization control of GPCRs, which may be applied in the prevention and treatment of intestinal inflammation and cardiovascular remodeling.
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Affiliation(s)
- Kazuhiro Nishiyama
- Laboratory of Prophylactic Pharmacology, Osaka Metropolitan University Graduate School of Veterinary Science, 1-58 Rinku-ohraikita, Izumisano, Osaka, 598-8531, Japan.
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15
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Xu F, Lu S, Pan N, Zhao F, Jia X, Wang S, Zhang Y, Zhou Y. Bromodomain protein 4 is a key molecular driver of TGFβ1-induced hepatic stellate cell activation. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119569. [PMID: 37597774 DOI: 10.1016/j.bbamcr.2023.119569] [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: 05/20/2023] [Revised: 08/03/2023] [Accepted: 08/13/2023] [Indexed: 08/21/2023]
Abstract
Liver fibrosis is characterized by the excessive deposition of extracellular matrix in liver. Chronic liver injury induces the activation of hepatic stellate cell (HSCs), a key step in liver fibrogenesis. The activated HSC is the primary source of ECM and contributes significantly to liver fibrosis. TGFβ1 is the most potent pro-fibrotic cytokine. Bromodomain protein 4 (BrD4), an epigenetic reader of histone acetylation marks, was crucial for profibrotic gene expression in HSCs. The present study aimed to investigate the roles of BRD4 in TGFβ1-dependent HSC activation and liver fibrosis, focusing on TGFβ1-induced alterations of the levels of the fibrotic-related important proteins in HSCs by employing the heterozygous TGFβ1 knockout mice and BrD4 knockdown in vivo and in vitro. Results revealed that BrD4 protein level was significantly upregulated by TGFβ1 and BrD4 knockdown reduced TGFβ1-induced HSC activation and liver fibrosis. BrD4 was required for the influences of TGFβ1 on PDGFβ receptor and on the pathways of Smad3, Stat3, and Akt. BrD4 also mediated TGFβ1-induced increases in histone acetyltransferase p300, the pivotal pro-inflammatory NFkB p65, and tissue inhibitor of metalloproteinase 1 whereas BrD4 reduced Caspase-3 protein levels in HSCs during liver injury, independent of TGFβ1. Further experiments indicated the interaction between TGFβ1-induced BrD4 and NFkB p65 in HSCs and in liver of TAA-induced liver injury. Human cirrhotic livers were demonstrated a parallel increase in the protein levels of BrD4 and NFkB p65 in HSCs. This study revealed that BrD4 was a key molecular driver of TGFβ1-induced HSC activation and liver fibrosis.
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Affiliation(s)
- Feifan Xu
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China
| | - Sidan Lu
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China
| | - Nachuan Pan
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, 1151 Richmond Street, London, Ontario N6A 3K7, Canada
| | - Feifei Zhao
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China
| | - Xin Jia
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China
| | - Shouwei Wang
- Department of Clinical Laboratory, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), 500 Yonghe Road, Nantong 226011, Jiangsu, China
| | - Yali Zhang
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China.
| | - Yajun Zhou
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China.
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16
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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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17
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Tak J, Kim SG. Effects of toxicants on endoplasmic reticulum stress and hepatic cell fate determination. Toxicol Res 2023; 39:533-547. [PMID: 37779594 PMCID: PMC10541383 DOI: 10.1007/s43188-023-00201-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/27/2023] [Accepted: 06/29/2023] [Indexed: 10/03/2023] Open
Abstract
Toxicant-induced injury is a significant global health issue. However, the mechanisms through which toxicants such as carbon tetrachloride, acetaminophen, dimethylformamide, cocaine, and morphine induce the death of multiple cell types and contribute to liver toxicity are highly complex. This phenomenon involves intricate signaling pathways in association with oxidative stress, inflammation, and activation of death receptors, which are closely linked to endoplasmic reticulum (ER) stress. ER stress initially triggers the unfolded protein response, which either promotes cell survival or causes cell death at later times, depending on the severity and duration of the stress. Thus, comprehending the molecular basis governing cell fate determination in the context of ER stress may provide key insights into the prevention and treatment of toxicant-induced injury. This review summarizes our current understanding of agents that trigger different forms of ER stress-mediated cell death, necroptosis, ferroptosis, pyroptosis, and apoptosis, and covers the underlying molecular basis of toxicant-induced ER stress, as well as potential target molecules.
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Affiliation(s)
- Jihoon Tak
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Kyeonggi-do 10326 Republic of Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang-si, Kyeonggi-do 10326 Republic of Korea
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18
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Jia X, Xu F, Lu S, Jie H, Guan W, Zhou Y. An unusual signal transducer GIV/Girdin engages in the roles of adipocyte-derived hormone leptin in liver fibrosis. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166797. [PMID: 37478565 DOI: 10.1016/j.bbadis.2023.166797] [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: 01/05/2023] [Revised: 06/06/2023] [Accepted: 06/22/2023] [Indexed: 07/23/2023]
Abstract
Obese patients usually have hyperleptinemia and are prone to develop liver fibrosis. Leptin is intimately linked to liver fibrogenesis, a multi-receptor-driven disease. Gα-Interacting Vesicle-associated protein (GIV) functions as a multimodular signal transducer and a guanine nucleotide exchange factor for Gi controling key signalings downstream of diverse receptors. This study aimed to examine the roles of GIV in leptin-caused liver fibrosis and employed the culture-activated hepatic stellate cells (HSCs) and leptin-deficient mice, respectively. Results indicated that leptin upregulated GIV expression in HSCs. GIV was involved in leptin-induced HSC activation and liver fibrosis. GIV mediated leptin regulation of TIMP1, MMP9, PDGFβ receptor and TGFβ receptor and was required for leptin stimulating the pathways of Erk1/2, Akt1, and Smad3. GIV was also a mediator for leptin-regulation of Cyclin D1 and Caspase-3 activity but GIV reduced Caspase-3 level independently of leptin in vivo. Erk1/2 signaling, Egr1 and c-Jun were associated with the effect of leptin on GIV expression in HSCs. Leptin-induced Erk1/2 signaling increased Egr1 and p-c-Jun levels and promoted their binding to GIV promoter at the sites between -190 bp and -180 bp and between -382 bp and - 376 bp, respectively. Egr1 knockdown lessened leptin-upregulation of GIV in vitro and in vivo. In human cirrhotic livers, the increase in GIV protein level parallelled with the elevated p-Erk1/2 and Egr1 levels in HSCs. In summary, the unusual signal transducer GIV was identified as an important mediator in leptin-induced liver fibrosis. GIV may have significant implications in liver fibrosis progression of obese patients with hyperleptinaemia.
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Affiliation(s)
- Xin Jia
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China
| | - Feifan Xu
- Department of Clinical Laboratory, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), 500 Yonghe Road, Nantong 226011, Jiangsu, China
| | - Sidan Lu
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China
| | - Huang Jie
- Department of Pharmacology, School of Pharmacy, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China
| | - Wei Guan
- Department of Pharmacology, School of Pharmacy, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China.
| | - Yajun Zhou
- Department of Biochemistry & Molecular Biology, Medical School, Nantong University, Qi xiou Road 19, Nantong 226001, Jiangsu, China.
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Wen D, Wang J. Research progress in effects of microRNA -15a and microRNA -16 on fibrotic diseases. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2023; 48:743-749. [PMID: 37539577 PMCID: PMC10930399 DOI: 10.11817/j.issn.1672-7347.2023.220129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Indexed: 08/05/2023]
Abstract
MicroRNA (miR) is a class of highly conserved non-coding single-stranded RNA widely existing in mammals, which can negatively regulate the expression of targeting genes after transcription. As a key regulator, miR negatively regulates the expression of the targeting genes and disrupts important molecular signaling pathways, leading to the imbalance of multiple pathways such as tissue repair and inflammation involved in the fibrotic process. Among them, miR-15a/16 can participate in regulating and controlling the fibrotic process of various organs, including liver, lung, heart, kidney and other fibrotic diseases by acting on cell proliferation and transformation, extracellular matrix proteins production and degradation, inflammation and other important cell functions. It has potential diagnostic and therapeutic value. Clarifying the biological function of miR-15a/16 and its mechanism for action and therapeutic application prospects in various fibrotic lesions are of great significance for the molecular targeted treatment of fibrotic diseases.
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Affiliation(s)
- Dada Wen
- Department of Immunology, School of Basic Medical Science, Central South University, Changsha 410078, China.
| | - Jie Wang
- Department of Immunology, School of Basic Medical Science, Central South University, Changsha 410078, China.
