Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C

Background & Aims: We aimed to elucidate whether hepatic insulin resistance may contribute to hepatocyte apoptosis and fibrogenesis in nonalcoholic fatty liver disease (NAFLD) and in chronic hepatitis C virus (HCV) infection. Methods: Twenty-seven nonalcoholic steatosis (NAST), 24 nonalcoholic steatohepatitis (NASH), 71 HCV, and 29 patients with histological normal liver (NL) were studied. Real-time PCR, the TUNEL assay, and Western blots were used to assess insulin-signaling molecules, hepatocyte apoptosis, antiapoptotic mediators, active caspase 3, and type I collagen in liver biopsies. HCV core-transfected human hepatocytes were used as an in vitro model. Results: In NAFLD patients, hepatic levels of insulin receptor substrate (IRS) 1, IRS2 2, the p85 alpha subunit of phosphatidylinositol 3-kinase (p85 alpha), phosphorylated protein kinase B (pAkt), phosphorylated forkhead box-containing protein O subfamily-1 (FoxO), and phosphorylated 5' adenosine monophosphate-activated protein kinase (pAMPK) as well as the antiapoptotic mediators B-cell lymphoma 2 protein (Bcl-2) and myeloid cell leukemia protein-1 (Mcl-1) were significantly lower in NASH than in NAST and NL. Furthermore, hepatocyte apoptosis and increased active caspase 3 were only present in NASH. In HCV patients, hepatic insulin signaling was markedly impaired, regardless of viral genotype and the presence of steatosis paralleled with enhanced apoptosis. In cultured human hepatocytes, HCV core protein decreased pAkt and increased phosphorylation of c-Jun N-terminal kinase (INK). This effect was more pronounced in lipid-loaded hepatocytes. Conclusions: Hepatic insulin signaling is impaired in NASH and HCV patients, and downregulation of insulin-sensitive targets is associated with increased apoptosis and fibrogenesis in both conditions. JNK might be a target for HCV-induced insulin resistance. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.