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Xia M, Li J, Martinez Aguilar LM, Wang J, Trillos Almanza MC, Li Y, Buist-Homan M, Moshage H. Arctigenin Attenuates Hepatic Stellate Cell Activation via Endoplasmic Reticulum-Associated Degradation (ERAD)-Mediated Restoration of Lipid Homeostasis. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025. [PMID: 40415275 DOI: 10.1021/acs.jafc.5c01366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2025]
Abstract
Arctigenin, a natural lignan from Arctium lappa L., exhibits potent antifibrotic activity, yet its molecular mechanisms remain unclear. Endoplasmic reticulum (ER) stress is known to promote hepatic stellate cell (HSC) activation and liver fibrosis. This study investigates the therapeutic potential of arctigenin in HSC activation through ER stress modulation. Primary rat HSCs were activated (3-7 days) and treated with tunicamycin (ER stress inducer) or 4-PBA (ER stress inhibitor). Arctigenin attenuated ER stress markers (e.g., GRP78) and suppressed the expression of fibrotic marker α-SMA in ER stress-challenged activating (day 3) and activated (day 7) HSCs. Arctigenin restored lipid homeostasis by modulation of both lipogenesis (via Dgat2 and Ppar-γ upregulation) and lipolysis (suppression via ATGL inhibition). ER stress activated ER-associated degradation (ERAD), triggering the formation of small lipid droplets (LD). Arctigenin normalized the ERAD activity, thereby rescuing LD integrity and suppressing HSC activation. Our findings demonstrate that arctigenin mitigates HSC activation by suppressing ER stress and restoring lipid homeostasis via modulating ERAD-mediated lipid dysregulation. As a dietary and medicinal compound, arctigenin emerges as a promising therapeutic candidate for liver fibrosis.
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Affiliation(s)
- Mengmeng Xia
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Jia Li
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Lizbeth Magnolia Martinez Aguilar
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Junyu Wang
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Maria Camila Trillos Almanza
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Yakun Li
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen 9713 GZ, The Netherlands
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2
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Tak J, Kim YS, Kim SG. Roles of X-box binding protein 1 in liver pathogenesis. Clin Mol Hepatol 2025; 31:1-31. [PMID: 39355873 PMCID: PMC11791611 DOI: 10.3350/cmh.2024.0441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 09/06/2024] [Accepted: 09/27/2024] [Indexed: 10/03/2024] Open
Abstract
The prevalence of drug-induced liver injury (DILI) and viral liver infections presents significant challenges in modern healthcare and contributes to considerable morbidity and mortality worldwide. Concurrently, metabolic dysfunctionassociated steatotic liver disease (MASLD) has emerged as a major public health concern, reflecting the increasing rates of obesity and leading to more severe complications such as fibrosis and hepatocellular carcinoma. X-box binding protein 1 (XBP1) is a distinct transcription factor with a basic-region leucine zipper structure, whose activity is regulated by alternative splicing in response to disruptions in endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR) activation. XBP1 interacts with a key signaling component of the highly conserved UPR and is critical in determining cell fate when responding to ER stress in liver diseases. This review aims to elucidate the emerging roles and molecular mechanisms of XBP1 in liver pathogenesis, focusing on its involvement in DILI, viral liver infections, MASLD, fibrosis/cirrhosis, and liver cancer. Understanding the multifaceted functions of XBP1 in these liver diseases offers insights into potential therapeutic strategies to restore ER homeostasis and mitigate liver damage.
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Affiliation(s)
- Jihoon Tak
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Korea
| | - Yun Seok Kim
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Korea
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Sang Geon Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang, Korea
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Tian Y, Sun D, Liu N, Zhao J, Zhao T, Liu X, Dong X, Dong L, Wang W, Jiao P, Ma J. Biomimetic mesenchymal stem cell membrane-coated nanoparticle delivery of MKP5 inhibits hepatic fibrosis through the IRE/XBP1 pathway. J Nanobiotechnology 2024; 22:741. [PMID: 39609656 PMCID: PMC11606114 DOI: 10.1186/s12951-024-03029-8] [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: 07/31/2024] [Accepted: 11/19/2024] [Indexed: 11/30/2024] Open
Abstract
Hepatic fibrosis is a common disease with high morbidity and mortality rates. The complex and poorly understood mechanisms underlying hepatic fibrosis represent a significant challenge for the development of more effective therapeutic strategies. MKP5 is a potential regulator of multiple fibrotic diseases. However, its precise role and mechanism of action in hepatic fibrosis remains unclear. This study identified a reduction in MKP5 expression in fibrotic liver tissues of mice treated with CCl4 and observed that MKP5 knockout mice exhibited a more pronounced development of hepatic fibrosis. In addition, RNA-seq data indicated activation of protein processing in the endoplasmic reticulum signalling pathway in fibrotic liver tissues of mice lacking MKP5. Mechanistically, MKP5 inhibits the activation of hepatic stellate cells (HSCs) and hepatocyte apoptosis through the regulation of the IRE/XBP1 pathway. Based on these findings, we developed PLGA-MKP5 nanoparticles coated with a mesenchymal stem cell membrane (MSCM). Our results demonstrated that MSCM-PLGA-MKP5 was most effective in attenuating hepatic inflammation and fibrosis in murine models by modulating the IRE/XBP1 axis. This study contributes to the current understanding of the pathogenesis of hepatic fibrosis, suggesting that the targeted delivery of MKP5 via a nano-delivery system may represent a promising therapeutic approach to treat hepatic fibrosis.
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Affiliation(s)
- Yafei Tian
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Dandan Sun
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Na Liu
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Jianan Zhao
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Tongjian Zhao
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Xiaonan Liu
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Xinzhe Dong
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Li Dong
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Wei Wang
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Ping Jiao
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China.
| | - Jie Ma
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China.
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Wilhelmsen I, Combriat T, Dalmao-Fernandez A, Stokowiec J, Wang C, Olsen PA, Wik JA, Boichuk Y, Aizenshtadt A, Krauss S. The effects of TGF-β-induced activation and starvation of vitamin A and palmitic acid on human stem cell-derived hepatic stellate cells. Stem Cell Res Ther 2024; 15:223. [PMID: 39044210 PMCID: PMC11267759 DOI: 10.1186/s13287-024-03852-8] [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: 05/06/2024] [Accepted: 07/14/2024] [Indexed: 07/25/2024] Open
Abstract
BACKGROUND Hepatic stellate cells (HSC) have numerous critical roles in liver function and homeostasis, while they are also known for their importance during liver injury and fibrosis. There is therefore a need for relevant in vitro human HSC models to fill current knowledge gaps. In particular, the roles of vitamin A (VA), lipid droplets (LDs), and energy metabolism in human HSC activation are poorly understood. METHODS In this study, human pluripotent stem cell-derived HSCs (scHSCs), benchmarked to human primary HSC, were exposed to 48-hour starvation of retinol (ROL) and palmitic acid (PA) in the presence or absence of the potent HSC activator TGF-β. The interventions were studied by an extensive set of phenotypic and functional analyses, including transcriptomic analysis, measurement of activation-related proteins and cytokines, VA- and LD storage, and cell energy metabolism. RESULTS The results show that though the starvation of ROL and PA alone did not induce scHSC activation, the starvation amplified the TGF-β-induced activation-related transcriptome. However, TGF-β-induced activation alone did not lead to a reduction in VA or LD stores. Additionally, reduced glycolysis and increased mitochondrial fission were observed in response to TGF-β. CONCLUSIONS scHSCs are robust models for activation studies. The loss of VA and LDs is not sufficient for scHSC activation in vitro, but may amplify the TGF-β-induced activation response. Collectively, our work provides an extensive framework for studying human HSCs in healthy and diseased conditions.
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Affiliation(s)
- Ingrid Wilhelmsen
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway.
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway.
| | - Thomas Combriat
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Andrea Dalmao-Fernandez
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
- Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068, Blindern, Oslo, 0316, Norway
| | - Justyna Stokowiec
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Chencheng Wang
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
- Department of Transplantation Medicine, Institute for Surgical Research, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
| | - Petter Angell Olsen
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Jonas Aakre Wik
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Yuliia Boichuk
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Aleksandra Aizenshtadt
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
| | - Stefan Krauss
- Department of Immunology and Transfusion Medicine, Oslo University Hospital, P.O. Box 4950, Nydalen, Oslo, 0424, Norway
- Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1110, Blindern, Oslo, 0317, Norway
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Horn P, Tacke F. Metabolic reprogramming in liver fibrosis. Cell Metab 2024; 36:1439-1455. [PMID: 38823393 DOI: 10.1016/j.cmet.2024.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 04/30/2024] [Accepted: 05/06/2024] [Indexed: 06/03/2024]
Abstract
Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression.
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Affiliation(s)
- Paul Horn
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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6
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Qian Q, Li M, Zhang Z, Davis SW, Rahmouni K, Norris AW, Cao H, Ding WX, Hotamisligil GS, Yang L. Obesity disrupts the pituitary-hepatic UPR communication leading to NAFLD progression. Cell Metab 2024; 36:1550-1565.e9. [PMID: 38718793 PMCID: PMC11222033 DOI: 10.1016/j.cmet.2024.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 03/05/2024] [Accepted: 04/17/2024] [Indexed: 07/05/2024]
Abstract
Obesity alters levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, dysregulation of which leads to nonalcoholic fatty liver disease (NAFLD). However, the impact of obesity on intra-pituitary homeostasis is largely unknown. Here, we uncovered a blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice and humans. Furthermore, we found that obesity inflames the pituitary gland, leading to impaired pituitary inositol-requiring enzyme 1α (IRE1α)-X-box-binding protein 1 (XBP1) UPR branch, which is essential for protecting against pituitary endocrine defects and NAFLD progression. Intriguingly, pituitary IRE1-deletion resulted in hypothyroidism and suppressed the thyroid hormone receptor B (THRB)-mediated activation of Xbp1 in the liver. Conversely, activation of the hepatic THRB-XBP1 axis improved NAFLD in mice with pituitary UPR defect. Our study provides the first evidence and mechanism of obesity-induced intra-pituitary cellular defects and the pathophysiological role of pituitary-liver UPR communication in NAFLD progression.
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Affiliation(s)
- Qingwen Qian
- 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 52242, USA
| | - Mark Li
- 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 52242, USA
| | - Zeyuan Zhang
- 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 52242, USA
| | - Shannon W Davis
- Department of Biological Sciences, College of Arts and Sciences, University of South Carolina, Columbia, SC 29208, USA
| | - Kamal Rahmouni
- Department of Neuroscience and Pharmacology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Andrew W Norris
- Division of Endocrinology and Diabetes, Department of Pediatrics, Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Huojun Cao
- Iowa Institute for Oral Health Research, Division of Biostatistics and Computational Biology, Department of Endodontics, University of Iowa College of Dentistry, Iowa City, IA 52242, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Gökhan S Hotamisligil
- Sabri Ülker Center for Metabolic Research, Department of Molecular Metabolism, Harvard T.H. School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02141, 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 52242, USA.