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Liu X, Tan S, Liu H, Jiang J, Wang X, Li L, Wu B. Hepatocyte-derived MASP1-enriched small extracellular vesicles activate HSCs to promote liver fibrosis. Hepatology 2023; 77:1181-1197. [PMID: 35849032 DOI: 10.1002/hep.32662] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 07/04/2022] [Accepted: 07/06/2023] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND AIMS Liver fibrosis is a chronic disease characterized by different etiological agents; dysregulated interactions between hepatocytes and HSCs contribute to this disease. β-arrestin 1 (ARRB1) plays an important role in liver fibrosis; however, the effect of ARRB1 on the crosstalk between hepatocytes and HSCs in liver fibrosis is unknown. The aim of this study is to investigate how ARRB1 modulates hepatocyte and HSC activation during liver fibrosis. APPROACH AND RESULTS Normal and fibrotic human liver and serum samples were obtained. CCl 4 -induced liver fibrosis and methionine-choline deficiency-induced NASH models were constructed. Primary hepatocytes and HSCs were isolated, and human hepatic LO2 and stellate LX2 cells were used. Small extracellular vesicles (EVs) were purified, and key proteins were identified. ARRB1 was up-regulated in hepatocytes and associated with autophagic blockage in liver fibrosis. ARRB1 increased the release of hepatocyte-derived small EVs by inhibiting multivesicular body lysosomal degradation and activating Rab27A, thereby activating HSCs. Proteomic analyses showed that mannan-binding lectin serine protease 1 (MASP1) was enriched in hepatocyte-derived small EVs and activated HSCs via p38 mitogen-activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling. ARRB1 up-regulated MASP1 expression in hepatocytes. MASP1 promoted liver fibrosis in mice. Clinically, MASP1 expression was increased in the serum and liver tissue of patients with liver fibrosis. CONCLUSIONS ARRB1 up-regulates the release of hepatocyte-derived MASP1-enriched small EVs by regulating the autophagic-lysosomal/multivesicular body pathway and Rab27A. Hepatocyte-derived MASP1 activates HSCs to promote liver fibrogenesis through p38 MAPK/ATF2 signaling. Thus, MASP1 is a pivotal therapeutic target in liver fibrosis.
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Affiliation(s)
- Xianzhi Liu
- Department of Gastroenterology , the Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , Guangdong Province , China
- Guangdong Provincial Key Laboratory of Liver Disease Research , Guangzhou , China
| | - Siwei Tan
- Department of Gastroenterology , the Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , Guangdong Province , China
- Guangdong Provincial Key Laboratory of Liver Disease Research , Guangzhou , China
| | - Huiling Liu
- Department of Gastroenterology , the Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , Guangdong Province , China
- Guangdong Provincial Key Laboratory of Liver Disease Research , Guangzhou , China
| | - Jie Jiang
- Department of Gastroenterology , the Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , Guangdong Province , China
- Guangdong Provincial Key Laboratory of Liver Disease Research , Guangzhou , China
| | - Xing Wang
- Department of Gastroenterology , the Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , Guangdong Province , China
- Guangdong Provincial Key Laboratory of Liver Disease Research , Guangzhou , China
| | - Leijia Li
- Department of Gastroenterology , the Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , Guangdong Province , China
- Guangdong Provincial Key Laboratory of Liver Disease Research , Guangzhou , China
| | - Bin Wu
- Department of Gastroenterology , the Third Affiliated Hospital of Sun Yat-Sen University , Guangzhou , Guangdong Province , China
- Guangdong Provincial Key Laboratory of Liver Disease Research , Guangzhou , China
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21
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Nishiyama K, Ariyoshi K, Nishimura A, Kato Y, Mi X, Kurose H, Kim SG, Nishida M. Knockout of Purinergic P2Y 6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis. Int J Mol Sci 2023; 24:ijms24043800. [PMID: 36835211 PMCID: PMC9963899 DOI: 10.3390/ijms24043800] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/10/2023] [Accepted: 02/13/2023] [Indexed: 02/16/2023] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a disease that progresses from nonalcoholic fatty liver (NAFL) and which is characterized by inflammation and fibrosis. The purinergic P2Y6 receptor (P2Y6R) is a pro-inflammatory Gq/G12 family protein-coupled receptor and reportedly contributes to intestinal inflammation and cardiovascular fibrosis, but its role in liver pathogenesis is unknown. Human genomics data analysis revealed that the liver P2Y6R mRNA expression level is increased during the progression from NAFL to NASH, which positively correlates with inductions of C-C motif chemokine 2 (CCL2) and collagen type I α1 chain (Col1a1) mRNAs. Therefore, we examined the impact of P2Y6R functional deficiency in mice crossed with a NASH model using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Feeding CDAHFD for 6 weeks markedly increased P2Y6R expression level in mouse liver, which was positively correlated with CCL2 mRNA induction. Unexpectedly, the CDAHFD treatment for 6 weeks increased liver weights with severe steatosis in both wild-type (WT) and P2Y6R knockout (KO) mice, while the disease marker levels such as serum AST and liver CCL2 mRNA in CDAHFD-treated P2Y6R KO mice were rather aggravated compared with those of CDAHFD-treated WT mice. Thus, P2Y6R may not contribute to the progression of liver injury, despite increased expression in NASH liver.
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Affiliation(s)
- Kazuhiro Nishiyama
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Kohei Ariyoshi
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Akiyuki Nishimura
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan
- Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan
| | - Yuri Kato
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Xinya Mi
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Hitoshi Kurose
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Sang Geon Kim
- College of Pharmacy, Dongguk University-Seoul, Goyang-si 10326, Gyeonggi-Do, Republic of Korea
| | - Motohiro Nishida
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan
- Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan
- Correspondence: ; Tel./Fax: +81-92-642-6556
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22
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Lv H, Zhou D, Liu G. PVT1/miR-16/CCND1 axis regulates gastric cancer progression. Open Med (Wars) 2023; 18:20220550. [PMID: 36760720 PMCID: PMC9896163 DOI: 10.1515/med-2022-0550] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 08/03/2022] [Accepted: 08/10/2022] [Indexed: 02/03/2023] Open
Abstract
Long non-coding RNA plasmacytoma variant translocation 1 (PVT1) has been reported to be a vital modulator in tumorigenesis of gastric cancer (GC). However, the detailed regulatory mechanism of PVT1 in GC remains largely unclear. In this work, the expressions of PVT1 and microRNA-16 (miR-16) were detected by quantitative real-time PCR (qRT-PCR) in GC tissues and cell lines. GC cell lines NCI-N87 and MKN45 cell lines were chosen for the following assays. After PVT1 was overexpressed or depleted, CCK-8 and Transwell assays were performed to examine the cell viability and invasive capacity. Cell cycle was analyzed by flow cytometry. The expression of cyclin D1 (CCND1) at mRNA and protein levels was measured by qRT-PCR and western blot. The competitive endogenous RNA molecular mechanism among PVT1, miR-16 and CCND1 was verified by bioinformatics analysis, luciferase-reporter gene assay and RNA immunoprecipitation assay. In the present study, it was revealed that PVT1 expression was remarkably evaluated in GC tissues and cell lines than that in the corresponding control group. PVT1 positively regulated the proliferation, migration and cell cycle progression of GC cells. Besides, miR-16 was identified as a target of PVT1, and CCND1 was identified as a target of miR-16. The depletion of PVT1 promoted the expression of miR-16 and suppressed CCND1 expression. Moreover, either miR-16 inhibitor or CCND1 overexpression plasmid could reverse the promoting effects of PVT1 on the malignant biological behaviors of GC cells. In conclusion, PVT1 promoted CCND1 expression by negatively regulating miR-16 expression to enhance the viability, invasion and cell cycle progression of GC cells.
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Affiliation(s)
- Haidong Lv
- Department of Tumor Surgery, Qinghai People’s Hospital, Xining810007, Qinghai, China
| | - Dixia Zhou
- Department of Tumor Surgery, Qinghai People’s Hospital, Xining810007, Qinghai, China
| | - Guoqing Liu
- Department of Tumor Surgery, Qinghai People’s Hospital, Republic Road No. 2, Xining810007, Qinghai, China
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23
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Wen D, Zhang H, Zhou Y, Wang J. The Molecular Mechanisms and Function of miR-15a/16 Dysregulation in Fibrotic Diseases. Int J Mol Sci 2022; 23:ijms232416041. [PMID: 36555676 PMCID: PMC9784154 DOI: 10.3390/ijms232416041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/13/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of short, endogenous, non-coding, single-stranded RNAs that can negatively regulate the post-transcriptional expression of target genes. Among them, miR-15a/16 is involved in the regulation of the occurrence and development of fibrosis in the liver, lungs, heart, kidneys, and other organs, as well as systemic fibrotic diseases, affecting important cellular functions, such as cell transformation, the synthesis and degradation of extracellular matrix, and the release of fibrotic mediators. Therefore, this article reviews the biological characteristics of miR-15a/16 and the molecular mechanisms and functions of their dysregulation in fibrotic diseases.
