title: Hepatocyte-specific hypoxia-inducible factor-1α is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice.
abstract: Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated hypoxia-inducible factor 1-α, (HIF-1α) may regulate liporegulatory genes, but the relationship of HIF-1 to steatosis remains unknown. We investigated HIF-1α in alcohol-induced hepatic lipid accumulation. Alcohol administration resulted in steatosis, increased liver triglyceride levels, and increased serum alanine aminotransferase (ALT) levels, suggesting liver injury in wild-type (WT) mice. There was increased hepatic HIF-1α messenger RNA (mRNA), protein, and DNA-binding activity in alcohol-fed mice compared with controls. Mice engineered with hepatocyte-specific HIF-1 activation (HIF1dPA) had increased HIF-1α mRNA, protein, and DNA-binding activity, and alcohol feeding in HIF1dPA mice increased hepatomegaly and hepatic triglyceride compared with WT mice. In contrast, hepatocyte-specific deletion of HIF-1α [HIF-1α(Hep(-/-) )], protected mice from alcohol- and lipopolysaccharide (LPS)-induced liver damage, serum ALT elevation, hepatomegaly, and lipid accumulation. HIF-1α(Hep(-/-) ), WT, and HIF1dPA mice had equally suppressed levels of peroxisome proliferator-activated receptor α mRNA after chronic ethanol, whereas the HIF target, adipocyte differentiation-related protein, was up-regulated in WT mice but not HIF-1α(Hep(-/-) ) ethanol-fed/LPS-challenged mice. The chemokine monocyte chemoattractant protein-1 (MCP-1) was cooperatively induced by alcohol feeding and LPS in WT but not HIF-1α(Hep(-/-) ) mice. Using Huh7 hepatoma cells in vitro, we found that MCP-1 treatment induced lipid accumulation and increased HIF-1α protein expression as well as DNA-binding activity. Small interfering RNA inhibition of HIF-1α prevented MCP-1-induced lipid accumulation, suggesting a mechanistic role for HIF-1α in hepatocyte lipid accumulation.
  
  
  CONCLUSIONS
  Alcohol feeding results in lipid accumulation in hepatocytes involving HIF-1α activation. The alcohol-induced chemokine MCP-1 triggers lipid accumulation in hepatocytes via HIF-1α activation, suggesting a mechanistic link between inflammation and hepatic steatosis in alcoholic liver disease.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Bharath
authors.initials: B
authors.lastname: Nath
authors.forename: Ivan
authors.initials: I
authors.lastname: Levin
authors.forename: Timea
authors.initials: T
authors.lastname: Csak
authors.forename: Jan
authors.initials: J
authors.lastname: Petrasek
authors.forename: Christian
authors.initials: C
authors.lastname: Mueller
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000818:Animals; D005235:Fatty Liver, Alcoholic / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D050356:Lipid Metabolism; D051379:Mice
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit