Role of Hypoxia Inducing Factor-1[beta] in Alcohol-Induced Autophagy, Steatosis and Liver Injury in Mice

• Published in: PloS one 2014-12, Vol.9 (12)
• Main Authors: Ni, Hong-Min, Bhakta, Amar, Wang, Shaogui, Li, Zhenrui, Manley, Sharon, Huang, Heqing, Copple, Bryan, Ding, Wen-Xing
• Format: Article
• Language: English
• Subjects: Analysis; Drinking (Alcoholic beverages); House mouse; Liver cirrhosis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0115849

Chronic alcohol causes liver hypoxia and steatosis, which eventually develops into alcoholic liver disease (ALD). While it has been known that alcohol consumption activates hepatic hypoxia inducing factor-1[alpha] (HIF-1[alpha]), conflicting results regarding the role of HIF-1[alpha] in alcohol-induced liver injury and steatosis in mice have been reported. In the present study, we aimed to use hepatocyte-specific HIF-1[beta] knockout mice to eliminate the possible compensatory effects of the single knockout of the 1[alpha] subunit of HIF to study the role of HIFs in ALD. C57BL/6 wild type mice were treated with acute ethanol to mimic human binge drinking. Matched wild-type and hepatocyte specific HIF-1[beta] knockout mice were also subjected to a recently established Gao-binge alcohol model to mimic chronic plus binge conditions, which is quite common in human alcoholics. We found that acute alcohol treatment increased BNIP3 and BNIP3L/NIX expression in primary cultured hepatocytes and in mouse livers, suggesting that HIF may be activated in these models. We further found that hepatocyte-specific HIF-1[beta] knockout mice developed less steatosis and liver injury following the Gao-binge model or acute ethanol treatment compared with their matched wild type mice. Mechanistically, protection against Gao-binge treatment-induced steatosis and liver injury was likely associated with increased FoxO3a activation and subsequent induction of autophagy in hepatocyte-specific HIF-1[beta] knockout mice.