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24
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Non-alcoholic fatty liver disease and liver secretome. Arch Pharm Res 2022; 45:938-963. [PMCID: PMC9703441 DOI: 10.1007/s12272-022-01419-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 11/15/2022] [Indexed: 11/29/2022]
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25
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Cho SS, Yang JH, Lee JH, Baek JS, Ku SK, Cho IJ, Kim KM, Ki SH. Ferroptosis contribute to hepatic stellate cell activation and liver fibrogenesis. Free Radic Biol Med 2022; 193:620-637. [PMID: 36370962 DOI: 10.1016/j.freeradbiomed.2022.11.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/04/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022]
Abstract
Ferroptosis is a widely known regulator of cell death in connection with the redox state as a consequence of the depletion of glutathione or accumulation of lipid peroxidation. Hepatic stellate cells (HSCs) play a pivotal role in the progression of hepatic fibrosis by increasing the production and secretion of the extracellular matrix. However, the role of ferroptosis in HSC activation and liver fibrogenesis has not been clearly elucidated. The ferroptosis inducer RAS-selective lethal 3 (RSL3) or erastin treatment in HSCs caused cell death. This effect was suppressed only after exposure to ferroptosis inhibitors. We observed induction of ferroptosis by RSL3 treatment in HSCs supported by decreased glutathione peroxidase 4, glutathione deficiency, reactive oxygen species generation, or lipid peroxidation. Interestingly, RSL3 treatment upregulated the expression of plasminogen activator inhibitor-1, a representative fibrogenic marker of HSCs. In addition, treatment with ferroptosis-inducing compounds increased c-JUN phosphorylation and activator protein 1 luciferase activity but did not alter Smad phosphorylation and Smad-binding element luciferase activity. Chronic administration of iron dextran to mice causes ferroptosis of liver in vivo. The expression of fibrosis markers, such as alpha-smooth muscle actin and plasminogen activator inhibitor-1, was increased in the livers of mice with iron accumulation. Hepatic injury accompanying liver fibrosis was observed based on the levels of alanine aminotransferase, aspartate aminotransferase, and hematoxylin and eosin staining. Furthermore, we found that both isolated primary hepatocyte and HSCs undergo ferroptosis. Consistently, cirrhotic liver tissue of patients indicated glutathione peroxidase 4 downregulation in fibrotic region. In conclusion, our results suggest that ferroptosis contribute to HSC activation and the progression of hepatic fibrosis.
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Affiliation(s)
- Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, Republic of Korea
| | - Ji Hyun Lee
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Jin Sol Baek
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Sae Kwang Ku
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Il Je Cho
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea; Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju, 61452, Republic of Korea.
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
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26
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Zhang WS, Zhang R, Ge Y, Wang D, Hu Y, Qin X, Kan J, Liu Y. S100a16 deficiency prevents hepatic stellate cells activation and liver fibrosis via inhibiting CXCR4 expression. Metabolism 2022; 135:155271. [PMID: 35914619 DOI: 10.1016/j.metabol.2022.155271] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/04/2022] [Accepted: 07/26/2022] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Liver fibrosis caused by hepatic stellate cells (HSCs) activation is implicated in the pathogenesis of liver diseases. To date, there has been no effective intervention means for this process. S100 proteins are calcium-binding proteins that regulate cell growth and differentiation. This study aimed to investigate whether S100A16 induces HSCs activation and participates in liver fibrosis progression. METHODS HSCs were isolated, and the relationship between S100A16 expression and HSCs activation was studied. S100a16 knockdown and transgenic mice were generated and subjected to HSCs activation and liver fibrosis stimulated by different models. Clinical samples were collected for further confirmation. Alterations in gene expression in HSCs were investigated, using transcriptome sequencing to determine the underlying mechanisms. RESULTS We observed increased S100A16 levels during HSCs activation. Genetic silencing of S100a16 prevented HSCs activation in vitro. Furthermore, S100a16 silencing exhibited obvious protective effects against HSCs activation and fibrosis progression in mice. In contrast, S100a16 transgenic mice exhibited spontaneous liver fibrosis. S100A16 was also upregulated in the HSCs of patients with fibrotic liver diseases. RNA sequencing revealed that C-X-C motif chemokine receptor 4 (Cxcr4) gene was a crucial regulator of S100A16 induction during HSCs activation. Mechanistically, S100A16 bound to P53 to induce its degradation; this augmented CXCR4 expression to activate ERK 1/2 and AKT signaling, which then promoted HSCs activation and liver fibrosis. CONCLUSIONS These data indicate that S100a16 deficiency prevents liver fibrosis by inhibiting Cxcr4 expression. Targeting S100A16 may provide insight into the pathogenesis of liver fibrosis and pave way for the design of novel clinical therapeutic strategies.
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Affiliation(s)
- Wen-Song Zhang
- Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Rihua Zhang
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yaoqi Ge
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Dan Wang
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yifang Hu
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xiaoxuan Qin
- Department of neurology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Jingbao Kan
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yun Liu
- Department of Pharmacy, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
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27
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O’Brien A, Zhou T, White T, Medford A, Chen L, Kyritsi K, Wu N, Childs J, Stiles D, Ceci L, Chakraborty S, Ekser B, Baiocchi L, Carpino G, Gaudio E, Wu C, Kennedy L, Francis H, Alpini G, Glaser S. FGF1 Signaling Modulates Biliary Injury and Liver Fibrosis in the Mdr2 -/- Mouse Model of Primary Sclerosing Cholangitis. Hepatol Commun 2022; 6:1574-1588. [PMID: 35271760 PMCID: PMC9234675 DOI: 10.1002/hep4.1909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 12/21/2021] [Accepted: 12/26/2021] [Indexed: 11/16/2022] Open
Abstract
Fibroblast growth factor 1 (FGF1) belongs to a family of growth factors involved in cellular growth and division. MicroRNA 16 (miR-16) is a regulator of gene expression, which is dysregulated during liver injury and insult. However, the role of FGF1 in the progression of biliary proliferation, senescence, fibrosis, inflammation, angiogenesis, and its potential interaction with miR-16, are unknown. In vivo studies were performed in male bile duct-ligated (BDL, 12-week-old) mice, multidrug resistance 2 knockout (Mdr2-/-) mice (10-week-old), and their corresponding controls, treated with recombinant human FGF1 (rhFGF1), fibroblast growth factor receptor (FGFR) antagonist (AZD4547), or anti-FGF1 monoclonal antibody (mAb). In vitro, the human cholangiocyte cell line (H69) and human hepatic stellate cells (HSCs) were used to determine the expression of proliferation, fibrosis, angiogenesis, and inflammatory genes following rhFGF1 treatment. PSC patient and control livers were used to evaluate FGF1 and miR-16 expression. Intrahepatic bile duct mass (IBDM), along with hepatic fibrosis and inflammation, increased in BDL mice treated with rhFGF1, with a corresponding decrease in miR-16, while treatment with AZD4547 or anti-FGF1 mAb decreased hepatic fibrosis, IBDM, and inflammation in BDL and Mdr2-/- mice. In vitro, H69 and HSCs treated with rhFGF1 had increased expression of proliferation, fibrosis, and inflammatory markers. PSC samples also showed increased FGF1 and FGFRs with corresponding decreases in miR-16 compared with healthy controls. Conclusion: Our study demonstrates that suppression of FGF1 and miR-16 signaling decreases the presence of hepatic fibrosis, biliary proliferation, inflammation, senescence, and angiogenesis. Targeting the FGF1 and miR-16 axis may provide therapeutic options in treating cholangiopathies such as PSC.
