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ANGPTL4 is a potential driver of HCV-induced peripheral insulin resistance
Diana Gomes1,2, Cyril Sobolewski3,4, Stéphanie Conzelmann1
1Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
Abstract:
Chronic hepatitis C (CHC) is associated with the development of metabolic disorders, including both hepatic and extra-hepatic insulin resistance (IR). Here, we aimed at identifying liver-derived factor(s) potentially inducing peripheral IR and uncovering the mechanisms whereby HCV can regulate the action of these factors. We found ANGPTL4 (Angiopoietin Like 4) mRNA expression levels to positively correlate with HCV RNA (r = 0.46, p < 0.03) and HOMA-IR score (r = 0.51, p = 0.01) in liver biopsies of lean CHC patients. Moreover, we observed an upregulation of ANGPTL4 expression in two models recapitulating HCV-induced peripheral IR, i.e. mice expressing core protein of HCV genotype 3a (HCV-3a core) in hepatocytes and hepatoma cells transduced with HCV-3a core. Treatment of differentiated myocytes with recombinant ANGPTL4 reduced insulin-induced Akt-Ser473 phosphorylation. In contrast, conditioned medium from ANGPTL4-KO hepatoma cells prevented muscle cells from HCV-3a core induced IR. Treatment of HCV-3a core expressing HepG2 cells with PPARγ antagonist resulted in a decrease of HCV-core induced ANGPTL4 upregulation. Together, our data identified ANGPTL4 as a potential driver of HCV-induced IR and may provide working hypotheses aimed at understanding the pathogenesis of IR in the setting of other chronic liver disorders.
Insights
Hepatitis C virus (HCV) infection can cause insulin resistance (IR). This study identifies Angiopoietin Like 4 (ANGPTL4) as a key liver-derived factor contributing to HCV-induced IR, offering new insights into metabolic complications.
Area of Science:
- Hepatology
- Metabolic Disorders
- Molecular Biology
Background:
- Chronic hepatitis C (CHC) is linked to metabolic disorders like insulin resistance (IR).
- Hepatitis C virus (HCV) infection can lead to both liver and systemic IR.
- Understanding the molecular mechanisms behind HCV-induced IR is crucial.
Purpose of the Study:
- To identify liver-derived factors that induce peripheral IR in CHC.
- To investigate how HCV regulates these factors.
- To elucidate the role of Angiopoietin Like 4 (ANGPTL4) in HCV-associated IR.
Main Methods:
- Correlation analysis of ANGPTL4 mRNA, HCV RNA, and HOMA-IR in CHC patient liver biopsies.
- In vitro and in vivo models of HCV-induced IR (HCV-3a core expressing mice and hepatoma cells).
- Experiments using recombinant ANGPTL4, ANGPTL4-knockout cells, and PPARγ antagonist.
Main Results:
- ANGPTL4 mRNA expression positively correlated with HCV RNA and HOMA-IR in CHC patients.
- ANGPTL4 expression was upregulated in HCV-3a core models.
- Recombinant ANGPTL4 impaired insulin signaling in myocytes; ANGPTL4-knockout cells protected against HCV-induced IR.
- PPARγ activation mediated HCV-core-induced ANGPTL4 upregulation.
Conclusions:
- ANGPTL4 is identified as a potential driver of insulin resistance in chronic hepatitis C.
- This finding provides a mechanistic link between HCV infection and metabolic dysfunction.
- The study offers hypotheses for understanding IR in other chronic liver diseases.
