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Caligiuri A, Gentilini A, Pastore M, Gitto S, Marra F. Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression. Cells 2021; 10:cells10102759. [PMID: 34685739 PMCID: PMC8534788 DOI: 10.3390/cells10102759] [Citation(s) in RCA: 148] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/08/2021] [Accepted: 10/09/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.
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Königshofer P, Brusilovskaya K, Petrenko O, Hofer BS, Schwabl P, Trauner M, Reiberger T. Nuclear Receptors in Liver Fibrosis. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166235. [PMID: 34339839 DOI: 10.1016/j.bbadis.2021.166235] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 07/18/2021] [Accepted: 07/27/2021] [Indexed: 12/12/2022]
Abstract
Nuclear receptors are ligand-activated transcription factors that regulate gene expression of a variety of key molecular signals involved in liver fibrosis. The primary cellular driver of liver fibrogenesis are activated hepatic stellate cells. Different NRs regulate the hepatic expression of pro-inflammatory and pro-fibrogenic cytokines that promote the transformation of hepatic stellate cells into fibrogenic myofibroblasts. Importantly, nuclear receptors regulate gene expression circuits that promote hepatic fibrogenesis and/or allow liver fibrosis regression. In this review, we highlight the direct and indirect influence of nuclear receptors on liver fibrosis, with a focus on hepatic stellate cells, and discuss potential therapeutic effects of nuclear receptor modulation in regard to anti-fibrotic and anti-inflammatory effects. Further research on nuclear receptors-related signaling may lead to the clinical development of effective anti-fibrotic therapies for patients with liver disease.
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Affiliation(s)
- Philipp Königshofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Ksenia Brusilovskaya
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Oleksandr Petrenko
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Benedikt Silvester Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Experimental Hepatic Hemodynamic Lab (HEPEX), Medical University of Vienna, Vienna, Austria; Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
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Zheng J, Li Z, Manabe Y, Kim M, Goto T, Kawada T, Sugawara T. Siphonaxanthin, a Carotenoid From Green Algae, Inhibits Lipogenesis in Hepatocytes via the Suppression of Liver X Receptor α Activity. Lipids 2018; 53:41-52. [PMID: 29446839 DOI: 10.1002/lipd.12002] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 09/20/2017] [Accepted: 10/17/2017] [Indexed: 12/14/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has shown an increasing morbidity in recent years. Here, we demonstrated that siphonaxanthin (SPX), a rare marine carotenoid, exhibits a strong inhibitory effect on aggravated hepatic lipogenesis in vitro and would be a promising candidate in the prevention and alleviation of NAFLD in the future. In this study, we conducted a preliminary assessment of the effect of SPX on hepatic lipogenesis by using the HepG2 cell line, derived from human liver cancer, as a model of the liver. SPX significantly suppressed the excess accumulation of triacylglycerol induced by liver X receptor α (LXRα) agonist by downregulating a nuclear transcription factor named sterol regulatory element-binding protein-1c and a set of related genes. Moreover, fatty acid translocase (CD36) and fatty acid-binding protein-1, which regulates fatty acid uptake, also exhibited significant decrease in transcriptional levels. Furthermore, we found that SPX blocked LXRα activation and would be a promising candidate for antagonist of LXRα.
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Affiliation(s)
- Jiawen Zheng
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Zhuosi Li
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Yuki Manabe
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
| | - Minji Kim
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, 611-0011, Japan
| | - Tsuyoshi Goto
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, 611-0011, Japan
| | - Teruo Kawada
- Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, 611-0011, Japan
| | - Tatsuya Sugawara
- Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan
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Makarev E, Izumchenko E, Aihara F, Wysocki PT, Zhu Q, Buzdin A, Sidransky D, Zhavoronkov A, Atala A. Common pathway signature in lung and liver fibrosis. Cell Cycle 2016; 15:1667-73. [PMID: 27267766 PMCID: PMC4957589 DOI: 10.1080/15384101.2016.1152435] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Fibrosis, a progressive accumulation of extracellular matrix components, encompasses a wide spectrum of distinct organs, and accounts for an increasing burden of morbidity and mortality worldwide. Despite the tremendous clinical impact, the mechanisms governing the fibrotic process are not yet understood, and to date, no clinically reliable therapies for fibrosis have been discovered. Here we applied Regeneration Intelligence, a new bioinformatics software suite for qualitative analysis of intracellular signaling pathway activation using transcriptomic data, to assess a network of molecular signaling in lung and liver fibrosis. In both tissues, our analysis detected major conserved signaling pathways strongly associated with fibrosis, suggesting that some of the pathways identified by our algorithm but not yet wet-lab validated as fibrogenesis related, may be attractive targets for future research. While the majority of significantly disrupted pathways were specific to histologically distinct organs, several pathways have been concurrently activated or downregulated among the hepatic and pulmonary fibrosis samples, providing new evidence of evolutionary conserved pathways that may be relevant as possible therapeutic targets. While future confirmatory studies are warranted to validate these observations, our platform proposes a promising new approach for detecting fibrosis-promoting pathways and tailoring the right therapy to prevent fibrogenesis.