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Affiliation(s)
- April O’Brien
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Tianhao Zhou
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Tori White
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Abigail Medford
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Lixian Chen
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Konstantina Kyritsi
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Nan Wu
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Jonathan Childs
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Danaleigh Stiles
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Ludovica Ceci
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
| | - Sanjukta Chakraborty
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
| | - Burcin Ekser
- Division of Transplant SurgeryDepartment of SurgeryIndiana University School of MedicineIndianapolisINUSA
| | - Leonardo Baiocchi
- Hepatology UnitDept of MedicineUniversity of Tor Vergata RomeRomeItaly
| | - Guido Carpino
- Department of MovementHuman and Health Sciences, University of Rome “Foro Italico”RomeItaly
| | - Eugenio Gaudio
- Department of AnatomicalHistologicalForensic Medicine and Orthopedics SciencesSapienza University of RomeRomeItaly
| | - Chaodong Wu
- Department of NutritionTexas A&M UniversityCollege StationTXUSA
| | - Lindsey Kennedy
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
- ResearchRichard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Heather Francis
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
- ResearchRichard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Gianfranco Alpini
- Division of Gastroenterology and HepatologyDepartment of MedicineIndiana University School of MedicineIndianapolisINUSA
- ResearchRichard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Shannon Glaser
- Department of Medical PhysiologyTexas A&M University College of MedicineBryanTXUSA
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28
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Hou LS, Zhang YW, Li H, Wang W, Huan ML, Zhou SY, Zhang BL. The regulatory role and mechanism of autophagy in energy metabolism-related hepatic fibrosis. Pharmacol Ther 2022; 234:108117. [PMID: 35077761 DOI: 10.1016/j.pharmthera.2022.108117] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/13/2022] [Accepted: 01/18/2022] [Indexed: 02/06/2023]
Abstract
Hepatic fibrosis is a key pathological process of chronic liver diseases, caused by alcohol, toxic and aberrant energy metabolism. It progresses to cirrhosis or even hepatic carcinoma without effective treatment. Studies have shown that autophagy has important regulatory effects on hepatic stellate cells (HSCs) energy metabolism, and then affect the activation state of HSCs. Autophagy maintains hepatic energy homeostasis, and the dysregulation of autophagy can lead to the activation of HSCs and the occurrence and development of hepatic fibrosis. It is necessary to explore the mechanism of autophagy in energy metabolism-related hepatic fibrosis. Herein, the current study summarizes the regulating mechanisms of autophagy through different targets and signal pathways in energy metabolism-related hepatic fibrosis, and discusses the regulatory effect of autophagy by natural plant-derived, endogenous and synthetic compounds for the treatment of hepatic fibrosis. A better comprehension of autophagy in hepatic stellate cells energy metabolism-related hepatic fibrosis may provide effective intervention of hepatic fibrosis, explore the potential clinical strategies and promote the drug treatment of hepatic fibrosis.
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Affiliation(s)
- Li-Shuang Hou
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Yao-Wen Zhang
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Hua Li
- Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an 710032, China; Department of Natural Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Wei Wang
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Meng-Lei Huan
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China; Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Si-Yuan Zhou
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China; Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Bang-Le Zhang
- Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China; Key Laboratory of Pharmacology of the State Administration of Traditional Chinese Medicine, Fourth Military Medical University, Xi'an 710032, China.
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29
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Garbuzenko DV. Pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. World J Clin Cases 2022; 10:3662-3676. [PMID: 35647163 PMCID: PMC9100727 DOI: 10.12998/wjcc.v10.i12.3662] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/17/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a complex pathological process controlled by a variety of cells, mediators and signaling pathways. Hepatic stellate cells play a central role in the development of liver fibrosis. In chronic liver disease, hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties. This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. They enter the cell cycle under the influence of various triggers. The "Initiation" phase of hepatic stellate cells activation overlaps and continues with the "Perpetuation" phase, which is characterized by a pronounced inflammatory and fibrogenic reaction. This is followed by a resolution phase if the injury subsides. Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis. In this respect, impairments in intracellular signaling, epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells. Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging, apoptosis, and/or clearance by immune cells, and serve as potential antifibrotic therapy. It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.
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30
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Guo P, Tai Y, Wang M, Sun H, Zhang L, Wei W, Xiang YK, Wang Q. Gα 12 and Gα 13: Versatility in Physiology and Pathology. Front Cell Dev Biol 2022; 10:809425. [PMID: 35237598 PMCID: PMC8883321 DOI: 10.3389/fcell.2022.809425] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/17/2022] [Indexed: 01/14/2023] Open
Abstract
G protein-coupled receptors (GPCRs), as the largest family of receptors in the human body, are involved in the pathological mechanisms of many diseases. Heterotrimeric G proteins represent the main molecular switch and receive cell surface signals from activated GPCRs. Growing evidence suggests that Gα12 subfamily (Gα12/13)-mediated signaling plays a crucial role in cellular function and various pathological processes. The current research on the physiological and pathological function of Gα12/13 is constantly expanding, Changes in the expression levels of Gα12/13 have been found in a wide range of human diseases. However, the mechanistic research on Gα12/13 is scattered. This review briefly describes the structural sequences of the Gα12/13 isoforms and introduces the coupling of GPCRs and non-GPCRs to Gα12/13. The effects of Gα12/13 on RhoA and other signaling pathways and their roles in cell proliferation, migration, and immune cell function, are discussed. Finally, we focus on the pathological impacts of Gα12/13 in cancer, inflammation, metabolic diseases, fibrotic diseases, and circulatory disorders are brought to focus.
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Affiliation(s)
- Paipai Guo
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yu Tai
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Manman Wang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Hanfei Sun
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Lingling Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Wei Wei
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Yang K Xiang
- Department of Pharmacology, University of California, Davis, Davis, CA, United States.,VA Northern California Health Care System, Mather, CA, United States
| | - Qingtong Wang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
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31
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Mastoridou EM, Goussia AC, Glantzounis GK, Kanavaros P, Charchanti AV. Autophagy and Exosomes: Cross-Regulated Pathways Playing Major Roles in Hepatic Stellate Cells Activation and Liver Fibrosis. Front Physiol 2022; 12:801340. [PMID: 35185602 PMCID: PMC8850693 DOI: 10.3389/fphys.2021.801340] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/27/2021] [Indexed: 12/14/2022] Open
Abstract
Chronic liver injury, regardless of the underlying disease, results in gradual alteration of the physiological hepatic architecture and in excessive production of extracellular matrix, eventually leading to cirrhosis Liver cellular architecture consists of different cell populations, among which hepatic stellate cells (HSCs) have been found to play a major role in the fibrotic process. Under normal conditions, HSCs serve as the main storage site for vitamin A, however, pathological stimuli lead to their transdifferentiation into myofibroblast cells, with autophagy being the key regulator of their activation, through lipophagy of their lipid droplets. Nevertheless, the role of autophagy in liver fibrosis is multifaceted, as increased autophagic levels have been associated with alleviation of the fibrotic process. In addition, it has been found that HSCs receive paracrine stimuli from neighboring cells, such as injured hepatocytes, Kupffer cells, sinusoidal endothelial cells, which promote liver fibrosis. These stimuli have been found to be transmitted via exosomes, which are incorporated by HSCs and can either be degraded through lysosomes or be secreted back into the extracellular space via fusion with the plasma membrane. Furthermore, it has been demonstrated that autophagy and exosomes may be concomitantly or reciprocally regulated, depending on the cellular conditions. Given that increased levels of autophagy are required to activate HSCs, it is important to investigate whether autophagy levels decrease at later stages of hepatic stellate cell activation, leading to increased release of exosomes and further propagation of hepatic fibrosis.
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Affiliation(s)
- Eleftheria M. Mastoridou
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Anna C. Goussia
- Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Georgios K. Glantzounis
- Hepato-Pancreatico-Biliary Unit, Department of Surgery, University General Hospital of Ioannina and School of Medicine, University of Ioannina, Ioannina, Greece
| | - Panagiotis Kanavaros
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Antonia V. Charchanti
- Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
- *Correspondence: Antonia V. Charchanti,
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Zhou JC, Wang JL, Ren HZ, Shi XL. Autophagy plays a double-edged sword role in liver diseases. J Physiol Biochem 2022; 78:9-17. [PMID: 34657993 PMCID: PMC8873123 DOI: 10.1007/s13105-021-00844-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 09/07/2021] [Indexed: 12/12/2022]
Abstract
As a highly evolutionarily conserved process, autophagy can be found in all types of eukaryotic cells. Such a constitutive process maintains cellular homeostasis in a wide variety of cell types through the encapsulation of damaged proteins or organelles into double-membrane vesicles. Autophagy not only simply eliminates materials but also serves as a dynamic recycling system that produces new building blocks and energy for cellular renovation and homeostasis. Previous studies have primarily recognized the role of autophagy in the degradation of dysfunctional proteins and unwanted organelles. However, there are findings of autophagy in physiological and pathological processes. In hepatocytes, autophagy is not only essential for homeostatic functions but also implicated in some diseases, such as viral hepatitis, alcoholic hepatitis, and hepatic failure. In the present review, we summarized the molecular mechanisms of autophagy and its role in several liver diseases and put forward several new strategies for the treatment of liver disease.