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7
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Hazari Y, Chevet E, Bailly-Maitre B, Hetz C. ER stress signaling at the interphase between MASH and HCC. Hepatology 2024:01515467-990000000-00844. [PMID: 38626349 DOI: 10.1097/hep.0000000000000893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 03/28/2024] [Indexed: 04/18/2024]
Abstract
HCC is the most frequent primary liver cancer with an extremely poor prognosis and often develops on preset of chronic liver diseases. Major risk factors for HCC include metabolic dysfunction-associated steatohepatitis, a complex multifactorial condition associated with abnormal endoplasmic reticulum (ER) proteostasis. To cope with ER stress, the unfolded protein response engages adaptive reactions to restore the secretory capacity of the cell. Recent advances revealed that ER stress signaling plays a critical role in HCC progression. Here, we propose that chronic ER stress is a common transversal factor contributing to the transition from liver disease (risk factor) to HCC. Interventional strategies to target the unfolded protein response in HCC, such as cancer therapy, are also discussed.
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Affiliation(s)
- Younis Hazari
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Department of Biotechnology, University of Kashmir, Srinagar, India
| | - Eric Chevet
- Inserm U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Béatrice Bailly-Maitre
- Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1065, Université Côte d'Azur (UCA), Centre Méditerranéen de Médecine Moléculaire (C3M), 06204 Nice, France Team "Metainflammation and Hematometabolism", Metabolism Department, France
- Université Côte d'Azur, INSERM, U1065, C3M, 06200 Nice, France
| | - Claudio Hetz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Faculty of Medicine, Biomedical Neuroscience Institute (BNI), University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- Buck Institute for Research on Aging, Novato, California, USA
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8
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Sinha S, Hassan N, Schwartz RE. Organelle stress and alterations in interorganelle crosstalk during liver fibrosis. Hepatology 2024; 79:482-501. [PMID: 36626634 DOI: 10.1097/hep.0000000000000012] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 10/03/2022] [Indexed: 01/12/2023]
Abstract
The synchronous functioning and quality control of organelles ensure cell survival and function and are essential for maintaining homeostasis. Prolonged exposure to stressors (viruses, bacteria, parasitic infections, alcohol, drugs) or genetic mutations often disrupt the functional integrity of organelles which plays a critical role in the initiation and progression of several diseases including chronic liver diseases. One of the most important pathologic consequences of chronic liver diseases is liver fibrosis, characterized by tissue scarring due to the progressive accumulation of extracellular matrix components. Left untreated, fibrosis may advance to life-threatening complications such as cirrhosis, hepatic decompensation, and HCC, which collectively accounts for ∼1 million deaths per year worldwide. Owing to the lack of treatment options that can regress or reverse cirrhosis, liver transplantation is currently the only available treatment for end-stage liver disease. However, the limited supply of usable donor organs, adverse effects of lifelong immunosuppressive regimes, and financial considerations pose major challenges and limit its application. Hence, effective therapeutic strategies are urgently needed. An improved understanding of the organelle-level regulation of fibrosis can help devise effective antifibrotic therapies focused on reducing organelle stress, limiting organelle damage, improving interorganelle crosstalk, and restoring organelle homeostasis; and could be a potential clinical option to avoid transplantation. This review provides a timely update on the recent findings and mechanisms covering organelle-specific dysfunctions in liver fibrosis, highlights how correction of organelle functions opens new treatment avenues and discusses the potential challenges to clinical application.
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Affiliation(s)
- Saloni Sinha
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, New York, USA
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Hanquier Z, Misra J, Baxter R, Maiers JL. Stress and Liver Fibrogenesis: Understanding the Role and Regulation of Stress Response Pathways in Hepatic Stellate Cells. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1363-1376. [PMID: 37422148 PMCID: PMC10548279 DOI: 10.1016/j.ajpath.2023.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/24/2023] [Accepted: 06/06/2023] [Indexed: 07/10/2023]
Abstract
Stress response pathways are crucial for cells to adapt to physiological and pathologic conditions. Increased transcription and translation in response to stimuli place a strain on the cell, necessitating increased amino acid supply, protein production and folding, and disposal of misfolded proteins. Stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), allow cells to adapt to stress and restore homeostasis; however, their role and regulation in pathologic conditions, such as hepatic fibrogenesis, are unclear. Liver injury promotes fibrogenesis through activation of hepatic stellate cells (HSCs), which produce and secrete fibrogenic proteins to promote tissue repair. This process is exacerbated in chronic liver disease, leading to fibrosis and, if unchecked, cirrhosis. Fibrogenic HSCs exhibit activation of both the UPR and ISR, due in part to increased transcriptional and translational demands, and these stress responses play important roles in fibrogenesis. Targeting these pathways to limit fibrogenesis or promote HSC apoptosis is a potential antifibrotic strategy, but it is limited by our lack of mechanistic understanding of how the UPR and ISR regulate HSC activation and fibrogenesis. This article explores the role of the UPR and ISR in the progression of fibrogenesis, and highlights areas that require further investigation to better understand how the UPR and ISR can be targeted to limit hepatic fibrosis progression.
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Affiliation(s)
- Zachary Hanquier
- Department of Molecular and Medical Genetics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jagannath Misra
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Reese Baxter
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jessica L Maiers
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
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10
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Sharma S, Le Guillou D, Chen JY. Cellular stress in the pathogenesis of nonalcoholic steatohepatitis and liver fibrosis. Nat Rev Gastroenterol Hepatol 2023; 20:662-678. [PMID: 37679454 DOI: 10.1038/s41575-023-00832-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2023] [Indexed: 09/09/2023]
Abstract
The burden of chronic liver disease is rising substantially worldwide. Fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the common pathway leading to cirrhosis, and limited treatment options are available. There is increasing evidence suggesting the role of cellular stress responses contributing to fibrogenesis. This Review provides an overview of studies that analyse the role of cellular stress in different cell types involved in fibrogenesis, including hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells and macrophages.
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Affiliation(s)
- Sachin Sharma
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- The Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Dounia Le Guillou
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- The Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Jennifer Y Chen
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
- The Liver Center, University of California, San Francisco, San Francisco, CA, USA.
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11
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Hendi Z, Asadi Sarabi P, Hay D, Vosough M. XBP1 as a novel molecular target to attenuate drug resistance in hepatocellular carcinoma. Expert Opin Ther Targets 2023; 27:1207-1215. [PMID: 38078890 DOI: 10.1080/14728222.2023.2293746] [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: 09/13/2023] [Accepted: 12/07/2023] [Indexed: 12/31/2023]
Abstract
INTRODUCTION Despite improvements in clinical management of hepatocellular carcinoma (HCC), prognosis remains poor with a 5-year survival rate less than 40%. Drug resistance in HCC makes it challenging to treat; therefore, it is imperative to develop new therapeutic strategies. Higher expression of X-box binding protein 1 (XBP1) in tumor cells is highly correlated with poor prognosis. In tumor cells, XBP1 modulates the unfolded protein response (UPR) to restore homeostasis in endoplasmic reticulum. Targeting XBP1 could be a promising therapeutic strategy to overcome HCC resistance and improve the survival rate of patients. AREAS COVERED This review provides the recent evidence that indicates XBP1 is involved in HCC drug resistance via DNA damage response, drug inactivation, and inhibition of apoptosis. In addition, the potential roles of XBP1 in inducing resistance in HCC cells were highlighted, and we showed how its inhibition could sensitize tumor cells to controlled cell death. EXPERT OPINION Due to the diversity in molecular mechanism of multidrug-resistance, targeting one specific pathway is inadequate. XBP1 inhibition could be a potential therapeutic target to overcome verity of resistance mechanisms. The main function of this transcription factor in HCC treatment response is an attractive area for further studies and should be discussed more.
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Affiliation(s)
- Zahra Hendi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Department of Animal Biology-Cell and Developmental, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Pedram Asadi Sarabi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - David Hay
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, Edinburgh, UK
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital-Huddinge, Huddinge, Sweden
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12
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Mann MW, Fu Y, Gearhart RL, Xu X, Roberts DS, Li Y, Zhou J, Ge Y, Brasier AR. Bromodomain-containing Protein 4 regulates innate inflammation via modulation of alternative splicing. Front Immunol 2023; 14:1212770. [PMID: 37435059 PMCID: PMC10331468 DOI: 10.3389/fimmu.2023.1212770] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 06/05/2023] [Indexed: 07/13/2023] Open
Abstract
Introduction Bromodomain-containing Protein 4 (BRD4) is a transcriptional regulator which coordinates gene expression programs controlling cancer biology, inflammation, and fibrosis. In the context of airway viral infection, BRD4-specific inhibitors (BRD4i) block the release of pro-inflammatory cytokines and prevent downstream epithelial plasticity. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not well understood. Given BRD4's interaction with the transcriptional elongation complex and spliceosome, we hypothesize that BRD4 is a functional regulator of mRNA processing. Methods To address this question, we combine data-independent analysis - parallel accumulation-serial fragmentation (diaPASEF) with RNA-sequencing to achieve deep and integrated coverage of the proteomic and transcriptomic landscapes of human small airway epithelial cells exposed to viral challenge and treated with BRD4i. Results We discover that BRD4 regulates alternative splicing of key genes, including Interferon-related Developmental Regulator 1 (IFRD1) and X-Box Binding Protein 1 (XBP1), related to the innate immune response and the unfolded protein response (UPR). We identify requirement of BRD4 for expression of serine-arginine splicing factors, splicosome components and the Inositol-Requiring Enzyme 1 IREα affecting immediate early innate response and the UPR. Discussion These findings extend the transcriptional elongation-facilitating actions of BRD4 in control of post-transcriptional RNA processing via modulating splicing factor expression in virus-induced innate signaling.
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Affiliation(s)
- Morgan W. Mann
- Department of Medicine, University of Wisconsin – Madison, Madison, WI, United States
| | - Yao Fu
- Department of Medicine, University of Wisconsin – Madison, Madison, WI, United States
| | - Robert L. Gearhart
- Department of Chemistry, University of Wisconsin – Madison, Madison, WI, United States
| | - Xiaofang Xu
- Department of Medicine, University of Wisconsin – Madison, Madison, WI, United States
| | - David S. Roberts
- Department of Chemistry, University of Wisconsin – Madison, Madison, WI, United States
| | - Yi Li
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States
| | - Jia Zhou
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States
| | - Ying Ge
- Department of Chemistry, University of Wisconsin – Madison, Madison, WI, United States
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, United States
- Human Proteomics Program, University of Wisconsin-Madison, Madison, WI, United States
| | - Allan R. Brasier
- Department of Medicine, University of Wisconsin – Madison, Madison, WI, United States
- Institute for Clinical and Translational Research, University of Wisconsin-Madison, Madison, WI, United States
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13
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Hazari Y, Urra H, Garcia Lopez VA, Diaz J, Tamburini G, Milani M, Pihan P, Durand S, Aprahamia F, Baxter R, Huang M, Dong XC, Vihinen H, Batista-Gonzalez A, Godoy P, Criollo A, Ratziu V, Foufelle F, Hengstler JG, Jokitalo E, Bailly-Maitre B, Maiers JL, Plate L, Kroemer G, Hetz C. The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.02.538835. [PMID: 37205565 PMCID: PMC10187203 DOI: 10.1101/2023.05.02.538835] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl 4 ) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states.
