ABSTRACT: Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated hypoxia-inducible factor 1-?, (HIF-1?) may regulate liporegulatory genes, but the relationship of HIF-1 to steatosis remains unknown. We investigated HIF-1? 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-1? 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-1? 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-1? [HIF-1?(Hep(-/-) )], protected mice from alcohol- and lipopolysaccharide (LPS)-induced liver damage, serum ALT elevation, hepatomegaly, and lipid accumulation. HIF-1?(Hep(-/-) ), WT, and HIF1dPA mice had equally suppressed levels of peroxisome proliferator-activated receptor ? mRNA after chronic ethanol, whereas the HIF target, adipocyte differentiation-related protein, was up-regulated in WT mice but not HIF-1?(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-1?(Hep(-/-) ) mice. Using Huh7 hepatoma cells in vitro, we found that MCP-1 treatment induced lipid accumulation and increased HIF-1? protein expression as well as DNA-binding activity. Small interfering RNA inhibition of HIF-1? prevented MCP-1-induced lipid accumulation, suggesting a mechanistic role for HIF-1? in hepatocyte lipid accumulation.Alcohol feeding results in lipid accumulation in hepatocytes involving HIF-1? activation. The alcohol-induced chemokine MCP-1 triggers lipid accumulation in hepatocytes via HIF-1? activation, suggesting a mechanistic link between inflammation and hepatic steatosis in alcoholic liver disease.
