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

Authors


  • Potential conflict of interest: G. S. is a member of the University of Massachusetts Diabetes Endocrinology Research Center.

  • Supported by grants R21 AA017544 (to G. S.) and F30 AA017030 (to B. N.) from the National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health. The core resources supported by the Diabetes Endocrinology Research Center grant DK32520 were also used.

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. Conclusion: 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. (HEPATOLOGY 2011;)

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