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14
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Wiering L, Subramanian P, Hammerich L. Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2023; 15:1277-1292. [PMID: 36828280 PMCID: PMC10148161 DOI: 10.1016/j.jcmgh.2023.02.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 02/15/2023] [Accepted: 02/15/2023] [Indexed: 02/26/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a fast growing, chronic liver disease affecting ∼25% of the global population. Nonalcoholic fatty liver disease severity ranges from the less severe simple hepatic steatosis to the more advanced nonalcoholic steatohepatitis (NASH). The presence of NASH predisposes individuals to liver fibrosis, which can further progress to cirrhosis and hepatocellular carcinoma. This makes hepatic fibrosis an important indicator of clinical outcomes in patients with NASH. Hepatic stellate cell activation dictates fibrosis development during NASH. Here, we discuss recent advances in the analysis of the profibrogenic pathways and mediators of hepatic stellate cell activation and inactivation, which ultimately determine the course of disease in nonalcoholic fatty liver disease/NASH.
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Affiliation(s)
- Leke Wiering
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany
| | - Pallavi Subramanian
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Linda Hammerich
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany.
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15
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Mann M, Fu Y, Xu X, Roberts DS, Li Y, Zhou J, Ge Y, Brasier AR. Bromodomain-containing Protein 4 Regulates Innate Inflammation in Airway Epithelial Cells via Modulation of Alternative Splicing. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.17.524257. [PMID: 36711789 PMCID: PMC9882210 DOI: 10.1101/2023.01.17.524257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Bromodomain-containing Protein 4 (BRD4) is a transcriptional regulator which coordinates gene expression programs controlling cancer biology, inflammation, and fibrosis. In airway viral infection, non-toxic BRD4-specific inhibitors (BRD4i) block the release of pro-inflammatory cytokines and prevent downstream remodeling. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not as well understood. Based on its interaction with the transcriptional elongation complex and spliceosome, we hypothesize that BRD4 is a functional regulator of mRNA processing. To address this question, we combine data-independent analysis - parallel accumulation-serial fragmentation (diaPASEF) with RNA-sequencing to achieve deep and integrated coverage of the proteomic and transcriptomic landscapes of human small airway epithelial cells exposed to viral challenge and treated with BRD4i. The transcript-level data was further interrogated for alternative splicing analysis, and the resulting data sets were correlated to identify pathways subject to post-transcriptional regulation. We discover that BRD4 regulates alternative splicing of key genes, including Interferon-related Developmental Regulator 1 ( IFRD1 ) and X-Box Binding Protein 1 ( XBP1 ), related to the innate immune response and the unfolded protein response, respectively. These findings extend the transcriptional elongation-facilitating actions of BRD4 in control of post-transcriptional RNA processing in innate signaling.
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Affiliation(s)
- Morgan Mann
- Department of Medicine, University of Wisconsin – Madison, Madison, 53705, Wisconsin, USA
| | - Yao Fu
- Department of Medicine, University of Wisconsin – Madison, Madison, 53705, Wisconsin, USA
| | - Xiaofang Xu
- Department of Medicine, University of Wisconsin – Madison, Madison, 53705, Wisconsin, USA
| | - David S. Roberts
- Department of Chemistry, University of Wisconsin – Madison, Madison, 53705, Wisconsin, USA
| | - Yi Li
- Department of Pharmacology and Toxicology, University of Texas, Medical Branch, Galveston, 77550, Texas, USA
| | - Jia Zhou
- Department of Pharmacology and Toxicology, University of Texas, Medical Branch, Galveston, 77550, Texas, USA
| | - Ying Ge
- Department of Chemistry, University of Wisconsin – Madison, Madison, 53705, Wisconsin, USA,Human Proteomics Program, University of Wisconsin – Madison, Madison, 53705, Wisconsin, USA,Department of Cell and Regenerative Biology, University of Wisconsin – Madison, Madison, 53705, Wisconsin, USA
| | - Allan R. Brasier
- Institute for Clinical and Translational Research (ICTR), University of Wisconsin – Madison, Madison, 53705, Wisconsin, USA
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16
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Bourebaba L, Serwotka-Suszczak A, Pielok A, Sikora M, Mularczyk M, Marycz K. The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses. Front Endocrinol (Lausanne) 2023; 14:1149610. [PMID: 37020593 PMCID: PMC10067883 DOI: 10.3389/fendo.2023.1149610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Accepted: 03/08/2023] [Indexed: 04/07/2023] Open
Abstract
BACKGROUND Equine metabolic syndrome (EMS) is a multifactorial pathology gathering insulin resistance, low-grade inflammation and past or chronic laminitis. Among the several molecular mechanisms underlying EMS pathogenesis, increased negative insulin signalling regulation mediated by protein tyrosine phosphatase 1 B (PTP1B) has emerged as a critical axis in the development of liver insulin resistance and general metabolic distress associated to increased ER stress, inflammation and disrupted autophagy. Thus, the use of PTP1B selective inhibitors such as MSI-1436 might be considered as a golden therapeutic tool for the proper management of EMS and associated conditions. Therefore, the present investigation aimed at verifying the clinical efficacy of MSI-1436 systemic administration on liver metabolic balance, insulin sensitivity and inflammatory status in EMS affected horses. Moreover, the impact of MSI-1436 treatment on liver autophagy machinery and associated ER stress in liver tissue has been analysed. METHODS Liver explants isolated from healthy and EMS horses have been treated with MSI-1436 prior to gene and protein expression analysis of main markers mediating ER stress, mitophagy and autophagy. Furthermore, EMS horses have been intravenously treated with a single dose of MSI-1436, and evaluated for their metabolic and inflammatory status. RESULTS Clinical application of MSI-1436 to EMS horses restored proper adiponectin levels and attenuated the typical hyperinsulinemia and hyperglycemia. Moreover, administration of MSI-1436 further reduced the circulating levels of key pro-inflammatory mediators including IL-1β, TNF-α and TGF-β and triggered the Tregs cells activation. At the molecular level, PTP1B inhibition resulted in a noticeable mitigation of liver ER stress, improvement of mitochondrial dynamics and consequently, a regulation of autophagic response. Similarly, short-term ex vivo treatment of EMS liver explants with trodusquemine (MSI-1436) substantially enhanced autophagy by upregulating the levels of HSC70 and Beclin-1 at both mRNA and protein level. Moreover, the PTP1B inhibitor potentiated mitophagy and associated expression of MFN2 and PINK1. Interestingly, inhibition of PTP1B resulted in potent attenuation of ER stress key mediators' expression namely, CHOP, ATF6, HSPA5 and XBP1. CONCLUSION Presented findings shed for the first time promising new insights in the development of an MSI-1436-based therapy for proper equine metabolic syndrome intervention and may additionally find potential translational application to human metabolic syndrome treatment.
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Affiliation(s)
- Lynda Bourebaba
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
- International Institute of Translational Medicine, Wisznia Mała, Poland
| | - Anna Serwotka-Suszczak
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
| | - Ariadna Pielok
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
| | - Mateusz Sikora
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
| | - Malwina Mularczyk
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
- International Institute of Translational Medicine, Wisznia Mała, Poland
| | - Krzysztof Marycz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Wrocław, Poland
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
- *Correspondence: Krzysztof Marycz,
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17
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A Survey of Naturally Occurring Molecules as New Endoplasmic Reticulum Stress Activators with Selective Anticancer Activity. Cancers (Basel) 2022; 15:cancers15010293. [PMID: 36612288 PMCID: PMC9818656 DOI: 10.3390/cancers15010293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/23/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
The last century has witnessed the establishment of neoplastic disease as the second cause of death in the world. Nonetheless, the road toward desirable success rates of cancer treatments is still long and paved with uncertainty. This work aims to select natural products that act via endoplasmic reticulum (ER) stress, a known vulnerability of malignant cells, and display selective toxicity against cancer cell lines. Among an in-house chemical library, nontoxic molecules towards noncancer cells were assessed for toxicity towards cancer cells, namely the human gastric adenocarcinoma cell line AGS and the lung adenocarcinoma cell line A549. Active molecules towards at least one of these cell lines were studied in a battery of ensuing assays to clarify the involvement of ER stress and unfolded protein response (UPR) in the cytotoxic effect. Several natural products are selectively cytotoxic against malignant cells, and the effect often relies on ER stress induction. Berberine was the most promising molecule, being active against both cell models by disrupting Ca2+ homeostasis, inducing UPR target gene expression and ER-resident caspase-4 activation. Our results indicate that berberine and emodin are potential leads for the development of more potent ER stressors to be used as selective anticancer agents.
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18
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Zhang J, Guo J, Yang N, Huang Y, Hu T, Rao C. Endoplasmic reticulum stress-mediated cell death in liver injury. Cell Death Dis 2022; 13:1051. [PMID: 36535923 PMCID: PMC9763476 DOI: 10.1038/s41419-022-05444-x] [Citation(s) in RCA: 151] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 11/13/2022] [Accepted: 11/15/2022] [Indexed: 12/23/2022]
Abstract
The endoplasmic reticulum is an important intracellular organelle that plays an important role in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are induced when the body is exposed to adverse external stimuli. It has been established that ERS can induce different cell death modes, including autophagy, apoptosis, ferroptosis, and pyroptosis, through three major transmembrane receptors on the ER membrane, including inositol requirement enzyme 1α, protein kinase-like endoplasmic reticulum kinase and activating transcription factor 6. These different modes of cell death play an important role in the occurrence and development of various diseases, such as neurodegenerative diseases, inflammation, metabolic diseases, and liver injury. As the largest metabolic organ, the liver is rich in enzymes, carries out different functions such as metabolism and secretion, and is the body's main site of protein synthesis. Accordingly, a well-developed endoplasmic reticulum system is present in hepatocytes to help the liver perform its physiological functions. Current evidence suggests that ERS is closely related to different stages of liver injury, and the death of hepatocytes caused by ERS may be key in liver injury. In addition, an increasing body of evidence suggests that modulating ERS has great potential for treating the liver injury. This article provided a comprehensive overview of the relationship between ERS and four types of cell death. Moreover, we discussed the mechanism of ERS and UPR in different liver injuries and their potential therapeutic strategies.
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Affiliation(s)
- Jian Zhang
- grid.411304.30000 0001 0376 205XSchool of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China ,grid.411304.30000 0001 0376 205XR&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China
| | - Jiafu Guo
- grid.411304.30000 0001 0376 205XSchool of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China ,grid.411304.30000 0001 0376 205XR&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China
| | - Nannan Yang
- grid.411304.30000 0001 0376 205XSchool of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China ,grid.411304.30000 0001 0376 205XR&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China
| | - Yan Huang
- grid.411304.30000 0001 0376 205XSchool of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China ,grid.411304.30000 0001 0376 205XR&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China
| | - Tingting Hu
- grid.411304.30000 0001 0376 205XSchool of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China ,grid.411304.30000 0001 0376 205XR&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China
| | - Chaolong Rao
- grid.411304.30000 0001 0376 205XSchool of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China ,grid.411304.30000 0001 0376 205XR&D Center for Efficiency, Safety and Application in Chinese Materia Medica with Medical and Edible Values, School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China ,grid.411304.30000 0001 0376 205XState Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137 China
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19
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Pavlović N, Heindryckx F. Targeting ER stress in the hepatic tumor microenvironment. FEBS J 2022; 289:7163-7176. [PMID: 34331743 DOI: 10.1111/febs.16145] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/13/2021] [Accepted: 07/30/2021] [Indexed: 01/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. It currently ranks as one of the most aggressive and deadly cancers worldwide, with an increasing mortality rate and limited treatment options. An important hallmark of liver pathologies, such as liver fibrosis and HCC, is the accumulation of misfolded and unfolded proteins in the lumen of the endoplasmic reticulum (ER), which induces ER stress and leads to the activation of the unfolded protein response (UPR). Upon accumulation of misfolded proteins, ER stress is sensed through three transmembrane proteins, IRE1α, PERK, and ATF6, which trigger the UPR to either alleviate ER stress or induce apoptosis. Increased expression of ER stress markers has been widely shown to correlate with fibrosis, inflammation, drug resistance, and overall HCC aggressiveness, as well as poor patient prognosis. While preclinical in vivo cancer models and in vitro approaches have shown promising results by pharmacologically targeting ER stress mediators, the major challenge of this therapeutic strategy lies in specifically and effectively targeting ER stress in HCC. Furthermore, both ER stress inducers and inhibitors have been shown to ameliorate HCC progression, adding to the complexity of targeting ER stress players as an anticancer strategy. More studies are needed to better understand the dual role and molecular background of ER stress in HCC, as well as its therapeutic potential for patients with liver cancer.
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Affiliation(s)
- Nataša Pavlović
- Department of Medical Cell Biology, Uppsala University, Sweden
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20
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Liu X, Taylor SA, Celaj S, Levitsky J, Green RM. Expression of unfolded protein response genes in post-transplantation liver biopsies. BMC Gastroenterol 2022; 22:380. [PMID: 35948878 PMCID: PMC9364610 DOI: 10.1186/s12876-022-02459-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/30/2022] [Indexed: 11/29/2022] Open
Abstract
Background Cholestatic liver diseases are a major source of morbidity and mortality that can progress to end-stage liver disease and hyperbilirubinemia is a hallmark of cholestasis. There are few effective medical therapies for primary biliary cholangitis, primary sclerosing cholangitis and other cholestatic liver diseases, in part, due to our incomplete understanding of the pathogenesis of cholestatic liver injury. The hepatic unfolded protein response (UPR) is an adaptive cellular response to endoplasmic reticulum stress that is important in the pathogenesis of many liver diseases and recent animal studies have demonstrated the importance of the UPR in the pathogenesis of cholestatic liver injury. However, the role of the UPR in human cholestatic liver diseases is largely unknown. Methods RNA was extracted from liver biopsies from patients after liver transplantation. RNA-seq was performed to determine the transcriptional profile and hepatic UPR gene expression that is associated with liver injury and cholestasis. Results Transcriptome analysis revealed that patients with hyperbilirubinemia had enhanced expression of hepatic UPR pathways. Alternatively, liver biopsy samples from patients with acute rejection had enhanced gene expression of LAG3 and CDK1. Pearson correlation analysis of serum alanine aminotransferase, aspartate aminotransferase and total bilirubin levels demonstrated significant correlations with the hepatic expression of several UPR genes, as well as genes involved in hepatic bile acid metabolism and inflammation. In contrast, serum alkaline phosphatase levels were correlated with the level of hepatic bile acid metabolism gene expression but not liver UPR gene expression. Conclusions Overall, these data indicate that hepatic UPR pathways are increased in cholestatic human liver biopsy samples and supports an important role of the UPR in the mechanism of human cholestatic liver injury.
Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02459-8.
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Affiliation(s)
- Xiaoying Liu
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
| | - Sarah A Taylor
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Stela Celaj
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Richard M Green
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
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21
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Zhou L, Shen H, Li X, Wang H. Endoplasmic reticulum stress in innate immune cells - a significant contribution to non-alcoholic fatty liver disease. Front Immunol 2022; 13:951406. [PMID: 35958574 PMCID: PMC9361020 DOI: 10.3389/fimmu.2022.951406] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 06/28/2022] [Indexed: 12/12/2022] Open
Abstract
Liver disease and its complications affect millions of people worldwide. NAFLD (non-alcoholic fatty liver disease) is the liver disease associated with metabolic dysfunction and consists of four stages: steatosis with or without mild inflammation (NAFLD), non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. With increased necroinflammation and progression of liver fibrosis, NAFLD may progress to cirrhosis or even hepatocellular carcinoma. Although the underlying mechanisms have not been clearly elucidated in detail, what is clear is that complex immune responses are involved in the pathogenesis of NASH, activation of the innate immune system is critically involved in triggering and amplifying hepatic inflammation and fibrosis in NAFLD/NASH. Additionally, disruption of endoplasmic reticulum (ER) homeostasis in cells, also known as ER stress, triggers the unfolded protein response (UPR) which has been shown to be involved to inflammation and apoptosis. To further develop the prevention and treatment of NAFLD/NASH, it is imperative to clarify the relationship between NAFLD/NASH and innate immune cells and ER stress. As such, this review focuses on innate immune cells and their ER stress in the occurrence of NAFLD and the progression of cirrhosis.
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Affiliation(s)
- Liangliang Zhou
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Haiyuan Shen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xiaofeng Li
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- *Correspondence: Hua Wang,
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22
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Nascè A, Gariani K, Jornayvaz FR, Szanto I. NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook. Antioxidants (Basel) 2022; 11:antiox11061131. [PMID: 35740032 PMCID: PMC9219746 DOI: 10.3390/antiox11061131] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 12/15/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and is the most frequent complication of type 2 diabetes mellitus (T2DM). One of the features connecting NAFLD, insulin resistance and T2DM is cellular oxidative stress. Oxidative stress refers to a redox imbalance due to an inequity between the capacity of production and the elimination of reactive oxygen species (ROS). One of the major cellular ROS sources is NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce ROS purposefully in a timely and spatially regulated manner and are crucial regulators of various cellular events linked to metabolism, receptor signal transmission, proliferation and apoptosis. In contrast, dysregulated NOX-derived ROS production is related to the onset of diverse pathologies. This review provides a synopsis of current knowledge concerning NOX enzymes as connective elements between NAFLD, insulin resistance and T2DM and weighs their potential relevance as pharmacological targets to alleviate fatty liver disease.
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Affiliation(s)
- Alberto Nascè
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
| | - Karim Gariani
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
| | - François R. Jornayvaz
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
| | - Ildiko Szanto
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland; (A.N.); (K.G.)
- Department of Medicine, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland
- Correspondence: (F.R.J.); (I.S.)
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23
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Flessa C, Kyrou I, Nasiri‐Ansari N, Kaltsas G, Kassi E, Randeva HS. Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD). J Cell Biochem 2022; 123:1585-1606. [PMID: 35490371 DOI: 10.1002/jcb.30247] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/09/2022] [Accepted: 03/28/2022] [Indexed: 02/06/2023]
Affiliation(s)
- Christina‐Maria Flessa
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
- Centre for Sport, Exercise and Life Sciences, Research Institute for Health & Wellbeing Coventry University Coventry UK
- Aston Medical School, College of Health and Life Sciences Aston University Birmingham UK
- Department of Food Science & Human Nutrition Agricultural University of Athens Athens Greece
| | - Narjes Nasiri‐Ansari
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School National and Kapodistrian University of Athens Athens Greece
- Endocrine Unit, 1st Department of Propaedeutic and Internal Medicine, Laiko Hospital National and Kapodistrian University of Athens Athens Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM) University Hospitals Coventry and Warwickshire NHS Trust Coventry UK
- Division of Translational and Experimental Medicine, Metabolic and Vascular Health, Warwick Medical School University of Warwick Coventry UK
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24
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Komatsu S, Fan L, Idell S, Shetty S, Ikebe M. Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts. Int J Mol Sci 2022; 23:ijms23063316. [PMID: 35328736 PMCID: PMC8950460 DOI: 10.3390/ijms23063316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/10/2022] [Accepted: 03/15/2022] [Indexed: 12/04/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by an excess deposition of extracellular matrix in the pulmonary interstitium. Caveolin-1 scaffolding domain peptide (CSP) has been found to mitigate pulmonary fibrosis in several animal models. However, its pathophysiological role in IPF is obscure, and it remains critical to understand the mechanism by which CSP protects against pulmonary fibrosis. We first studied the delivery of CSP into cells and found that it is internalized and accumulated in the Endoplasmic Reticulum (ER). Furthermore, CSP reduced ER stress via suppression of inositol requiring enzyme1α (IRE1α) in transforming growth factor β (TGFβ)-treated human IPF lung fibroblasts (hIPF-Lfs). Moreover, we found that CSP enhanced the gelatinolytic activity of TGFβ-treated hIPF-Lfs. The IRE1α inhibitor; 4µ8C also augmented the gelatinolytic activity of TGFβ-treated hIPF-Lfs, supporting the concept that CSP induced inhibition of the IRE1α pathway. Furthermore, CSP significantly elevated expression of MMPs in TGFβ-treated hIPF-Lfs, but conversely decreased the secretion of collagen 1. Similar results were observed in two preclinical murine models of PF, bleomycin (BLM)- and adenovirus expressing constitutively active TGFβ (Ad-TGFβ)-induced PF. Our findings provide new insights into the mechanism by which lung fibroblasts contribute to CSP dependent protection against lung fibrosis.
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25
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Alshawsh MA, Alsalahi A, Alshehade SA, Saghir SAM, Ahmeda AF, Al Zarzour RH, Mahmoud AM. A Comparison of the Gene Expression Profiles of Non-Alcoholic Fatty Liver Disease between Animal Models of a High-Fat Diet and Methionine-Choline-Deficient Diet. Molecules 2022; 27:858. [PMID: 35164140 PMCID: PMC8839835 DOI: 10.3390/molecules27030858] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) embraces several forms of liver disorders involving fat disposition in hepatocytes ranging from simple steatosis to the severe stage, namely, non-alcoholic steatohepatitis (NASH). Recently, several experimental in vivo animal models for NAFLD/NASH have been established. However, no reproducible experimental animal model displays the full spectrum of pathophysiological, histological, molecular, and clinical features associated with human NAFLD/NASH progression. Although methionine-choline-deficient (MCD) diet and high-fat diet (HFD) models can mimic histological and metabolic abnormalities of human disease, respectively, the molecular signaling pathways are extremely important for understanding the pathogenesis of the disease. This review aimed to assess the differences in gene expression patterns and NAFLD/NASH progression pathways among the most common dietary animal models, i.e., HFD- and MCD diet-fed animals. Studies showed that the HFD and MCD diet could induce either up- or downregulation of the expression of genes and proteins that are involved in lipid metabolism, inflammation, oxidative stress, and fibrogenesis pathways. Interestingly, the MCD diet model could spontaneously develop liver fibrosis within two to four weeks and has significant effects on the expression of genes that encode proteins and enzymes involved in the liver fibrogenesis pathway. However, such effects in the HFD model were found to occur after 24 weeks with insulin resistance but appear to cause less severe fibrosis. In conclusion, assessing the abnormal gene expression patterns caused by different diet types provides valuable information regarding the molecular mechanisms of NAFLD/NASH and predicts the clinical progression of the disease. However, expression profiling studies concerning genetic variants involved in the development and progression of NAFLD/NASH should be conducted.