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Affiliation(s)
- Eugene Makarev
- a Atlas Regeneration, Inc. , Winston-Salem , NC , USA.,b Insilico Medicine, Inc., ETC, Johns Hopkins University , Baltimore , MD , USA
| | - Evgeny Izumchenko
- c Department of Otolaryngology-Head & Neck Surgery , Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Fumiaki Aihara
- d Advanced Academic Programs, Johns Hopkins University , Baltimore , MD , USA
| | - Piotr T Wysocki
- c Department of Otolaryngology-Head & Neck Surgery , Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Qingsong Zhu
- b Insilico Medicine, Inc., ETC, Johns Hopkins University , Baltimore , MD , USA
| | - Anton Buzdin
- e The Biogerontology Research Foundation , London , UK
| | - David Sidransky
- c Department of Otolaryngology-Head & Neck Surgery , Johns Hopkins University School of Medicine , Baltimore , MD , USA
| | - Alex Zhavoronkov
- b Insilico Medicine, Inc., ETC, Johns Hopkins University , Baltimore , MD , USA.,f Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine , Winston-Salem , NC , USA
| | - Anthony Atala
- a Atlas Regeneration, Inc. , Winston-Salem , NC , USA.,g Pathway Pharmaceuticals, Ltd , Hong Kong , Hong Kong
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Elpek G&O. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update. World J Gastroenterol 2014; 20:7260-7276. [PMID: 24966597 PMCID: PMC4064072 DOI: 10.3748/wjg.v20.i23.7260] [Citation(s) in RCA: 286] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 02/08/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023] Open
Abstract
There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis. Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis. Therefore, efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis. Activation of hepatic stellate cells (HSCs) remains a central event in fibrosis, complemented by other sources of matrix-producing cells, including portal fibroblasts, fibrocytes and bone marrow-derived myofibroblasts. These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury. Defining the interaction of different cell types, revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets. Moreover, the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies. This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies. The pathogenesis of liver fibrosis associated with alcoholic liver disease, non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.
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Bai T, Yao YL, Jin XJ, Lian LH, Li Q, Yang N, Jin Q, Wu YL, Nan JX. Acanthoic acid, a diterpene in Acanthopanax koreanum, ameliorates the development of liver fibrosis via LXRs signals. Chem Biol Interact 2014; 218:63-70. [PMID: 24802811 DOI: 10.1016/j.cbi.2014.04.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 03/21/2014] [Accepted: 04/24/2014] [Indexed: 01/02/2023]
Abstract
Liver X receptors (LXRs)-mediated signals in acanthoic acid (AA) ameliorating liver fibrosis were examined in carbon tetrachloride (CCl4)-induced mice and TGF-β stimulated hepatic stellate cells (HSCs). AA was isolated from the root of Acanthopanax koreanum Nakai (Araliaceae). CCl4-treated mice were intraperitoneally injected with 10% CCl4 in olive oil (2 mL/kg for 8 weeks). In AA treated groups, mice were intragastrically administrated with AA (20 mg/kg or 50 mg/kg) 3 times per week for 8 weeks. Administration of AA reduced serum aminotransferase and tissue necrosis factor-α (TNF-α) levels evoked by CCl4, and the reverse of liver damage was further confirmed by histopathological staining. Administration of AA reduced the expression of fibrosis markers and regulated the ratio of MMP-13/TIMP-1, further reversed the development of liver fibrosis. TGF-β (5 ng/ml) was added to activate HSC-T6 cells for 2 h, and then treated with AA (1, 3, or 10 μmol/l) for 24 h before analysis. Cells were collected and proteins were extracted to detect the expressions of LXRs. AA could inhibit the expression of α-SMA stimulated by TGF-β and increase the expression of LXRβ. In vivo and in vitro experiments, AA could modulate liver fibrosis induced by CCl4-treatment via activation of LXRα and LXRβ, while inhibit HSCs activation only via activation of LXRβ. Acanthoic acid might ameliorate liver fibrosis induced by CCl4 via LXRs signals.
