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Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice

Abstract : Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNF/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans.
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https://hal-cnrs.archives-ouvertes.fr/hal-03108281
Contributor : Colette Orange <>
Submitted on : Wednesday, January 13, 2021 - 9:44:18 AM
Last modification on : Friday, January 15, 2021 - 3:20:34 AM

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H Lerat, Mr Imache, J Polyte, A Gaudin, M Mercey, et al.. Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2017, 292 (31), pp.12860-12873. ⟨10.1074/jbc.M117.785030⟩. ⟨hal-03108281⟩

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