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Affiliation(s)
| | - Abdulsamad Alsalahi
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia;
| | - Salah Abdalrazak Alshehade
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia (USM), Gelugor 11800, Malaysia; (S.A.A.); (R.H.A.Z.)
| | - Sultan Ayesh Mohammed Saghir
- Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Medical Sciences, Al-Hussein Bin Talal University, Ma’an 71111, Jordan;
| | - Ahmad Faheem Ahmeda
- Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates;
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman P.O. Box 346, United Arab Emirates
| | - Raghdaa Hamdan Al Zarzour
- Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia (USM), Gelugor 11800, Malaysia; (S.A.A.); (R.H.A.Z.)
| | - Ayman Moawad Mahmoud
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt;
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26
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Solhi R, Lotfi AS, Lotfinia M, Farzaneh Z, Piryaei A, Najimi M, Vosough M. Hepatic stellate cell activation by TGFβ induces hedgehog signaling and endoplasmic reticulum stress simultaneously. Toxicol In Vitro 2022; 80:105315. [PMID: 35051607 DOI: 10.1016/j.tiv.2022.105315] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/07/2022] [Accepted: 01/11/2022] [Indexed: 12/11/2022]
Abstract
Activation of hepatic stellates (HSCs) is known as the major cause of initiation and progression of liver fibrosis. A wide array of events occurs during HSC activation including induction of hedgehog (Hh) signaling and endoplasmic reticulum (ER) stress. Targeting HSC activation may provide promising insights into liver fibrosis treatment. In this regard, establishing in vitro models which can mimic the molecular pathways of interest is very important. We aimed to activate HSC in which Hh signaling and ER stress are stimulated simultaneously. We used 5 ng/ml TGFβ to activate LX-2 cells, HSC cell line. Gene expression analysis using qRT-PCR, immunostaining and immunoblotting were performed to show HSC activation associated markers. Furthermore, the migration capacity of the TGFβ treated cells is evaluated. The results demonstrated that major fibrogenic markers including collagen1a, lysyl oxidase, and tissue inhibitor of matrix metalloproteinase 1 genes are up-regulated significantly. In addition, our immunofluorescence and immunoblotting results showed that protein levels of GLI-2 and XBP1, were enhanced. Moreover, we found that TGFβ treatment reduced the migration of LX-2 cells. Our results are compatible with high throughput data analysis with respect to differentially expressed genes of activated HSC compared to the quiescent ones. Moreover, our findings suggest that quercetin can reduce fibrogenic markers of activated HSCs as well as osteopontin expression, a target gene of hedgehog signaling.
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Affiliation(s)
- Roya Solhi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Abbas Sahebghadam Lotfi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Majid Lotfinia
- Physiology Research Center, Basic Sciences Research Institute, Kashan University of Medical Sciences, Kashan, Iran; Core Research Lab, Kashan University of Medical Sciences, Kashan, Iran
| | - Zahra Farzaneh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran
| | - Abbas Piryaei
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Massoud Vosough
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 1665659911, Iran; Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran.
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27
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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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28
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Baghaei K, Mazhari S, Tokhanbigli S, Parsamanesh G, Alavifard H, Schaafsma D, Ghavami S. Therapeutic potential of targeting regulatory mechanisms of hepatic stellate cell activation in liver fibrosis. Drug Discov Today 2021; 27:1044-1061. [PMID: 34952225 DOI: 10.1016/j.drudis.2021.12.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 11/11/2021] [Accepted: 12/17/2021] [Indexed: 11/03/2022]
Abstract
Hepatic fibrosis is a manifestation of different etiologies of liver disease with the involvement of multiple mediators in complex network interactions. Activated hepatic stellate cells (aHSCs) are the central driver of hepatic fibrosis, given their potential to induce connective tissue formation and extracellular matrix (ECM) protein accumulation. Therefore, identifying the cellular and molecular pathways involved in the activation of HSCs is crucial in gaining mechanistic and therapeutic perspectives to more effectively target the disease. In addition to a comprehensive summary of our current understanding of the role of HSCs in liver fibrosis, we also discuss here the proposed therapeutic strategies based on targeting HSCs.
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Affiliation(s)
- Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Sogol Mazhari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Samaneh Tokhanbigli
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Gilda Parsamanesh
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran 1985717413, Iran
| | | | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
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29
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Fan C, Ma Y, Chen S, Zhou Q, Jiang H, Zhang J, Wu F. Comprehensive Analysis of the Transcriptome-Wide m6A Methylation Modification Difference in Liver Fibrosis Mice by High-Throughput m6A Sequencing. Front Cell Dev Biol 2021; 9:767051. [PMID: 34869362 PMCID: PMC8635166 DOI: 10.3389/fcell.2021.767051] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/01/2021] [Indexed: 01/01/2023] Open
Abstract
N6-Methyladenosine (m6A), a unique and common mRNA modification method in eukaryotes, is involved in the occurrence and development of many diseases. Liver fibrosis (LF) is a common response to chronic liver injury and may lead to cirrhosis and even liver cancer. However, the involvement of m6A methylation in the development of LF is still unknown. In this study, we performed a systematic evaluation of hepatic genome-wide m6A modification and mRNA expression by m6A-seq and RNA-seq using LF mice. There were 3,315 genes with significant differential m6A levels, of which 2,498 were hypermethylated and 817 hypomethylated. GO and KEGG analyses illustrated that differentially expressed m6A genes were closely correlated with processes such as the endoplasmic reticulum stress response, PPAR signaling pathway and TGF-β signaling pathway. Moreover, a total of 90 genes had both a significant change in the m6A level and mRNA expression shown by joint analysis of m6A-seq and RNA-seq. Hence, the critical elements of m6A modification, including methyltransferase WTAP, demethylases ALKBH5 and binding proteins YTHDF1 were confirmed by RT-qPCR and Western blot. In an additional cell experiment, we also observed that the decreased expression of WTAP induced the development of LF as a result of promoting hepatic stellate cell (HSC) activation. Therefore, this study revealed unique differential m6A methylation patterns in LF mice and suggested that m6A methylation was associated with the occurrence and course of LF to some extent.
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Affiliation(s)
- Chang Fan
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Yanzhen Ma
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Sen Chen
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China
| | - Qiumei Zhou
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Hui Jiang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.,School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.,Key Laboratory of Xin'an Medicine of the Ministry of Education, Anhui University of Chinese Medicine, Hefei, China
| | - Jiafu Zhang
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Furong Wu
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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30
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Carlisle RE, Mohammed-Ali Z, Lu C, Yousof T, Tat V, Nademi S, MacDonald ME, Austin RC, Dickhout JG. TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease. Cell Death Dis 2021; 12:921. [PMID: 34625532 PMCID: PMC8501078 DOI: 10.1038/s41419-021-04197-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 08/17/2021] [Accepted: 09/08/2021] [Indexed: 12/28/2022]
Abstract
Chronic kidney disease (CKD) is characterized by the gradual loss of renal function and is a major public health concern. Risk factors for CKD include hypertension and proteinuria, both of which are associated with endoplasmic reticulum (ER) stress. ER stress-induced TDAG51 protein expression is increased at an early time point in mice with CKD. Based on these findings, wild-type and TDAG51 knock-out (TDKO) mice were used in an angiotensin II/deoxycorticosterone acetate/salt model of CKD. Both wild-type and TDKO mice developed hypertension, increased proteinuria and albuminuria, glomerular injury, and tubular damage. However, TDKO mice were protected from apoptosis and renal interstitial fibrosis. Human proximal tubular cells were used to demonstrate that TDAG51 expression induces apoptosis through a CHOP-dependent mechanism. Further, a mouse model of intrinsic acute kidney injury demonstrated that CHOP is required for ER stress-mediated apoptosis. Renal fibroblasts were used to demonstrate that TGF-β induces collagen production through an IRE1-dependent mechanism; cells treated with a TGF-β receptor 1 inhibitor prevented XBP1 splicing, a downstream consequence of IRE1 activation. Interestingly, TDKO mice express significantly less TGF-β receptor 1, thus, preventing TGF-β-mediated XBP1 splicing. In conclusion, TDAG51 induces apoptosis in the kidney through a CHOP-dependent mechanism, while contributing to renal interstitial fibrosis through a TGF-β-IRE1-XBP1 pathway.
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Affiliation(s)
- Rachel E Carlisle
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Zahraa Mohammed-Ali
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Chao Lu
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Tamana Yousof
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Victor Tat
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Samera Nademi
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Melissa E MacDonald
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Richard C Austin
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada
| | - Jeffrey G Dickhout
- McMaster University and The Research Institute of St. Joe's Hamilton, Department of Medicine, Division of Nephrology, Hamilton, Canada.
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31
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Zhang Z, Qian Q, Li M, Shao F, Ding WX, Lira VA, Chen SX, Sebag SC, Hotamisligil GS, Cao H, Yang L. The unfolded protein response regulates hepatic autophagy by sXBP1-mediated activation of TFEB. Autophagy 2021; 17:1841-1855. [PMID: 32597296 PMCID: PMC8386593 DOI: 10.1080/15548627.2020.1788889] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Defective macroautophagy/autophagy and a failure to initiate the adaptive unfolded protein response (UPR) in response to the endoplasmic reticulum (ER) stress contributes to obesity-associated metabolic dysfunction. However, whether and how unresolved ER stress leads to defects in the autophagy pathway and to the progression of obesity-associated hepatic pathologies remains unclear. Obesity suppresses the expression of hepatic spliced XBP1 (X-box binding protein 1; sXBP1), the key transcription factor that promotes the adaptive UPR. Our RNA-seq analysis revealed that sXBP1 regulates genes involved in lysosomal function in the liver under fasting conditions. Chromatin immunoprecipitation (ChIP) analyzes of both primary hepatocytes and whole livers further showed that sXBP1 occupies the -743 to -523 site of the promoter of Tfeb (transcription factor EB), a master regulator of autophagy and lysosome biogenesis. Notably, this occupancy was significantly reduced in livers from patients with steatosis. In mice, hepatic deletion of Xbp1 (xbp1 LKO) suppressed the transcription of Tfeb as well as autophagy, whereas hepatic overexpression of sXbp1 enhanced Tfeb transcription and autophagy. Moreover, overexpression of Tfeb in the xbp1 LKO mouse liver ameliorated glucose intolerance and steatosis in mice with diet-induced obesity (DIO). Conversely, loss of TFEB function impaired the protective role of sXBP1 in hepatic steatosis in mice with DIO. These data indicate that sXBP1-Tfeb signaling has direct functional consequences in the context of obesity. Collectively, our data provide novel insight into how two organelle stress responses are integrated to protect against obesity-associated metabolic dysfunction.Abbreviations: AAV8: adeno-associated virus serotype 8; ACTB: actin, beta; ANOVA: analysis of variance; ATF6: activating transcription factor-6; ATG: autophagy related; BECN1: beclin 1; BMI: body mass index; ChIP: chromatin immunoprecipitation; CLEAR: coordinated lysosomal expression and regulation; Cre: cre recombinase; DIO: diet-induced obesity; EBSS: Earle's balanced salt solution; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum (ER) to nucleus signaling 1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HFD: high-fat diet; h: hours; HSCs: hepatic stellate cells; INS: insulin; L/A: ammonium chloride and leupeptin; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mRNA: messenger RNA; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; RD: regular diet; RFP: red fluorescent protein; SERPINA7/TBG: serpin family A member 7; SQSTM1/p62: sequestome 1; sXbp1 LOE: liver-specific overexpression of spliced Xbp1; TFEB: transcription factor EB; TG: thapsigargin; TN: tunicamycin; UPR: unfolded protein response; wks: weeks; WT: wild type; XBP1: X-box binding protein 1; xbp1 LKO: liver-specific Xbp1 knockout.
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Affiliation(s)
- Zeyuan Zhang
- 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
| | - Qingwen Qian
- 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
| | - Mark Li
- 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
| | - Fan Shao
- Iowa Institute for Oral Health Research, Division of Biostatistics and Computational Biology, Department of Endodontics, University of Iowa College of Dentistry, Iowa City, IA, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS, USA
| | - Vitor A. Lira
- Department of Health and Human Physiology, Fraternal Order of Eagles Diabetes Research Center, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA, USA
| | - Sophia X. Chen
- 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
| | - Sara C. Sebag
- 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
| | - Gökhan S. Hotamisligil
- Sabri Ülker Center for Metabolic Research and Dept. Molecular Metabolism, Harvard TH Chan School of Public Health, Broad Institute of Harvard-MIT, Boston, MA, USA
| | - Huojun Cao
- Iowa Institute for Oral Health Research, Division of Biostatistics and Computational Biology, Department of Endodontics, University of Iowa College of Dentistry, Iowa City, IA, USA,CONTACT 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; Huojun Cao Iowa Institute for Oral Health Research, Division of Biostatistics and Computational Biology, Department of Endodontics, University of Iowa College of Dentistry, Iowa City, IA, 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,CONTACT 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; Huojun Cao Iowa Institute for Oral Health Research, Division of Biostatistics and Computational Biology, Department of Endodontics, University of Iowa College of Dentistry, Iowa City, IA, USA
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Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis. Cells 2021; 10:cells10071764. [PMID: 34359934 PMCID: PMC8305108 DOI: 10.3390/cells10071764] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 12/18/2022] Open
Abstract
Liver fibrosis is a potentially reversible pathophysiological event, leading to excess deposition of extracellular matrix (ECM) components and taking place as the net result of liver fibrogenesis, a dynamic and highly integrated process occurring during chronic liver injury of any etiology. Liver fibrogenesis and fibrosis, together with chronic inflammatory response, are primarily involved in the progression of chronic liver diseases (CLD). As is well known, a major role in fibrogenesis and fibrosis is played by activated myofibroblasts (MFs), as well as by macrophages and other hepatic cell populations involved in CLD progression. In the present review, we will focus the attention on the emerging pathogenic role of hypoxia, hypoxia-inducible factors (HIFs) and related mediators in the fibrogenic progression of CLD.
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Sharma P, Alizadeh J, Juarez M, Samali A, Halayko AJ, Kenyon NJ, Ghavami S, Zeki AA. Autophagy, Apoptosis, the Unfolded Protein Response, and Lung Function in Idiopathic Pulmonary Fibrosis. Cells 2021; 10:1642. [PMID: 34209019 PMCID: PMC8307368 DOI: 10.3390/cells10071642] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 01/18/2023] Open
Abstract
Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject's lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar-capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF.
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Affiliation(s)
- Pawan Sharma
- Center for Translational Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA;
| | - Javad Alizadeh
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada;
| | - Maya Juarez
- Davis Lung Center, School of Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Davis, CA 95616, USA; (M.J.); (N.J.K.)
| | - Afshin Samali
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland;
| | - Andrew J. Halayko
- Department of Physiology and Pathophysiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada;
| | - Nicholas J. Kenyon
- Davis Lung Center, School of Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Davis, CA 95616, USA; (M.J.); (N.J.K.)
- Veterans Affairs Medical Center, Mather, CA 95655, USA
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada;
- Research Institute of Hematology and Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
- Faculty of Medicine, Katowice School of Technology, 40-555 Katowice, Poland
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran
| | - Amir A. Zeki
- Davis Lung Center, School of Medicine; Division of Pulmonary, Critical Care, and Sleep Medicine, University of California, Davis, CA 95616, USA; (M.J.); (N.J.K.)
- Veterans Affairs Medical Center, Mather, CA 95655, USA
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Zhao J, Hu Y, Peng J. Targeting programmed cell death in metabolic dysfunction-associated fatty liver disease (MAFLD): a promising new therapy. Cell Mol Biol Lett 2021; 26:17. [PMID: 33962586 PMCID: PMC8103580 DOI: 10.1186/s11658-021-00254-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
Most currently recommended therapies for metabolic dysfunction-associated fatty liver disease (MAFLD) involve diet control and exercise therapy. We searched PubMed and compiled the most recent research into possible forms of programmed cell death in MAFLD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis. Here, we summarize the state of knowledge on the signaling mechanisms for each type and, based on their characteristics, discuss how they might be relevant in MAFLD-related pathological mechanisms. Although significant challenges exist in the translation of fundamental science into clinical therapy, this review should provide a theoretical basis for innovative MAFLD clinical treatment plans that target programmed cell death.
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Affiliation(s)
- Jianan Zhao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China
| | - Yiyang Hu
- Institute of Clinical Pharmacology, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China.
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong District, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528, Zhangheng Road, Shanghai, China.
| | - Jinghua Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528, Zhangheng Road, Shanghai, China.
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong District, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528, Zhangheng Road, Shanghai, China.
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Xue F, Lu J, Buchl SC, Sun L, Shah VH, Malhi H, Maiers JL. Coordinated signaling of activating transcription factor 6α and inositol-requiring enzyme 1α regulates hepatic stellate cell-mediated fibrogenesis in mice. Am J Physiol Gastrointest Liver Physiol 2021; 320:G864-G879. [PMID: 33728997 PMCID: PMC8202196 DOI: 10.1152/ajpgi.00453.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver injury and the unfolded protein response (UPR) are tightly linked, but their relationship differs with cell type and injurious stimuli. UPR initiation promotes hepatic stellate cell (HSC) activation and fibrogenesis, but the underlying mechanisms are unclear. Despite the complexity and overlap downstream of UPR transducers inositol-requiring protein 1α (IRE1α), activating transcription factor 6α (ATF6α), and protein kinase RNA-like ER kinase (PERK), previous research in HSCs primarily focused on IRE1α. Here, we investigated the fibrogenic role of ATF6α or PERK in vitro and HSC-specific UPR signaling in vivo. Overexpression of ATF6α, but not the PERK effector activating transcription factor 4 (ATF4), promoted HSC activation and fibrogenic gene transcription in immortalized HSCs. Furthermore, ATF6α inhibition through Ceapin-A7, or Atf6a deletion, disrupted transforming growth factor β (TGFβ)-mediated activation of primary human hepatic stellate cells (hHSCs) or murine hepatic stellate cells (mHSCs), respectively. We investigated the fibrogenic role of ATF6α in vivo through conditional HSC-specific Atf6a deletion. Atf6aHSCΔ/Δ mice displayed reduced fibrosis and HSC activation following bile duct ligation (BDL) or carbon tetrachloride (CCl4)-induced injury. The Atf6aHSCΔ/Δ phenotype differed from HSC-specific Ire1a deletion, as Ire1aHSCΔ/Δ mice showed reduced fibrogenic gene transcription but no changes in fibrosis compared with Ire1afl/fl mice following BDL. Interestingly, ATF6α signaling increased in Ire1aΔ/Δ HSCs, whereas IRE1α signaling was upregulated in Atf6aΔ/Δ HSCs. Finally, we asked whether co-deletion of Atf6a and Ire1a additively limits fibrosis. Unexpectedly, fibrosis worsened in Atf6aHSCΔ/ΔIre1aHSCΔ/Δ mice following BDL, and Atf6aΔ/ΔIre1aΔ/Δ mHSCs showed increased fibrogenic gene transcription. ATF6α and IRE1α individually promote fibrogenic transcription in HSCs, and ATF6α drives fibrogenesis in vivo. Unexpectedly, disruption of both pathways sensitizes the liver to fibrogenesis, suggesting that fine-tuned UPR signaling is critical for regulating HSC activation and fibrogenesis.NEW & NOTEWORTHY ATF6α is a critical driver of hepatic stellate cell (HSC) activation in vitro. HSC-specific deletion of Atf6a limits fibrogenesis in vivo despite increased IRE1α signaling. Conditional deletion of Ire1α from HSCs limits fibrogenic gene transcription without impacting overall fibrosis. This could be due in part to observed upregulation of the ATF6α pathway. Dual loss of Atf6a and Ire1a from HSCs worsens fibrosis in vivo through enhanced HSC activation.
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Affiliation(s)
- Fei Xue
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Jianwen Lu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Samuel C. Buchl
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Liankang Sun
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Jessica L. Maiers
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Zhang X, Zhang F, Zhang C, Li J. miRNA-125b Signaling Ameliorates Liver Injury Against Obstructive Jaundice-Induced Excessive Fibrosis in Experimental Rats. Yonsei Med J 2021; 62:453-460. [PMID: 33908217 PMCID: PMC8084692 DOI: 10.3349/ymj.2021.62.5.453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/12/2020] [Accepted: 04/19/2020] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Multiple pathways are involved in inducing liver fibrosis, which can damage the integrity of liver. Among them, miR-125b has been found to exert an activating action on hepatic stellate cells. Endoplasmic reticulum stress and autophagy lead to liver disorders. Here, we evaluated the therapeutic influence of miR-125b on the endoplasmic reticulum function in injured livers submitted to bile duct ligation. MATERIALS AND METHODS For inducing injury, bile duct ligation was done on miR-125b transgenic rats (miR-125b-Tg) in wild type rats. The rat T-6 cells received transfection of miR-125b mimic and Tunicamycin. Protein expressions were observed by western blot analysis. RESULTS Compared to wild type rats, liver-injured rats showed significant impairment of liver function as assessed by the total bilirubin levels. The miR-125b-Tg rats showed decrease in activity of aspartate transaminase and alanine transaminase. Liver tissues of miR-125b-Tg rats showed weaker fibrotic matrix formation. Upregulation of miR-125b decreased the bile duct ligation-mediated hepatic disturbances for the expressions of endoplasmic reticulum kinase, inositol-requiring kinase 1alpha, sXBP1, CHOP, LC3, p62, ULK, and caspase-3/-8/-9. T-6 cells transfected with miR-125b mimic and treated with Tunicamycin caused decrease in levels of cleaved caspase-3, sXBP1, CHOP, and LC3. The miR-125b signaling showed protective effect on the liver tissues subjected to injury and fibrosis histopathology. CONCLUSION This study demonstrates a novel insight into the miR125b-mediated stabilization of endoplasmic reticulum integrity, which slows the progression of injury-induced hepatic deterioration.
