Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

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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Network Pharmacological Analysis and Experimental Validation of the Mechanisms of Action of Si-Ni-San Against Liver Fibrosis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.656115 ◽

2021 ◽

Vol 12 ◽

Author(s):

Siliang Wang ◽

Cheng Tang ◽

Heng Zhao ◽

Peiliang Shen ◽

Chao Lin ◽

...

Keyword(s):

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Mechanisms Of Action ◽

Network Pharmacology ◽

Related Factor ◽

Alcoholic Fatty Liver ◽

Ppar Γ ◽

Liver Tissues

Background: Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear.Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays.Results: SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further in vivo experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-α and Act D in vitro. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained in vitro by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation.Conclusion: SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition.

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Sa.93. The CYP450 Mouse Model for Autoimmune Liver Disease: Virus-induced Activation of Hepatic Stellate Cells Causes Liver Fibrosis

Clinical Immunology ◽

10.1016/j.clim.2008.03.314 ◽

2008 ◽

Vol 127 ◽

pp. S111

Author(s):

Edith Hintermann ◽

Martin Holdener ◽

Monika Bayer ◽

Michael Manns ◽

Matthias von Herrath ◽

...

Keyword(s):

Liver Disease ◽

Liver Fibrosis ◽

Mouse Model ◽

Disease Virus ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Autoimmune Liver Disease

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Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells

Journal of Virology ◽

10.1128/jvi.02225-16 ◽

2017 ◽

Vol 91 (6) ◽

Cited By ~ 45

Author(s):

Pradip B. Devhare ◽

Reina Sasaki ◽

Shubham Shrivastava ◽

Adrian M. Di Bisceglie ◽

Ranjit Ray ◽

...

Keyword(s):

Hepatitis C Virus ◽

Liver Disease ◽

Hepatitis C ◽

Liver Fibrosis ◽

Intercellular Communication ◽

Hepatic Stellate Cells ◽

Molecular Mechanisms ◽

Stellate Cells ◽

Hcv Infection ◽

Marker Genes

ABSTRACT Fibrogenic pathways in the liver are principally regulated by activation of hepatic stellate cells (HSC). Fibrosis is associated with chronic hepatitis C virus (HCV) infection, although the mechanism is poorly understood. HSC comprise the major population of nonparenchymal cells in the liver. Since HCV does not replicate in HSC, we hypothesized that exosomes secreted from HCV-infected hepatocytes activate HSC. Primary or immortalized human hepatic stellate (LX2) cells were exposed to exosomes derived from HCV-infected hepatocytes (HCV-exo), and the expression of fibrosis-related genes was examined. Our results demonstrated that HCV-exo internalized to HSC and increased the expression of profibrotic markers. Further analysis suggested that HCV-exo carry miR-19a and target SOCS3 in HSC, which in turn activates the STAT3-mediated transforming growth factor β (TGF-β) signaling pathway and enhances fibrosis marker genes. The higher expression of miR-19a in exosomes was also observed from HCV-infected hepatocytes and in sera of chronic HCV patients with fibrosis compared to healthy volunteers and non-HCV-related liver disease patients with fibrosis. Together, our results demonstrated that miR-19a carried through the exosomes from HCV-infected hepatocytes activates HSC by modulating the SOCS-STAT3 axis. Our results implicated a novel mechanism of exosome-mediated intercellular communication in the activation of HSC for liver fibrosis in HCV infection. IMPORTANCE HCV-associated liver fibrosis is a critical step for end-stage liver disease progression. However, the molecular mechanisms for hepatic stellate-cell activation by HCV-infected hepatocytes are underexplored. Here, we provide a role for miR-19a carried through the exosomes in intercellular communication between HCV-infected hepatocytes and HSC in fibrogenic activation. Furthermore, we demonstrate the role of exosomal miR-19a in activation of the STAT3–TGF-β pathway in HSC. This study contributes to the understanding of intercellular communication in the pathogenesis of liver disease during HCV infection.