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Affiliation(s)
- Ting Bai
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China
| | - You-li Yao
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China
| | - Xue-jun Jin
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China
| | - Li-hua Lian
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China
| | - Qian Li
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China
| | - Ning Yang
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China
| | - Quan Jin
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China
| | - Yan-ling Wu
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
| | - Ji-xing Nan
- Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
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Guillot A, Hamdaoui N, Bizy A, Zoltani K, Souktani R, Zafrani ES, Mallat A, Lotersztajn S, Lafdil F. Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver. Hepatology 2014; 59:296-306. [PMID: 23813495 DOI: 10.1002/hep.26598] [Citation(s) in RCA: 87] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 06/17/2013] [Indexed: 12/19/2022]
Abstract
UNLABELLED Interleukin (IL)-17 is a proinflammatory and fibrogenic cytokine mainly produced by T-helper (Th)17 lymphocytes, together with the hepatoprotective and antifibrogenic cytokine, IL-22. Cannabinoid receptor 2 (CB2) is predominantly expressed in immune cells and displays anti-inflammatory and antifibrogenic effects. In the present study, we further investigated the mechanism underlying antifibrogenic properties of CB2 receptor and explored its effect on the profibrogenic properties of IL-17. After bile duct ligation (BDL), the hepatic expression of Th17 markers and IL-17 production were enhanced in CB2(-/-) mice, as compared to wild-type (WT) counterparts, and correlated with increased fibrosis in these animals. In contrast, IL-22-induced expression was similar in both animal groups. Inhibition of Th17 differentiation by digoxin lowered Th17 marker gene expression and IL-17 production and strongly reduced liver fibrosis in CB2(-/-) BDL mice. In vitro, differentiation of CD4(+) naïve T cells into Th17 lymphocytes was decreased by the CB2 agonist, JWH-133, and was associated with reduced Th17 marker messenger RNA expression and IL-17 production, without modification of IL-22 release. The inhibitory effect of JWH-133 on IL-17 production relied on signal transducer and activator of transcription (STAT)5 phosphorylation. Indeed, STAT5 phosphorylation and translocation into the nucleus was enhanced in JWH133-treated Th17 lymphocytes, and the addition of a STAT5 inhibitor reversed the inhibitory effect of the CB2 agonist on IL-17 production, without affecting IL-22 levels. Finally, in vitro studies also demonstrated that CB2 receptor activation in macrophages and hepatic myofibroblasts blunts IL-17-induced proinflammatory gene expression. CONCLUSION These data demonstrate that CB2 receptor activation decreases liver fibrosis by selectively reducing IL-17 production by Th17 lymphocytes via a STAT5-dependent pathway, and by blunting the proinflammatory effects of IL-17 on its target cells, while preserving IL-22 production.
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Affiliation(s)
- Adrien Guillot
- Inserm, U955, Créteil, France; Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, France
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Bian Z, Ma X. Liver fibrogenesis in non-alcoholic steatohepatitis. Front Physiol 2012; 3:248. [PMID: 22934006 PMCID: PMC3429026 DOI: 10.3389/fphys.2012.00248] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2012] [Accepted: 06/17/2012] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common chronic liver diseases in developed western countries. Non-alcoholic steatohepatitis (NASH) is the most severe form of NAFLD, and can progress to more severe forms of liver disease, including fibrosis, cirrhosis, and even hepatocellular carcinoma. The activation of hepatic stellate cells plays a critical role in NASH-related fibrogenesis. Multiple factors, such as insulin resistance, oxidative stress, pro-inflammatory cytokines and adipokines, and innate immune responses, are known to contribute to the development of NASH-related fibrogenesis. Furthermore, these factors may share synergistic interactions, which could contribute to the process of liver fibrosis. Given the complex etiology of NASH, combined treatment regimes that target these different factors provide potential treatment strategies for NASH-related liver fibrosis.
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Affiliation(s)
- Zhaolian Bian
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai Jiao-Tong University School of Medicine Shanghai, China
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Jakobsson T, Treuter E, Gustafsson JÅ, Steffensen KR. Liver X receptor biology and pharmacology: new pathways, challenges and opportunities. Trends Pharmacol Sci 2012; 33:394-404. [PMID: 22541735 DOI: 10.1016/j.tips.2012.03.013] [Citation(s) in RCA: 245] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 03/05/2012] [Accepted: 03/26/2012] [Indexed: 01/12/2023]
Abstract
Nuclear receptors (NRs) are master regulators of transcriptional programs that integrate the homeostatic control of almost all biological processes. Their direct mode of ligand regulation and genome interaction is at the core of modern pharmacology. The two liver X receptors LXRα and LXRβ are among the emerging newer drug targets within the NR family. LXRs are best known as nuclear oxysterol receptors and physiological regulators of lipid and cholesterol metabolism that also act in an anti-inflammatory way. Because LXRs control diverse pathways in development, reproduction, metabolism, immunity and inflammation, they have potential as therapeutic targets for diseases as diverse as lipid disorders, atherosclerosis, chronic inflammation, autoimmunity, cancer and neurodegenerative diseases. Recent insights into LXR signaling suggest future targeting strategies aiming at increasing LXR subtype and pathway selectivity. This review discusses the current status of our understanding of LXR biology and pharmacology, with an emphasis on the molecular aspects of LXR signaling that constitute the potential of LXRs as drug targets.
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Affiliation(s)
- Tomas Jakobsson
- Center for Biosciences, Department of Biosciences and Nutrition, Karolinska Institutet, S-14183 Stockholm, Sweden
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