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Affiliation(s)
- Jing-Chao Zhou
- Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jing-Lin Wang
- Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Hao-Zhen Ren
- Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
| | - Xiao-Lei Shi
- Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
- Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
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Wang A, Bu FT, Li JJ, Zhang YF, Jia PC, You HM, Wu S, Wu YY, Zhu S, Huang C, Li J. MicroRNA-195-3p promotes hepatic stellate cell activation and liver fibrosis by suppressing PTEN expression. Toxicol Lett 2022; 355:88-99. [PMID: 34838997 DOI: 10.1016/j.toxlet.2021.11.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/07/2021] [Accepted: 11/24/2021] [Indexed: 02/07/2023]
Abstract
Liver fibrosis is a reversible wound healing reaction characterized by abnormal accumulation of extracellular matrix (ECM) in response to liver injury. Recent studies have shown that it can be epigenetically regulated, especially by microRNAs (miRNAs). It has been acknowledged that activation of hepatic stellate cells (HSCs) is a pivotal step in the initiation and progression of liver fibrosis. Notably, our results showed that miR-195-3p was increased in HSCs isolated from CCl4-treated mice and that the increase was more pronounced as the degree of liver fibrosis increased. Moreover, treatment of LX-2 cells, a human immortalized hepatic stellate cell line, with TGF-β1 resulted remarkable upregulation of miR-195-3p. Gain-of-function and loss-of-function experiments have suggested that the increased levels of miR-195-3p inhibit the expression of phosphatase and tension homolog deleted on chromosome 10 (PTEN), a negative regulator of the PI3K/Akt/mTOR signaling pathway in liver fibrosis, thereby contributing to HSC activation and proliferation and promoting the expression of profibrotic genes, such as α-SMA and collagen I, in LX-2 cells, which accelerates the accumulation of fibrous extracellular matrix deposition in the liver, while knockdown of miR-195-3p induced the opposite effect. Taken together, these results provide evidence for the harmful role of miR-195-3p in CCl4-treated mouse liver fibrosis.
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Affiliation(s)
- Ao Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Fang-Tian Bu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Juan-Juan Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Ya-Fei Zhang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Peng-Cheng Jia
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Hong-Mei You
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Sha Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yuan-Yuan Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Sai Zhu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Cheng Huang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
| | - Jun Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
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Li M, Yang L. Autophagy in the liver. AUTOPHAGY IN HEALTH AND DISEASE 2022:161-179. [DOI: 10.1016/b978-0-12-822003-0.00014-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hong CH, Ko MS, Kim JH, Cho H, Lee CH, Yoon JE, Yun JY, Baek IJ, Jang JE, Lee SE, Cho YK, Baek JY, Oh SJ, Lee BY, Lim JS, Lee J, Hartig SM, Conde de la Rosa L, Garcia-Ruiz C, Lee KU, Fernández-Checa JC, Choi JW, Kim S, Koh EH. Sphingosine 1-Phosphate Receptor 4 Promotes Nonalcoholic Steatohepatitis by Activating NLRP3 Inflammasome. Cell Mol Gastroenterol Hepatol 2021; 13:925-947. [PMID: 34890841 PMCID: PMC8810559 DOI: 10.1016/j.jcmgh.2021.12.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear. METHODS We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n -octylphenyl)ethyl]-1,3- propanediol hydrochloride)-like sphingolipid-focused library. RESULTS The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1pr4. Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1pr4+/- mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca++ release and deactivated the Nod-like receptor pyrin domain-containning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate-receptor-dependent [Ca++] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1pr4+/- mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome. CONCLUSIONS S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages.
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Affiliation(s)
- Chung Hwan Hong
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Myoung Seok Ko
- Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae Hyun Kim
- College of Pharmacy, Seoul National University, Seoul, Korea,College of Pharmacy, Kangwon National University, Chuncheon, Korea
| | - Hyunkyung Cho
- College of Pharmacy, Seoul National University, Seoul, Korea
| | - Chi-Ho Lee
- College of Pharmacy, Gachon University, Incheon, Korea
| | - Ji Eun Yoon
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji-Young Yun
- Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In-Jeoung Baek
- Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jung Eun Jang
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung Eun Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yun Kyung Cho
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji Yeon Baek
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Soo Jin Oh
- New Drug Development Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Joon Seo Lim
- Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jongkook Lee
- College of Pharmacy, Kangwon National University, Chuncheon, Korea
| | - Sean M. Hartig
- Molecular and Cellular Biology, Division of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, Texas
| | - Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona and Liver Unit-Hospital Clinic-Instituto de Investigaciones Biomédicas August Pi i Sunyer, Centro de Investigación Biomédica en Red, Barcelona, Spain
| | - Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona and Liver Unit-Hospital Clinic-Instituto de Investigaciones Biomédicas August Pi i Sunyer, Centro de Investigación Biomédica en Red, Barcelona, Spain,Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Ki-Up Lee
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jose C. Fernández-Checa
- Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona and Liver Unit-Hospital Clinic-Instituto de Investigaciones Biomédicas August Pi i Sunyer, Centro de Investigación Biomédica en Red, Barcelona, Spain,Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, California,Correspondence Address correspondence to: Jose C. Fernández-Checa, PhD, Department of Cell Death and Proliferation, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Cientificas, Barcelona and Liver Unit-Hospital Clinic–Instituto de Investigaciones Biomédicas August Pi i Sunyer, Centro de Investigación Biomédica en Red, Barcelona 08036, Spain. fax: (34) 93-3129405.
| | - Ji Woong Choi
- College of Pharmacy, Gachon University, Incheon, Korea,Ji Woong Choi, PhD, Laboratory of Pharmacology, College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon 21936, Korea. fax: (82) 32-820-4829.
| | - Sanghee Kim
- College of Pharmacy, Seoul National University, Seoul, Korea,Sanghee Kim, PhD, College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 08826, Korea. fax: (82) 2-762-8322.
| | - Eun Hee Koh
- Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,Eun Hee Koh, MD, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. fax: (82) 2-3010-6962.
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Kimura T, Singh S, Tanaka N, Umemura T. Role of G Protein-Coupled Receptors in Hepatic Stellate Cells and Approaches to Anti-Fibrotic Treatment of Non-Alcoholic Fatty Liver Disease. Front Endocrinol (Lausanne) 2021; 12:773432. [PMID: 34938271 PMCID: PMC8685252 DOI: 10.3389/fendo.2021.773432] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is globally increasing. Gaining control over disease-related events in non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, is currently an unmet medical need. Hepatic fibrosis is a critical prognostic factor in NAFLD/NASH. Therefore, a better understanding of the pathophysiology of hepatic fibrosis and the development of related therapies are of great importance. G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of a great variety of extracellular ligands. GPCRs represent major drug targets, as indicated by the fact that about 40% of all drugs currently used in clinical practice mediate their therapeutic effects by acting on GPCRs. Like many other organs, various GPCRs play a role in regulating liver function. It is predicted that more than 50 GPCRs are expressed in the liver. However, our knowledge of how GPCRs regulate liver metabolism and fibrosis in the different cell types of the liver is very limited. In particular, a better understanding of the role of GPCRs in hepatic stellate cells (HSCs), the primary cells that regulate liver fibrosis, may lead to the development of drugs that can improve hepatic fibrosis in NAFLD/NASH. In this review, we describe the functions of multiple GPCRs expressed in HSCs, their roles in liver fibrogenesis, and finally speculate on the development of novel treatments for NAFLD/NASH.
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Affiliation(s)
- Takefumi Kimura
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Simran Singh
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India
| | - Naoki Tanaka
- International Relations Office, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeji Umemura
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
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Cho SS, Lee JH, Kim KM, Park EY, Ku SK, Cho IJ, Yang JH, Ki SH. REDD1 attenuates hepatic stellate cell activation and liver fibrosis via inhibiting of TGF-β/Smad signaling pathway. Free Radic Biol Med 2021; 176:246-256. [PMID: 34614448 DOI: 10.1016/j.freeradbiomed.2021.10.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 09/27/2021] [Accepted: 10/01/2021] [Indexed: 12/20/2022]
Abstract
Liver fibrosis is caused by repetitive hepatic injury. Regulated in development and DNA damage response 1 (REDD1) gene is induced by various stresses and has been studied in cell proliferation and survival. However, the role of REDD1 in hepatic stellate cell activation and hepatic fibrogenesis has not yet been investigated. In the current study, we examined the effect of REDD1 on hepatic fibrogenesis and the underlying molecular mechanism. REDD1 protein was upregulated in the activated primary hepatic stellate cells and transforming growth factor-β (TGF-β)-treated LX-2 cells. REDD1 mRNA levels were also elevated by TGF-β treatment. TGF-β signaling is primarily transduced via the activation of the Smad transcription factor. However, TGF-β-mediated REDD1 induction was not Smad-dependent. Thus, we investigated the transcription factors that influence the REDD1 expression by TGF-β. We found that c-JUN, a component of AP-1, upregulated the REDD1 expression that was specifically suppressed by p38 inhibitor. In silico analysis of the REDD1 promoter region showed putative AP-1-binding sites; additionally, its deletion mutants demonstrated that the AP-1-binding site between -716 and -587 bp within the REDD1 promoter is critical for TGF-β-mediated REDD1 induction. Moreover, REDD1 overexpression markedly inhibited TGF-β-induced plasminogen activator inhibitor-1 (PAI-1) expression and Smad phosphorylation. REDD1 adenovirus infection inhibited CCl4-induced hepatic injury in mice, which was demonstrated by reduced ALT/AST levels and collagen accumulation. In addition, we observed that REDD1 inhibited CCl4-induced fibrogenic gene induction and restored GSH and malondialdehyde levels. Our findings implied that REDD1 has the potential to inhibit HSC activation and protect against liver fibrosis.
