Sa.93. The CYP450 Mouse Model for Autoimmune Liver Disease: Virus-induced Activation of Hepatic Stellate Cells Causes 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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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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P625 HEPATIC STELLATE CELLS ARE THE MAIN SOURCE OF MYOFIBROBLASTS IN A MOUSE MODEL OF CHRONIC CHOLESTATIC LIVER DISEASE

Journal of Hepatology ◽

10.1016/s0168-8278(14)60787-x ◽

2014 ◽

Vol 60 (1) ◽

pp. S277

Author(s):

U.J. Lemberger ◽

M. Trauner ◽

C.H. Österreicher

Keyword(s):

Liver Disease ◽

Mouse Model ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Cholestatic Liver Disease

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Dynamics of Sept4 expression in fibrotic livers of mice infected with Schistosoma japonicum

Parasitology ◽

10.1017/s0031182011000667 ◽

2011 ◽

Vol 138 (8) ◽

pp. 1003-1010 ◽

Cited By ~ 10

Author(s):

Y. N. DUAN ◽

H. Y. QIAN ◽

Y. W. QIN ◽

D. D. ZHU ◽

X. X. HE ◽

...

Keyword(s):

Smooth Muscle ◽

Liver Fibrosis ◽

Mouse Model ◽

Schistosoma Japonicum ◽

Hepatic Stellate Cells ◽

Immunohistochemical Staining ◽

Smooth Muscle Actin ◽

Stellate Cells ◽

Muscle Actin ◽

Qrt Pcr

SUMMARYIn order to investigate the dynamics of Septin4 (Sept4) expression and its function in the formation of fibrotic livers in mice infected with Schistosoma japonicum, we constructed the mouse model of S. japonicum egg-induced liver fibrosis for 24 weeks. Immunohistochemical staining, qRT-PCR and Western blot were used to detect the expression of Sept4 and α-smooth muscle actin (α-SMA). We found Sept4 localized in the perisinusoidal space where hepatic stellate cells (HSCs) distribute in the periphery of circumoval granulomas and the portal venule. The expression of Sept4 and α-SMA had a similar significant tendency of an up-regulation to a peak at 12 weeks post-infection (p.i.) followed by a down-regulation. At 24 weeks p.i. both were at a low level. These results suggest that Sept4 and α-SMA may interact together in HSCs. Based on this evidence, we hypothesize that Sept4 seems to be involved in the formation of inflammatory granulomata and subsequent liver fibrosis by regulating HSCs activation.

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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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