title: Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C.
abstract: OBJECTIVE
  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 p85α subunit of phosphatidylinositol 3-kinase (p85α), 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 (JNK). 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.
authors.affiliation: Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
authors.forename: Carmelo
authors.initials: C
authors.lastname: García-Monzón
authors.forename: Oreste
authors.initials: O
authors.lastname: Lo Iacono
authors.forename: Rafael
authors.initials: R
authors.lastname: Mayoral
authors.forename: Agueda
authors.initials: A
authors.lastname: González-Rodríguez
authors.forename: María E
authors.initials: ME
authors.lastname: Miquilena-Colina
authors.forename: Tamara
authors.initials: T
authors.lastname: Lozano-Rodríguez
authors.forename: Leonor
authors.initials: L
authors.lastname: García-Pozo
authors.forename: Javier
authors.initials: J
authors.lastname: Vargas-Castrillón
authors.forename: Marta
authors.initials: M
authors.lastname: Casado
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
authors.forename: Angela M
authors.initials: AM
authors.lastname: Valverde
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D005234:Fatty Liver / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D019254:Genes, bcl-2; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D065626:Non-alcoholic Fatty Liver Disease; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014758:Viral Core Proteins / Q000235:genetics
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014758:Viral Core Proteins