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Role of G Protein-Coupled Receptors in Hepatic Stellate Cells and Approaches to Anti-Fibrotic Treatment of Non-Alcoholic Fatty Liver Disease

Frontiers in Endocrinology ◽

10.3389/fendo.2021.773432 ◽

2021 ◽

Vol 12 ◽

Author(s):

Takefumi Kimura ◽

Simran Singh ◽

Naoki Tanaka ◽

Takeji Umemura

Keyword(s):

Liver Disease ◽

Hepatic Fibrosis ◽

Hepatic Stellate Cells ◽

Fatty Liver Disease ◽

Stellate Cells ◽

G Protein Coupled Receptors ◽

Alcoholic Fatty Liver ◽

G Protein Coupled ◽

Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) is globally increasing. Gaining control over disease-related events in non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, is currently an unmet medical need. Hepatic fibrosis is a critical prognostic factor in NAFLD/NASH. Therefore, a better understanding of the pathophysiology of hepatic fibrosis and the development of related therapies are of great importance. G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of a great variety of extracellular ligands. GPCRs represent major drug targets, as indicated by the fact that about 40% of all drugs currently used in clinical practice mediate their therapeutic effects by acting on GPCRs. Like many other organs, various GPCRs play a role in regulating liver function. It is predicted that more than 50 GPCRs are expressed in the liver. However, our knowledge of how GPCRs regulate liver metabolism and fibrosis in the different cell types of the liver is very limited. In particular, a better understanding of the role of GPCRs in hepatic stellate cells (HSCs), the primary cells that regulate liver fibrosis, may lead to the development of drugs that can improve hepatic fibrosis in NAFLD/NASH. In this review, we describe the functions of multiple GPCRs expressed in HSCs, their roles in liver fibrogenesis, and finally speculate on the development of novel treatments for NAFLD/NASH.

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Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells

Gut ◽

10.1136/gutjnl-2019-318372 ◽

2019 ◽

Vol 69 (5) ◽

pp. 920-932 ◽

Cited By ~ 8

Author(s):

Alberto Martí-Rodrigo ◽

Fernando Alegre ◽

Ángela B Moragrega ◽

Francisco García-García ◽

Pablo Martí-Rodrigo ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Injury ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Chronic Liver ◽

Janus Kinase ◽

In Vivo Models ◽

Major Health Problem ◽

Alcoholic Fatty Liver ◽

Duct Ligation

ObjectiveLiver fibrosis constitutes a major health problem worldwide due to its rapidly increasing prevalence and the lack of specific and effective treatments. Growing evidence suggests that signalling through cytokine-activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathways regulates liver fibrosis and regeneration. Rilpivirine (RPV) is a widely used anti-HIV drug not reported to produce hepatotoxicity. We aimed to describe the potential hepatoprotective effects of RPV in different models of chronic liver injury, focusing on JAK-STAT signalling regulation.DesignThe effects of RPV on hepatic steatosis, inflammation and fibrogenesis were studied in a nutritional mouse model of non-alcoholic fatty liver disease, carbon tetrachloride-induced fibrosis and bile duct ligation-induced fibrosis. Primary human hepatic stellate cells (hHSC) and human cell lines LX-2 and Hep3B were used to investigate the underlying molecular mechanisms.ResultsRPV exerted a clear anti-inflammatory and antifibrotic effect in all the in vivo models of liver injury employed, and enhanced STAT3-dependent proliferation in hepatocytes and apoptosis in HSC through selective STAT1 activation. These results were reproduced in vitro; RPV undermined STAT3 activation and triggered STAT1-mediated pathways and apoptosis in HSC. Interestingly, this selective pro-apoptotic effect completely disappeared when STAT1 was silenced. Conditioned medium experiments showed that HSC apoptosis activated STAT3 in hepatocytes in an interleukin-6-dependent mechanism.ConclusionRPV ameliorates liver fibrosis through selective STAT1-dependent induction of apoptosis in HSC, which exert paracrinal effects in hepatocytes, thus promoting liver regeneration. RPV’s actions may represent an effective strategy to treat chronic liver diseases of different aetiologies and help identify novel therapeutic targets.

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Truncated Milk Fat Globule-EGF-Like Factor 8 Ameliorates Liver Fibrosis via Inhibition of Integrin-TGFβ Receptor Interaction

Biomedicines ◽

10.3390/biomedicines9111529 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1529

Author(s):

Geun Ho An ◽

Jaehun Lee ◽

Xiong Jin ◽

Jinwoo Chung ◽

Joon-Chul Kim ◽

...

Keyword(s):

Liver Disease ◽

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Milk Fat ◽

Transforming Growth Factor ◽

Stellate Cells ◽

Receptor Interaction ◽

Female Rat ◽

Milk Fat Globule ◽

Fat Globule

Milk fat globule-EGF factor 8 (MFG-E8) protein is known as an immunomodulator in various diseases, and we previously demonstrated the anti-fibrotic role of MFG-E8 in liver disease. Here, we present a truncated form of MFG-E8 that provides an advanced therapeutic benefit in treating liver fibrosis. The enhanced therapeutic potential of the modified MFG-E8 was demonstrated in various liver fibrosis animal models, and the efficacy was further confirmed in human hepatic stellate cells and a liver spheroid model. In the subsequent analysis, we found that the modified MFG-E8 more efficiently suppressed transforming growth factor β (TGF- β) signaling than the original form of MFG-E8, and it deactivated the proliferation of hepatic stellate cells in the liver disease environment through interfering with the interactions between integrins (αvβ3 & αvβ5) and TGF-βRI. Furthermore, the protein preferentially delivered in the liver after administration, and the safety profiles of the protein were demonstrated in male and female rat models. Therefore, in conclusion, this modified MFG-E8 provides a promising new therapeutic strategy for treating fibrotic diseases.

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Generation of liver organoids from human induced pluripotent stem cells as liver fibrosis and steatosis models

10.1101/2021.06.29.450347 ◽

2021 ◽

Author(s):

Hoi Ying Tsang ◽

Paulisally Hau Yi Lo ◽

Kenneth Ka Ho Lee

Keyword(s):

Stem Cells ◽

Liver Disease ◽

Liver Fibrosis ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Alcoholic Fatty Liver ◽

Obesity And Diabetes ◽

Liver Functions ◽

Induced Pluripotent ◽

Liver Organoids

Background & Aims: Liver cirrhosis is a major cause of death worldwide, and its prevalence is growing rapidly due to the growth of obesity and diabetes population with non-alcoholic fatty liver disease (NAFLD). Yet, no effective therapeutics have been developed to treat NAFLD or its more advanced stage, non-alcoholic steatohepatitis (NASH). This has raised great concern for a representative liver model to be developed so that novel drugs could be screened, identified and developed. Presently, we aim to develop a liver organoid entirely from human induced pluripotent stem cells (hiPSC) to model liver fibrogenesis and NAFLD. Methods: Hepatoblasts (HBs), mesenchymal stem cells (MSCs), hepatic stellate cell (HSCs) and endothelial cells (ECs) were derived from hiPSCs, allowed to self-organized and differentiated into liver organoids. Liver functions, transcriptomic and protein expression of liver organoids were characterized and validated. Liver organoids were exposed to thioacetamide (TAA) and free fatty acids (FFA) to be induced into liver disease model. Results: The liver organoids we fabricated were highly vascularized, exhibited liver-specific functions and hepatic cellular spatial organization. The presence of liver specific ECs, macrophages and cholangiocytes were found within our organoids. TAA induced fibrosis in our liver organoids that exhibited diminished liver functions, elevated pro-inflammatory cytokines and fibrosis-related gene expression, as well as extensive collagen deposit. Organoids treated with FFA developed steatosis, inflammation and fibrosis. Conclusions: We generated a novel method, that is Matrigel-independent and size-controllable, for making human liver organoids. These organoids can potentially be utilized as tissue-mimetic in vitro model for high throughput screening to identify drugs that can be used to treat liver fibrosis and NAFLD.

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