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Affiliation(s)
- Xingyuan Zhang
- Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Fang Zhang
- Nursing Department of Binzhou Medical University Hospital, Binzhou, China
| | - Changxi Zhang
- Department of Hepatobiliary Surgery, Binzhou Medical University Hospital, Binzhou, China
| | - Jie Li
- Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
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Signaling Nodes Associated with Endoplasmic Reticulum Stress during NAFLD Progression. Biomolecules 2021; 11:biom11020242. [PMID: 33567666 PMCID: PMC7915814 DOI: 10.3390/biom11020242] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 01/29/2021] [Accepted: 02/04/2021] [Indexed: 12/19/2022] Open
Abstract
Excess and sustained endoplasmic reticulum (ER) stress, paired with a failure of initial adaptive responses, acts as a critical trigger of nonalcoholic fatty liver disease (NAFLD) progression. Unfortunately, there is no drug currently approved for treatment, and the molecular basis of pathogenesis by ER stress remains poorly understood. Classical ER stress pathway molecules have distinct but inter-connected functions and complicated effects at each phase of the disease. Identification of the specific molecular signal mediators of the ER stress-mediated pathogenesis is, therefore, a crucial step in the development of new treatments. These signaling nodes may be specific to the cell type and/or the phase of disease progression. In this review, we highlight the recent advancements in knowledge concerning signaling nodes associated with ER stress and NAFLD progression in various types of liver cells.
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Sanz-García C, Fernández-Iglesias A, Gracia-Sancho J, Arráez-Aybar LA, Nevzorova YA, Cubero FJ. The Space of Disse: The Liver Hub in Health and Disease. LIVERS 2021; 1:3-26. [DOI: 10.3390/livers1010002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.
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Affiliation(s)
- Carlos Sanz-García
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Hepatology, Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland
| | - Luis Alfonso Arráez-Aybar
- Department of Anatomy and Embriology, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
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Abstract
Hepatic stellate cells (HSCs) are resident non-parenchymal liver pericytes whose plasticity enables them to regulate a remarkable range of physiologic and pathologic responses. To support their functions in health and disease, HSCs engage pathways regulating carbohydrate, mitochondrial, lipid, and retinoid homeostasis. In chronic liver injury, HSCs drive hepatic fibrosis and are implicated in inflammation and cancer. To do so, the cells activate, or transdifferentiate, from a quiescent state into proliferative, motile myofibroblasts that secrete extracellular matrix, which demands rapid adaptation to meet a heightened energy need. Adaptations include reprogramming of central carbon metabolism, enhanced mitochondrial number and activity, endoplasmic reticulum stress, and liberation of free fatty acids through autophagy-dependent hydrolysis of retinyl esters that are stored in cytoplasmic droplets. As an archetype for pericytes in other tissues, recognition of the HSC's metabolic drivers and vulnerabilities offer the potential to target these pathways therapeutically to enhance parenchymal growth and modulate repair.
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Affiliation(s)
- Parth Trivedi
- Division of Liver Diseases, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Shuang Wang
- Division of Liver Diseases, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Scott L Friedman
- Division of Liver Diseases, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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40
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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Robinson CM, Talty A, Logue SE, Mnich K, Gorman AM, Samali A. An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13020261. [PMID: 33445669 PMCID: PMC7828145 DOI: 10.3390/cancers13020261] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.
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Affiliation(s)
- Claire M. Robinson
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
| | - Aaron Talty
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
| | - Susan E. Logue
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- Research Institute in Oncology and Hematology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Katarzyna Mnich
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
| | - Adrienne M. Gorman
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
| | - Afshin Samali
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
- Correspondence:
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Peng C, Stewart AG, Woodman OL, Ritchie RH, Qin CX. Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments. Front Pharmacol 2020; 11:603926. [PMID: 33343375 PMCID: PMC7745178 DOI: 10.3389/fphar.2020.603926] [Citation(s) in RCA: 154] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 10/19/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia. NASH patients with significant fibrosis have increased risk of developing cirrhosis and liver failure. Currently, NASH is the second leading cause for liver transplant in the United States. More importantly, the risk of developing hepatocellular carcinoma from NASH has also been highlighted in recent studies. Patients may have NAFLD for years before progressing into NASH. Although the pathogenesis of NASH is not completely understood, the current “multiple-hits” hypothesis suggests that in addition to fat accumulation, elevated oxidative and ER stress may also drive liver inflammation and fibrosis. The development of clinically relevant animal models and pharmacological treatments for NASH have been hampered by the limited understanding of the disease mechanism and a lack of sensitive, non-invasive diagnostic tools. Currently, most pre-clinical animal models are divided into three main groups which includes: genetic models, diet-induced, and toxin + diet-induced animal models. Although dietary models mimic the natural course of NASH in humans, the models often only induce mild liver injury. Many genetic and toxin + diet-induced models rapidly induce the development of metabolic disruption and serious liver injury, but not without their own shortcomings. This review provides an overview of the “multiple-hits” hypothesis and an evaluation of the currently existing animal models of NASH. This review also provides an update on the available interventions for managing NASH as well as pharmacological agents that are currently undergoing clinical trials for the treatment of NASH.
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Affiliation(s)
- Cheng Peng
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia
| | - Alastair G Stewart
- Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia.,Australian Research Council, Centre for Personalised Therapeutics Technologies, Lancaster, CBR, Australia
| | - Owen L Woodman
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia
| | - Rebecca H Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia
| | - Cheng Xue Qin
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, VIC, Australia.,Baker Heart & Diabetes Institute, Melbourne, VIC, Australia.,Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia
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43
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Xia SW, Wang ZM, Sun SM, Su Y, Li ZH, Shao JJ, Tan SZ, Chen AP, Wang SJ, Zhang ZL, Zhang F, Zheng SZ. Endoplasmic reticulum stress and protein degradation in chronic liver disease. Pharmacol Res 2020; 161:105218. [PMID: 33007418 DOI: 10.1016/j.phrs.2020.105218] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/21/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023]
Abstract
Endoplasmic reticulum (ER) stress is easily observed in chronic liver disease, which often causes accumulation of unfolded or misfolded proteins in the ER, leading to unfolded protein response (UPR). Regulating protein degradation is an integral part of UPR to relieve ER stress. The major protein degradation system includes the ubiquitin-proteasome system (UPS) and autophagy. All three arms of UPR triggered in response to ER stress can regulate UPS and autophagy. Accumulated misfolded proteins could activate these arms, and then generate various transcription factors to regulate the expression of UPS-related and autophagy-related genes. The protein degradation process regulated by UPR has great significance in many chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), viral hepatitis, liver fibrosis, and hepatocellular carcinoma(HCC). In most instances, the degradation of excessive proteins protects cells with ER stress survival from apoptosis. According to the specific functions of protein degradation in chronic liver disease, choosing to promote or inhibit this process is promising as a potential method for treating chronic liver disease.
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Affiliation(s)
- Si-Wei Xia
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhi-Min Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Su-Min Sun
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ying Su
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhang-Hao Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jiang-Juan Shao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Shan-Zhong Tan
- Nanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - An-Ping Chen
- Department of Pathology, School of Medicine, Saint Louis University, MO 63104, USA
| | - Shi-Jun Wang
- Shandong University of Traditional Chinese Medicine, Jinan 250035, China
| | - Zi-Li Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Feng Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Shi-Zhong Zheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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44
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Pavlović N, Calitz C, Thanapirom K, Mazza G, Rombouts K, Gerwins P, Heindryckx F. Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma. eLife 2020; 9:e55865. [PMID: 33103995 PMCID: PMC7661042 DOI: 10.7554/elife.55865] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line-specific direct effects of inhibiting IRE1α in tumor cells.
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Affiliation(s)
- Nataša Pavlović
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
| | - Carlemi Calitz
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
| | - Kess Thanapirom
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Guiseppe Mazza
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Krista Rombouts
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Pär Gerwins
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
- Department of Radiology, Uppsala University HospitalUppsalaSweden
| | - Femke Heindryckx
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
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45
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McLellan MA, Skelly DA, Dona MSI, Squiers GT, Farrugia GE, Gaynor TL, Cohen CD, Pandey R, Diep H, Vinh A, Rosenthal NA, Pinto AR. High-Resolution Transcriptomic Profiling of the Heart During Chronic Stress Reveals Cellular Drivers of Cardiac Fibrosis and Hypertrophy. Circulation 2020; 142:1448-1463. [PMID: 32795101 PMCID: PMC7547893 DOI: 10.1161/circulationaha.119.045115] [Citation(s) in RCA: 174] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Supplemental Digital Content is available in the text. Background: Cardiac fibrosis is a key antecedent to many types of cardiac dysfunction including heart failure. Physiological factors leading to cardiac fibrosis have been recognized for decades. However, the specific cellular and molecular mediators that drive cardiac fibrosis, and the relative effect of disparate cell populations on cardiac fibrosis, remain unclear. Methods: We developed a novel cardiac single-cell transcriptomic strategy to characterize the cardiac cellulome, the network of cells that forms the heart. This method was used to profile the cardiac cellular ecosystem in response to 2 weeks of continuous administration of angiotensin II, a profibrotic stimulus that drives pathological cardiac remodeling. Results: Our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to pathological remodeling of the extracellular matrix of the heart. Two phenotypically distinct fibroblast populations, Fibroblast-Cilp and Fibroblast-Thbs4, emerged after induction of tissue stress to promote fibrosis in the absence of smooth muscle actin–expressing myofibroblasts, a key profibrotic cell population. After angiotensin II treatment, Fibroblast-Cilp develops as the most abundant fibroblast subpopulation and the predominant fibrogenic cell type. Mapping intercellular communication networks within the heart, we identified key intercellular trophic relationships and shifts in cellular communication after angiotensin II treatment that promote the development of a profibrotic cellular microenvironment. Furthermore, the cellular responses to angiotensin II and the relative abundance of fibrogenic cells were sexually dimorphic. Conclusions: These results offer a valuable resource for exploring the cardiac cellular landscape in health and after chronic cardiovascular stress. These data provide insights into the cellular and molecular mechanisms that promote pathological remodeling of the mammalian heart, highlighting early transcriptional changes that precede chronic cardiac fibrosis.
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Affiliation(s)
- Micheal A McLellan
- The Jackson Laboratory, Bar Harbor, ME (M.A.M., D.A.S., G.T.S., R.P., N.A.R.).,Graduate School of Biomedical Sciences, Tufts University, Boston, MA (M.A.M.)
| | - Daniel A Skelly
- The Jackson Laboratory, Bar Harbor, ME (M.A.M., D.A.S., G.T.S., R.P., N.A.R.)
| | - Malathi S I Dona
- Baker Heart and Diabetes Research Institute, Melbourne, Victoria, Australia (M.S.I.D., G.E.F., T.L.G., C.D.C., A.R.P.)
| | - Galen T Squiers
- The Jackson Laboratory, Bar Harbor, ME (M.A.M., D.A.S., G.T.S., R.P., N.A.R.)
| | - Gabriella E Farrugia
- Baker Heart and Diabetes Research Institute, Melbourne, Victoria, Australia (M.S.I.D., G.E.F., T.L.G., C.D.C., A.R.P.)
| | - Taylah L Gaynor
- Baker Heart and Diabetes Research Institute, Melbourne, Victoria, Australia (M.S.I.D., G.E.F., T.L.G., C.D.C., A.R.P.)
| | - Charles D Cohen
- Baker Heart and Diabetes Research Institute, Melbourne, Victoria, Australia (M.S.I.D., G.E.F., T.L.G., C.D.C., A.R.P.)
| | - Raghav Pandey
- The Jackson Laboratory, Bar Harbor, ME (M.A.M., D.A.S., G.T.S., R.P., N.A.R.)
| | - Henry Diep
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, Victoria, Australia (T.L.G, C.D.C., H.D., A.V., A.R.P.)
| | - Antony Vinh
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, Victoria, Australia (T.L.G, C.D.C., H.D., A.V., A.R.P.)
| | - Nadia A Rosenthal
- The Jackson Laboratory, Bar Harbor, ME (M.A.M., D.A.S., G.T.S., R.P., N.A.R.)
| | - Alexander R Pinto
- Baker Heart and Diabetes Research Institute, Melbourne, Victoria, Australia (M.S.I.D., G.E.F., T.L.G., C.D.C., A.R.P.).,Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, Victoria, Australia (T.L.G, C.D.C., H.D., A.V., A.R.P.)
