Hepatocyte-Specific Hypoxia-Inducible Factor-1α Is a Determinant of Lipid Accumulation and Liver Injury in Alcohol-Induced Steatosis in Mice

Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated hypoxia-inducible factor 1-alpha, (HIF-1 alpha) may regulate liporegulatory genes, but the relationship of HIF-1 to steatosis remains unknown. We investigated HIF-1 alpha 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 alpha 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 alpha 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 alpha [HIF-1 alpha(Hep(-/-))], protected mice from alcohol-and lipopolysaccharide (LPS)-induced liver damage, serum ALT elevation, hepatomegaly, and lipid accumulation. HIF-1 alpha(Hep(-/-)), WT, and HIF1dPA mice had equally suppressed levels of peroxisome proliferator-activated receptor a mRNA after chronic ethanol, whereas the HIF target, adipocyte differentiation-related protein, was up-regulated in WT mice but not HIF-1 alpha(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 alpha(Hep(-/-)) mice. Using Huh7 hepatoma cells in vitro, we found that MCP-1 treatment induced lipid accumulation and increased HIF-1 alpha protein expression as well as DNA-binding activity. Small interfering RNA inhibition of HIF-1 alpha prevented MCP-1-induced lipid accumulation, suggesting a mechanistic role for HIF-1 alpha in hepatocyte lipid accumulation. Conclusion: Alcohol feeding results in lipid accumulation in hepatocytes involving HIF-1 alpha activation. The alcohol-induced chemokine MCP-1 triggers lipid accumulation in hepatocytes via HIF-1 alpha activation, suggesting a mechanistic link between inflammation and hepatic steatosis in alcoholic liver disease. (HEPATOLOGY 2011;53:1526-1537)