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Affiliation(s)
- Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Ji Hyun Lee
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea; Department of Biomedical Science, College of Natural Science, Chosun University, Gwangju, 61452, Republic of Korea
| | - Eun Young Park
- College of Pharmacy, Mokpo National University, Muan-gun, Jeollanam-do, 58554, Republic of Korea
| | - Sae Kwang Ku
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Il Je Cho
- College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do, 38610, Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do, 58245, Republic of Korea.
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea.
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Zhang Z, Liu X, Shen Z, Quan J, Lin C, Li X, Hu G. Endostatin in fibrosis and as a potential candidate of anti-fibrotic therapy. Drug Deliv 2021; 28:2051-2061. [PMID: 34595978 PMCID: PMC8491667 DOI: 10.1080/10717544.2021.1983071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Fibrotic diseases pose significant clinical challenges due to their broadness and complexity. Thus, a better understanding of fibrogenesis and the development of more effective treatments is imperative. Recent evidence suggests a significant antifibrotic potential of an endogenous glycoprotein, endostatin. While endostatin has been widely studied for its role as an anticancer adjuvant by inhibiting tumor angiogenesis, its possible implication in fibrosis remains largely unclear. Here, we review the role of endostatin in various cellular processes and highlight its antifibrotic activity. We hypothesize that endostatin conveys a homeostatic function in the process of fibrosis by regulating (a) TGF-β1 and its downstream signaling; (b) RhoA/ROCK pathway; (c) NF-κB signaling pathway; (d) expression of EGR-1; (e) PDGF/PDGFR pathway; (f) autophagy-related pathways; (g) pathways associated with cell proliferation and apoptosis. Finally, we propose a schematic model of the antifibrotic roles and mechanisms of endostatin; also, we outline future research directions of endostatin and aim to present a potential therapeutic approach for fibrosis.
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Affiliation(s)
- Zequn Zhang
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xi Liu
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhaolong Shen
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jun Quan
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Changwei Lin
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiaorong Li
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Gui Hu
- Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Dong XC, Chowdhury K, Huang M, Kim HG. Signal Transduction and Molecular Regulation in Fatty Liver Disease. Antioxid Redox Signal 2021; 35:689-717. [PMID: 33906425 PMCID: PMC8558079 DOI: 10.1089/ars.2021.0076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Significance: Fatty liver disease is a major liver disorder in the modern societies. Comprehensive understanding of the pathophysiology and molecular mechanisms is essential for the prevention and treatment of the disease. Recent Advances: Remarkable progress has been made in the recent years in basic and translational research in the field of fatty liver disease. Multiple signaling pathways have been implicated in the development of fatty liver disease, including AMP-activated protein kinase, mechanistic target of rapamycin kinase, endoplasmic reticulum stress, oxidative stress, inflammation, transforming growth factor β, and yes1-associated transcriptional regulator/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). In addition, critical molecular regulations at the transcriptional and epigenetic levels have been linked to the pathogenesis of fatty liver disease. Critical Issues: Some critical issues remain to be solved so that research findings can be translated into clinical applications. Robust and reliable biomarkers are needed for diagnosis of different stages of the fatty liver disease. Effective and safe molecular targets remain to be identified and validated. Prevention strategies require solid scientific evidence and population-wide feasibility. Future Directions: As more data are generated with time, integrative approaches are needed to comprehensively understand the disease pathophysiology and mechanisms at multiple levels from population, organismal system, organ/tissue, to cell. The interactions between genes and environmental factors require deeper investigation for the purposes of prevention and personalized treatment of fatty liver disease. Antioxid. Redox Signal. 35, 689-717.
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Affiliation(s)
- Xiaocheng Charlie Dong
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Department of BioHealth Informatics, School of Informatics and Computing, Indiana University Purdue University Indianapolis, Indianapolis, Indiana, USA
| | - Kushan Chowdhury
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Menghao Huang
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hyeong Geug Kim
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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40
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Xiu AY, Ding Q, Li Z, Zhang CQ. Doxazosin Attenuates Liver Fibrosis by Inhibiting Autophagy in Hepatic Stellate Cells via Activation of the PI3K/Akt/mTOR Signaling Pathway. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:3643-3659. [PMID: 34456560 PMCID: PMC8387324 DOI: 10.2147/dddt.s317701] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022]
Abstract
Purpose To investigate the effect of doxazosin on autophagy and the activation of hepatic stellate cells (HSCs) in vivo and in vitro and determine the underlying mechanism. Methods In vivo, a mouse liver fibrosis model was induced by the intraperitoneal injection of carbon tetrachloride (CCl4). Doxazosin was administered at doses of 2.5, 5 and 10 mg/(kg*day) by gavage. After 20 weeks, blood and liver tissues were collected for serological and histological analysis, respectively. Blood analysis, hematoxylin and eosin (HE) staining, Masson’s trichrome staining, immunohistochemistry and immunofluorescence staining were used to measure the extent of liver fibrosis in model and control mice. In vitro, the human HSC cell line LX-2 was cultured and treated with different doses of doxazosin for the indicated times. The effects of doxazosin on LX-2 cell proliferation and migration were examined by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. The number of autophagosomes in LX-2 cells was observed by transmission electron microscopy (TEM). Infection with green fluorescent protein (GFP)-LC3B adenovirus, GFP-red fluorescent protein (RFP)-LC3B adenovirus and mCherry-EGFP-LC3 adeno-associated virus was performed to examine changes in autophagic flux in vitro and in vivo. Cell apoptosis was measured by flow cytometry in vitro and by TUNEL assays both in vitro and in vivo. Immunoblotting was performed to evaluate the expression levels of proteins related to fibrosis, autophagy, apoptosis, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR). Results Doxazosin inhibited HSC proliferation and migration. HSC activation was attenuated by doxazosin in a concentration-dependent manner in vivo and in vitro. Doxazosin also blocked autophagic flux and induced apoptosis in HSCs. In addition, the PI3K/Akt/mTOR pathway was activated by doxazosin and regulated fibrosis, autophagy and apoptosis in HSCs. Conclusion The study confirmed that doxazosin could inhibit autophagy by activating the PI3K/Akt/mTOR signaling pathway and attenuate liver fibrosis.
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Affiliation(s)
- Ai-Yuan Xiu
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China
| | - Qian Ding
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China
| | - Zhen Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China
| | - Chun-Qing Zhang
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.,Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China
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Yang F, Li H, Li Y, Hao Y, Wang C, Jia P, Chen X, Ma S, Xiao Z. Crosstalk between hepatic stellate cells and surrounding cells in hepatic fibrosis. Int Immunopharmacol 2021; 99:108051. [PMID: 34426110 DOI: 10.1016/j.intimp.2021.108051] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 07/28/2021] [Accepted: 08/04/2021] [Indexed: 02/08/2023]
Abstract
Hepatic fibrosis represents as a dynamic pathological process characterized by the net accumulation of extracellular matrix in the progression of various chronic liver diseases, including viral hepatitis, alcoholic liver disease, and metabolic associated fatty liver disease (MAFLD). Activation of hepatic stellate cells (HSCs) is well-defined to play a central role in the initiation and progression of hepatic fibrosis. However, the activation of HSCs is affected by the complicated microenvironments in liver, which largely attributes to the communication between hepatocytes and multiple tissue-resident cells, including sinusoidal endothelial cells, bile duct epithelial cells, platelets, T cells, B cells, macrophages, natural killer cells, neutrophils, dendritic cells, in the direct or indirect mechanisms. Cellular crosstalk between HSCs and surrounding cells contributes to the activation of HSCs and the progression of hepatic fibrosis. Currently, accumulating evidence have proven the complexity and plasticity of HSCs activation, and further clarification of cellular communication between HSCs and surrounding cells will provide sufficient clue to the development of novel diagnostic methods and therapeutic strategies for hepatic fibrosis.
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Affiliation(s)
- Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Heng Li
- Laboratory of Anti-inflammation and Immunopharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yanmin Li
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yaokun Hao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Chenxiao Wang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Pan Jia
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Xinju Chen
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
| | - Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China.
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Sun M, Tan L, Hu M. The role of autophagy in hepatic fibrosis. Am J Transl Res 2021; 13:5747-5757. [PMID: 34306323 PMCID: PMC8290830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 04/08/2021] [Indexed: 06/13/2023]
Abstract
Hepatic fibrosis is a chronic liver injury process, and its continuous development can lead to cirrhosis, hepatic failure and even hepatocellular carcinoma (HCC). Autophagy has attracted much attention because of its controversial role in the course of hepatic fibrosis. In this review, we introduce the mechanism related to noncoding RNAs and some of the signaling pathways that promote or inhibit fibrosis by affecting autophagy. Finally, we list some targets related to autophagy that enable hepatic fibrosis therapy and forecast its prospect in hepatic fibrosis. This review will provide new ideas in diagnosing and treating hepatic fibrosis, which will be helpful to reduce the incidence of cirrhosis and its complications.