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46
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Novo E, Bocca C, Foglia B, Protopapa F, Maggiora M, Parola M, Cannito S. Liver fibrogenesis: un update on established and emerging basic concepts. Arch Biochem Biophys 2020; 689:108445. [PMID: 32524998 DOI: 10.1016/j.abb.2020.108445] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/20/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrogenesis is defined as a dynamic and highly integrated process occurring during chronic injury to liver parenchyma that can result in excess deposition of extracellular matrix (ECM) components (i.e., liver fibrosis). Liver fibrogenesis, together with chronic inflammatory response, is then primarily involved in the progression of chronic liver diseases (CLD) irrespective of the specific etiology. In the present review we will first offer a synthetic and updated overview of major basic concepts in relation to the role of myofibroblasts (MFs), macrophages and other hepatic cell populations involved in CLD to then offer an overview of established and emerging issues and mechanisms that have been proposed to favor and/or promote CLD progression. A special focus will be dedicated to selected issues that include emerging features in the field of cholangiopathies, the emerging role of genetic and epigenetic factors as well as of hypoxia, hypoxia-inducible factors (HIFs) and related mediators.
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Affiliation(s)
- Erica Novo
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Claudia Bocca
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Beatrice Foglia
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Francesca Protopapa
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Marina Maggiora
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
| | - Maurizio Parola
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy.
| | - Stefania Cannito
- University of Torino, Dept. Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, Corso Raffaello 30, 10125, Torino, Italy
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47
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Chen S, Chen J, Hua X, Sun Y, Cui R, Sha J, Zhu X. The emerging role of XBP1 in cancer. Biomed Pharmacother 2020; 127:110069. [PMID: 32294597 DOI: 10.1016/j.biopha.2020.110069] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 02/21/2020] [Accepted: 03/03/2020] [Indexed: 12/20/2022] Open
Abstract
X-box binding protein 1 (XBP1) is a unique basic-region leucine zipper (bZIP) transcription factor whose dynamic form is controlled by an alternative splicing response upon disturbance of homeostasis in the endoplasmic reticulum (ER) and activation of the unfolded protein response (UPR). XBP1 was first distinguished as a key regulator of major histocompatibility complex (MHC) class II gene expression in B cells. XBP1 communicates with the foremost conserved signalling component of the UPR and is essential for cell fate determination in response to ER stress (ERS). Here, we review recent advances in our understanding of this multifaceted translation component in cancer. In this review, we briefly discuss the role of XBP1 mediators in the UPR and the transcriptional function of XBP1. In addition, we describe how XBP1 operates as a key factor in tumour progression and metastasis. We mainly review XBP1's expression, function and prognostic value in research on solid tumours. Finally, we discuss multiple approaches, especially those involving XBP1, that overcome the immunosuppressive effect of the UPR in cancer that could potentially be useful as antitumour therapies.
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Affiliation(s)
- Shanshan Chen
- School of Medicine, Southeast University, Nanjing, 210009, China.
| | - Jing Chen
- Department of Respiratory, Zhongda Hospital of Southeast University, Nanjing, 210009, China
| | - Xin Hua
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Yue Sun
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Rui Cui
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Jun Sha
- School of Medicine, Southeast University, Nanjing, 210009, China
| | - Xiaoli Zhu
- School of Medicine, Southeast University, Nanjing, 210009, China; Department of Respiratory, Zhongda Hospital of Southeast University, Nanjing, 210009, China.
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48
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Campos G, Schmidt-Heck W, De Smedt J, Widera A, Ghallab A, Pütter L, González D, Edlund K, Cadenas C, Marchan R, Guthke R, Verfaillie C, Hetz C, Sachinidis A, Braeuning A, Schwarz M, Weiß TS, Banhart BK, Hoek J, Vadigepalli R, Willy J, Stevens JL, Hay DC, Hengstler JG, Godoy P. Inflammation-associated suppression of metabolic gene networks in acute and chronic liver disease. Arch Toxicol 2020; 94:205-217. [PMID: 31919559 DOI: 10.1007/s00204-019-02630-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/20/2019] [Indexed: 02/07/2023]
Abstract
Inflammation has been recognized as essential for restorative regeneration. Here, we analyzed the sequential processes during onset of liver injury and subsequent regeneration based on time-resolved transcriptional regulatory networks (TRNs) to understand the relationship between inflammation, mature organ function, and regeneration. Genome-wide expression and TRN analysis were performed time dependently in mouse liver after acute injury by CCl4 (2 h, 8 h, 1, 2, 4, 6, 8, 16 days), as well as lipopolysaccharide (LPS, 24 h) and compared to publicly available data after tunicamycin exposure (mouse, 6 h), hepatocellular carcinoma (HCC, mouse), and human chronic liver disease (non-alcoholic fatty liver, HBV infection and HCC). Spatiotemporal investigation differentiated lobular zones for signaling and transcription factor expression. Acute CCl4 intoxication induced expression of gene clusters enriched for inflammation and stress signaling that peaked between 2 and 24 h, accompanied by a decrease of mature liver functions, particularly metabolic genes. Metabolism decreased not only in pericentral hepatocytes that underwent CCl4-induced necrosis, but extended to the surviving periportal hepatocytes. Proliferation and tissue restorative TRNs occurred only later reaching a maximum at 48 h. The same upstream regulators (e.g. inhibited RXR function) were implicated in increased inflammation and suppressed metabolism. The concomitant inflammation/metabolism TRN occurred similarly after acute LPS and tunicamycin challenges, in chronic mouse models and also in human liver diseases. Downregulation of metabolic genes occurs concomitantly to induce inflammation-associated genes as an early response and appears to be initiated by similar upstream regulators in acute and chronic liver diseases in humans and mice. In the acute setting, proliferation and restorative regeneration associated TRNs peak only later when metabolism is already suppressed.
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Affiliation(s)
- Gisela Campos
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Wolfgang Schmidt-Heck
- Leibniz Institute for Natural Product Research and Infection Biology e.V., Hans-Knöll Institute, Jena, Germany
| | | | - Agata Widera
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Ahmed Ghallab
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
- Department of Forensic and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Larissa Pütter
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Daniela González
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Karolina Edlund
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Cristina Cadenas
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Rosemarie Marchan
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany
| | - Reinhard Guthke
- Leibniz Institute for Natural Product Research and Infection Biology e.V., Hans-Knöll Institute, Jena, Germany
| | | | - Claudio Hetz
- Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism (GERO), Santiago, Chile
- The Buck Institute for Research in Aging, Novato, CA, 94945, USA
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
| | - Agapios Sachinidis
- Medical Faculty, Institute of Neurophysiology, University of Cologne, Cologne, Germany
| | - Albert Braeuning
- Department of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany
- Department of Food Safety, Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany
| | - Michael Schwarz
- Department of Experimental and Clinical Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany
| | - Thomas S Weiß
- Department of Pediatrics and Juvenile Medicine, Center for Liver Cell Research, University of Regensburg Hospital, Regensburg, Germany
| | - Benjamin K Banhart
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jan Hoek
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Rajanikanth Vadigepalli
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jeffrey Willy
- Vertex Pharmaceuticals, 3215 Merryfield Row, San Diego, CA, 92121, USA
| | - James L Stevens
- Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA
| | - David C Hay
- MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, E16 4UU, UK
| | - Jan G Hengstler
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany.
| | - Patricio Godoy
- IfADo-Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystrasse 67, 44139, Dortmund, Germany.
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49
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Khomich O, Ivanov AV, Bartosch B. Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis. Cells 2019; 9:24. [PMID: 31861818 PMCID: PMC7016711 DOI: 10.3390/cells9010024] [Citation(s) in RCA: 138] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/09/2019] [Accepted: 12/18/2019] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.
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Affiliation(s)
- Olga Khomich
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Alexander V. Ivanov
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia
| | - Birke Bartosch
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, CEDEX 03, 69424 Lyon, France;
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50
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Moscoso CG, Steer CJ. "Let my liver rather heat with wine" - a review of hepatic fibrosis pathophysiology and emerging therapeutics. Hepat Med 2019; 11:109-129. [PMID: 31565001 PMCID: PMC6731525 DOI: 10.2147/hmer.s213397] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 08/17/2019] [Indexed: 12/12/2022] Open
Abstract
Cirrhosis is characterized by extensive hepatic fibrosis, and it is the 14th leading cause of death worldwide. Numerous contributing conditions have been implicated in its development, including infectious etiologies, medication overdose or adverse effects, ingestible toxins, autoimmunity, hemochromatosis, Wilson’s disease and primary biliary cholangitis to list a few. It is associated with portal hypertension and its stigmata (varices, ascites, hepatic encephalopathy, combined coagulopathy and thrombophilia), and it is a major risk factor for hepatocellular carcinoma. Currently, orthotopic liver transplantation has been the only curative modality to treat cirrhosis, and the scarcity of donors results in many people waiting years for a transplant. Identification of novel targets for pharmacologic therapy through elucidation of key mechanistic components to induce fibrosis reversal is the subject of intense research. Development of robust models of hepatic fibrosis to faithfully characterize the interplay between activated hepatic stellate cells (the principal fibrogenic contributor to fibrosis initiation and perpetuation), hepatocytes and extracellular matrix components has the potential to identify critical components and mechanisms that can be exploited for targeted treatment. In this review, we will highlight key cellular pathways involved in the pathophysiology of fibrosis from extracellular ligands, effectors and receptors, to nuclear receptors, epigenetic mechanisms, energy homeostasis and cytokines. Further, molecular pathways of hepatic stellate cell deactivation are discussed, including apoptosis, senescence and reversal or transdifferentiation to an inactivated state resembling quiescence. Lastly, clinical evidence of fibrosis reversal induced by biologics and small molecules is summarized, current compounds under clinical trials are described and efforts for treatment of hepatic fibrosis with mesenchymal stem cells are highlighted. An enhanced understanding of the rich tapestry of cellular processes identified in the initiation, perpetuation and resolution of hepatic fibrosis, driven principally through phenotypic switching of hepatic stellate cells, should lead to a breakthrough in potential therapeutic modalities.
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Affiliation(s)
- Carlos G Moscoso
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition
| | - Clifford J Steer
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition.,Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, Minneapolis, MN 55455, USA
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