Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice

Bharath D. Nath, University of Massachusetts Medical School
Ivan Levin, University of Massachusetts Medical School
Timea Csak, University of Massachusetts Medical School
Jan Petrasek, University of Massachusetts Medical School
Christian Mueller, University of Massachusetts Medical School
Karen Kodys, University of Massachusetts Medical School
Donna Catalano, University of Massachusetts Medical School
Pranoti Mandrekar, University of Massachusetts Medical School
Gyongyi Szabo, University of Massachusetts Medical School

Document Type Article

Abstract

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

CONCLUSION: Alcohol feeding results in lipid accumulation in hepatocytes involving HIF-1alpha activation. The alcohol-induced chemokine MCP-1 triggers lipid accumulation in hepatocytes via HIF-1alpha activation, suggesting a mechanistic link between inflammation and hepatic steatosis in alcoholic liver disease.