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

• Published in: Hepatology (Baltimore, Md.) Vol. 53; no. 5; p. 1526
• Main Authors: Nath, Bharath, Levin, Ivan, Csak, Timea, Petrasek, Jan, Mueller, Christian, Kodys, Karen, Catalano, Donna, Mandrekar, Pranoti, Szabo, Gyongyi
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc 01-05-2011
• Subjects: Alcohol; Chemokines; Deoxyribonucleic acid; DNA; Hepatology; Hypoxia; Lipids; Liver; Proteins; Rodents
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.24256

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 [alpha] 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;)