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Affiliation(s)
- Mei Sun
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, China
| | - Li Tan
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, China
| | - Min Hu
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University Changsha 410011, Hunan, China
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43
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Qian H, Chao X, Williams J, Fulte S, Li T, Yang L, Ding WX. Autophagy in liver diseases: A review. Mol Aspects Med 2021; 82:100973. [PMID: 34120768 DOI: 10.1016/j.mam.2021.100973] [Citation(s) in RCA: 215] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/29/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023]
Abstract
The liver is a highly dynamic metabolic organ that plays critical roles in plasma protein synthesis, gluconeogenesis and glycogen storage, cholesterol metabolism and bile acid synthesis as well as drug/xenobiotic metabolism and detoxification. Research from the past decades indicate that autophagy, the cellular catabolic process mediated by lysosomes, plays an important role in maintaining cellular and metabolic homeostasis in the liver. Hepatic autophagy fluctuates with hormonal cues and the availability of nutrients that respond to fed and fasting states as well as circadian activities. Dysfunction of autophagy in liver parenchymal and non-parenchymal cells can lead to various liver diseases including non-alcoholic fatty liver diseases, alcohol associated liver disease, drug-induced liver injury, cholestasis, viral hepatitis and hepatocellular carcinoma. Therefore, targeting autophagy may be a potential strategy for treating these various liver diseases. In this review, we will discuss the current progress on the understanding of autophagy in liver physiology. We will also discuss several forms of selective autophagy in the liver and the molecular signaling pathways in regulating autophagy of different cell types and their implications in various liver diseases.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Jessica Williams
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Sam Fulte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA.
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Hwang S, Yang YM. Exosomal microRNAs as diagnostic and therapeutic biomarkers in non-malignant liver diseases. Arch Pharm Res 2021; 44:574-587. [PMID: 34165701 PMCID: PMC8223764 DOI: 10.1007/s12272-021-01338-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 06/20/2021] [Indexed: 12/16/2022]
Abstract
The liver is a vital organ responsible for various physiological functions, such as metabolism, immune response, digestion, and detoxification. Crosstalk between hepatocytes, hepatic macrophages, and hepatic stellate cells is critical for liver pathology. Exosomes are small extracellular vesicles (50-150 nm) that play an important role in cell-cell or organ-organ communication as they transfer their cargo, such as protein, DNA, and RNA to recipient cells or distant organs. In various liver diseases, the number of liver cell-derived exosomes is increased and the exosomal microRNA (miRNA) profile is altered. Early studies investigated the value of circulating exosomal miRNAs as biomarkers. Several exosomal miRNAs showed excellent diagnostic values, suggesting their potential as diagnostic biomarkers in liver diseases. Exosomal miRNAs have emerged as critical regulators of liver pathology because they control the expression of multiple genes in recipient cells. In this review, we discuss the biology of exosomes and summarize the recent findings of exosome-mediated intercellular and organ-to-organ communication during liver pathology. As there are many review articles dealing with exosomal miRNAs in liver cancer, we focused on non-malignant liver diseases. The therapeutic potential of exosomal miRNAs in liver pathology is also highlighted.
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Affiliation(s)
- Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, South Korea
| | - Yoon Mee Yang
- Department of Pharmacy, Kangwon National University, Chuncheon-si, Gangwon-do, 24341, South Korea.
- KNU Researcher training program for developing Anti-Viral Innovative Drugs, Kangwon National University, Chuncheon, 24341, South Korea.
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Lucantoni F, Martínez-Cerezuela A, Gruevska A, Moragrega ÁB, Víctor VM, Esplugues JV, Blas-García A, Apostolova N. Understanding the implication of autophagy in the activation of hepatic stellate cells in liver fibrosis: are we there yet? J Pathol 2021; 254:216-228. [PMID: 33834482 DOI: 10.1002/path.5678] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/29/2021] [Accepted: 04/07/2021] [Indexed: 01/18/2023]
Abstract
Liver fibrosis (LF) occurs as a result of persistent liver injury and can be defined as a pathologic, chronic, wound-healing process in which functional parenchyma is progressively replaced by fibrotic tissue. As a phenomenon involved in the majority of chronic liver diseases, and therefore prevalent, it exerts a significant impact on public health. This impact becomes even more patent given the lack of a specific pharmacological therapy, with LF only being ameliorated or prevented through the use of agents that alleviate the underlying causes. Hepatic stellate cells (HSCs) are fundamental mediators of LF, which, activated in response to pro-fibrotic stimuli, transdifferentiate from a quiescent phenotype into myofibroblasts that deposit large amounts of fibrotic tissue and mediate pro-inflammatory effects. In recent years, much effort has been devoted to understanding the mechanisms through which HSCs are activated or inactivated. Using cell culture and/or different animal models, numerous studies have shown that autophagy is enhanced during the fibrogenic process and have provided specific evidence to pinpoint the fundamental role of autophagy in HSC activation. This effect involves - though may not be limited to - the autophagic degradation of lipid droplets. Several hepatoprotective agents have been shown to reverse the autophagic alteration present in LF, but clinical confirmation of these effects is pending. On the other hand, there is evidence that implicates autophagy in several anti-fibrotic mechanisms in HSCs that stimulate HSC cell cycle arrest and cell death or prevent the generation of pro-fibrotic mediators, including excess collagen accumulation. The objective of this review is to offer a comprehensive analysis of published evidence of the role of autophagy in HSC activation and to provide hints for possible therapeutic targets for the treatment and/or prevention of LF related to autophagy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Federico Lucantoni
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
| | | | - Aleksandra Gruevska
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
| | - Ángela B Moragrega
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
| | - Víctor M Víctor
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Juan V Esplugues
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
| | - Ana Blas-García
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Nadezda Apostolova
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
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Fründt T, Krause L, Hussey E, Steinbach B, Köhler D, von Felden J, Schulze K, Lohse AW, Wege H, Schwarzenbach H. Diagnostic and Prognostic Value of miR-16, miR-146a, miR-192 and miR-221 in Exosomes of Hepatocellular Carcinoma and Liver Cirrhosis Patients. Cancers (Basel) 2021; 13:cancers13102484. [PMID: 34069692 PMCID: PMC8161187 DOI: 10.3390/cancers13102484] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Exosomes, carrying small non-coding RNA (miRNA), are known to play a pivotal role in the process of tumor progression. In this prospective study, we identified miR-16, miR-146a, miR-192, and miR- 221 to be significantly deregulated in the plasma of patients with hepatocellular carcinoma (HCC) compared to patients with liver cirrhosis and healthy individuals. MiR-146a revealed diagnostic potential to differentiate HCC patients from liver cirrhosis patients with a sensitivity of 81% and a specificity of 58% in logistic regression model. Furthermore, miR- 192 independently correlated with overall survival in patients with HCC. Abstract We aimed to identify a specific microRNA (miRNA) pattern to determine diagnostic and prognostic value in plasma exosomes of hepatocellular carcinoma (HCC) patients. A two-stage study was carried out: exosomal miRNAs were quantified in plasma of HCC patients and healthy individuals by PCR-based microarray cards containing 45 different miRNAs (training cohort). Then, four deregulated miRNAs (miR-16, miR-146a, miR-192, and miR-221) were quantified in the validation analysis using exosomes derived from 85 HCC patients, 50 liver cirrhosis patients, and 20 healthy individuals. Exosomal miR-146a (p = 0.0001), miR-192 (p = 0.002) and miR-221 (p = 0.032) were upregulated only in HCC patients. Repeated 10-fold cross validation showed that miR-146a differentiated HCC from liver cirrhosis patients with AUC of 0.80 ± 0.14 (sensitivity: 81 ± 13%, specificity: 58 ± 22%) in a logistic regression model. High miR-192 presence is associated with poor overall survival (OS) in all HCC patients (p = 0.027) and was predictor of OS in HCC patients in an uni- and multivariate Cox regression model. Moreover, decreased miR-16 levels correlated with OS in liver cirrhosis patients (p = 0.034). Our results emphasized that exosomes secreted into the plasma carry differentially expressed miRNAs of which in particular, miR-192, miR-146, and miR-16 are promising diagnostic and prognostic markers for both HCC and liver cirrhosis patients.
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Affiliation(s)
- Thorben Fründt
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (E.H.); (J.v.F.); (K.S.); (A.W.L.); (H.W.)
