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J Biol Chem. 2017 Aug 4;292(31):12860-12873. doi: 10.1074/jbc.M117.785030. Epub 2017 May 30.

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

Author information

1
From the INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France, herve.lerat@inserm.fr.
2
the Université Paris-Est Créteil Val de Marne, 94010 Créteil, France.
3
From the INSERM, U955, Team "Pathophysiology and Therapy of Chronic Viral Hepatitis and Related Cancers", 94010 Créteil, France.
4
the Unité de Biologie Fonctionnelle et Adaptative, Sorbonne Paris Cité, CNRS UMR 8251, Université Paris Diderot, 75013 Paris, France.
5
the INSERM, UMRS 1138, Centre de Recherche des Cordeliers, 75006 Paris, France, and.
6
the National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, AP-HP, 94010 Créteil, France.

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 TNFα/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.

KEYWORDS:

glucose metabolism; hepatitis C virus (HCV); insulin resistance; transgenic mice; type 2 diabetes

PMID:
28559285
PMCID:
PMC5546027
DOI:
10.1074/jbc.M117.785030
[Indexed for MEDLINE]
Free PMC Article

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