Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C.
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.
García-Monzón
Carmelo
C
Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
Lo Iacono
Oreste
O
Mayoral
Rafael
R
González-Rodríguez
Agueda
A
Miquilena-Colina
María E
ME
Lozano-Rodríguez
Tamara
T
García-Pozo
Leonor
L
Vargas-Castrillón
Javier
J
Casado
Marta
M
Boscá
Lisardo
L
Valverde
Angela M
AM
Martín-Sanz
Paloma
P
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
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