- Correspondence: ; Tel.: +49-40-7410-18056
| | - Linda Krause
- Institute of Medical Biometry and Epidemiology, 20246 Hamburg, Germany;
| | - Elaine Hussey
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (E.H.); (J.v.F.); (K.S.); (A.W.L.); (H.W.)
| | - Bettina Steinbach
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (B.S.); (H.S.)
| | - Daniel Köhler
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Johann von Felden
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (E.H.); (J.v.F.); (K.S.); (A.W.L.); (H.W.)
| | - Kornelius Schulze
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (E.H.); (J.v.F.); (K.S.); (A.W.L.); (H.W.)
| | - Ansgar W. Lohse
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (E.H.); (J.v.F.); (K.S.); (A.W.L.); (H.W.)
| | - Henning Wege
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (E.H.); (J.v.F.); (K.S.); (A.W.L.); (H.W.)
- Cancer Center Esslingen, 73730 Esslingen am NEckar, Germany
| | - Heidi Schwarzenbach
- Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; (B.S.); (H.S.)
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MiR-15b and miR-16 suppress TGF-β1-induced proliferation and fibrogenesis by regulating LOXL1 in hepatic stellate cells. Life Sci 2021; 270:119144. [PMID: 33545201 DOI: 10.1016/j.lfs.2021.119144] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/19/2021] [Accepted: 01/27/2021] [Indexed: 12/13/2022]
Abstract
Activation of hepatic stellate cells (HSCs) is an important event during the progress of liver fibrosis. MicroRNA (miR)-15b and miR-16 have been found to be involved in activation of HSCs. However, the roles of miR-15b/16 in liver fibrosis remain unclear. The expression of miR-15b/16 was decreased in TGF-β1-stimulated LX-2 cells. Overexpression of miR-15b/16 in LX-2 cells suppressed TGF-β1-induced cell proliferation and the expression levels of tissue inhibitor of metalloproteinase type 1, collagen type I, and α-smooth muscle actin. The activation of Smad2/3 caused by TGF-β1 was repressed by miR-15b/16 overexpression. The two miRNAs directly bound to the 3'-UTR of lysyl oxidase-like 1 (LOXL1) and suppressed the LOXL1 expression. Furthermore, knockdown of LOXL1 attenuated miR-15b/16 downregulation-induced cell proliferation, fibrogenic response and phosphorylation of Smad2/3. Collectively, miR-15b/16 exhibited anti-fibrotic activity through regulation of Smad2/3 pathway.
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Toyomoto M, Inoue A, Iida K, Denawa M, Kii I, Ngako Kadji FM, Kishi T, Im D, Shimamura T, Onogi H, Yoshida S, Iwata S, Aoki J, Hosoya T, Hagiwara M. S1PR3-G 12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation. Cell Chem Biol 2021; 28:1132-1144.e9. [PMID: 33561428 DOI: 10.1016/j.chembiol.2021.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 12/07/2020] [Accepted: 01/06/2021] [Indexed: 02/08/2023]
Abstract
Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis). By our shedding assay of transforming growth factor α in HEK293A cells, ALESIA was determined to act as a sphingosine-1-phosphate receptor 3-G12-biased agonist that promotes nitric oxide production and oxidative stress. The oxidative stress triggered by ALESIA resulted in the exhaustion of glucose, cellular NADPH deficiency, and then cancer cell death. Intraperitoneal administration of ALESIA improved the survival of mice with peritoneally disseminated rhabdomyosarcoma, indicating its potential as a new type of anticancer drug for glucose starvation therapy.
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Affiliation(s)
- Masayasu Toyomoto
- Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Asuka Inoue
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi 980-8578, Japan
| | - Kei Iida
- Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Masatsugu Denawa
- Medical Research Support Center, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Isao Kii
- Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Laboratory for Drug Target Research, Integrated Bioscience Division, Institute of Agriculture, Shinshu University, Nagano 399-4598, Japan
| | - Francois Marie Ngako Kadji
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi 980-8578, Japan
| | - Takayuki Kishi
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi 980-8578, Japan
| | - Dohyun Im
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Tatsuro Shimamura
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Hiroshi Onogi
- Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; KinoPharma, Inc., Tokyo 103-0023, Japan
| | - Suguru Yoshida
- Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
| | - So Iwata
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Junken Aoki
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi 980-8578, Japan; Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
| | - Takamitsu Hosoya
- Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
| | - Masatoshi Hagiwara
- Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
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Hou L, Zhang Z, Yang L, Chang N, Zhao X, Zhou X, Yang L, Li L. NLRP3 inflammasome priming and activation in cholestatic liver injury via the sphingosine 1-phosphate/S1P receptor 2/Gα (12/13)/MAPK signaling pathway. J Mol Med (Berl) 2021; 99:273-288. [PMID: 33388881 DOI: 10.1007/s00109-020-02032-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 12/04/2020] [Accepted: 12/23/2020] [Indexed: 12/19/2022]
Abstract
NLRP3 inflammasome-driven inflammation represents a key trigger for hepatic fibrogenesis during cholestatic liver injury. However, whether sphingosine 1-phosphate (S1P) plays a role in NLRP3 inflammasome priming and activation remains unknown. Here, we found that the expression of NLRP3 in macrophages and NLRP3 inflammasome activation were significantly elevated in the liver injured by bile duct ligation (BDL). In vitro, S1P promoted the NLRP3 inflammasome priming and activation via S1P receptor 2 (S1PR2) in bone marrow-derived monocyte/macrophages (BMMs). Focusing on BMMs, the gene silencing of Gα12 or Gα13 by specific siRNA suppressed NLRP3 inflammasome priming and pro-inflammatory cytokine (IL-1β and IL-18) secretion, whereas Gα(i/o) and Gαq were not involved in this process. The MAPK signaling pathways (P38, ERK, and JNK) mediated NLRP3 inflammasome priming and IL-1β and IL-18 secretion, whereas blockage of PI3K, ROCK, and Rho family had no such effect. Moreover, JTE-013 (S1PR2 inhibitor) treatment markedly reduced NLRP3 inflammasome priming and activation in BDL-injured liver. Collectively, S1P promotes NLRP3 inflammasome priming and pro-inflammatory cytokines (IL-1β and IL-18) secretion via the S1PR2/Gα(12/13)/MAPK pathway, which may represent an effective therapeutic strategy for liver disease. KEY MESSAGE: • Hepatic NLRP3 expression was significantly elevated in BMMs of BDL-injured mouse liver. • S1P promoted NLRP3 inflammasome priming and activation in BMMs, depending on the S1PR2/Gα(12/13)/MAPK pathway. • Blockade of S1PR2 by JTE-013 reduced NLRP3 inflammasome priming and activation inflammasome in vivo.
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Affiliation(s)
- Lei Hou
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Zhi Zhang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Le Yang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Na Chang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Xinhao Zhao
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Xuan Zhou
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Lin Yang
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China
| | - Liying Li
- Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, 100069, China.
- , Beijing, China.
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Kim SJ, Kim KM, Yang JH, Cho SS, Jeong EH, Kim JH, Lee JH, Seo KH, Park EY, Ki SH. Transforming Growth Factor Beta-Induced Foxo3a Acts as a Profibrotic Mediator in Hepatic Stellate Cells. Toxicol Sci 2021; 179:241-250. [PMID: 33372984 DOI: 10.1093/toxsci/kfaa185] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Hepatic stellate cells (HSCs) are major contributors to hepatic fibrogenesis facilitating liver fibrosis. Forkhead box O 3a (FoxO3a) is a member of the forkhead transcription factor family, which mediates cell proliferation and differentiation. However, the expression and function of FoxO3a during HSC activation remain largely unknown. FoxO3a overexpression was related to fibrosis in patients, and its expression was colocalized with desmin or α-smooth muscle actin, representative HSC markers. We also observed upregulated FoxO3a levels in two animal hepatic fibrosis models, a carbon tetrachloride-injected model and a bile duct ligation model. In addition, transforming growth factor beta (TGF-β) treatment in mouse primary HSCs or LX-2 cells elevated FoxO3a expression. When FoxO3a was upregulated by TGF-β in LX-2 cells, both the cytosolic and nuclear levels of FoxO3a increased. In addition, we found that the induction of FoxO3a by TGF-β was due to both transcriptional and proteasome-dependent mechanisms. Moreover, FoxO3a overexpression promoted TGF-β-mediated Smad activation. Furthermore, FoxO3a increased fibrogenic gene expression, which was reversed by FoxO3a knockdown. TGF-β-mediated FoxO3a overexpression in HSCs facilitated hepatic fibrogenesis, suggesting that FoxO3a may be a novel target for liver fibrosis prevention and treatment.
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Affiliation(s)
- Seung Jung Kim
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Kyu Min Kim
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Ji Hye Yang
- College of Korean Medicine, Dongshin University, Naju, Jeollanam-do 58245, Republic of Korea
| | - Sam Seok Cho
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Eun Hee Jeong
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Jae Hoon Kim
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Ji Hyun Lee
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Kyu Hwa Seo
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
| | - Eun Young Park
- College of Pharmacy, Mokpo National University, Muan-gun, Jeollanam-do 58554, Republic of Korea
| | - Sung Hwan Ki
- College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea
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