Alcohol Exacerbates Liver Injury and Fibrosis in Mice With Liver‐Specific Deficiency of Augmenter of Liver Regeneration

Abstract

Augmenter of liver regeneration (ALR) protein is expressed predominantly by hepatocytes in the liver, and is essential for their mitochondrial function. Liver‐specific ALR knockout (ALR‐L‐KO) mice develop accelerated steatohepatitis. Our aim was to investigate alcohol‐induced pathology in KO mice. WT or KO mice were fed isocaloric or 4% ethanol diet for 4 weeks. Ethanol‐fed KO mice showed retarded growth, excessive liver injury, increased serum ALT, but lower hepatic triglycerides as compared with WT ethanol‐fed mice. Whereas ethanol increased expressions of acetyl‐CoA carboxylase, fatty acid synthase and sterol regulatory element‐binding transcription factor 1 in WT mice, they were dramatically reduced in KO mice. Additionally, while expressions of alcohol dehydrogenase 1, acetaldehyde dehydrogenase 1 and Cyp2E1 increased in ethanol‐fed WT mice, they decreased in KO mice. These pathologies in KO mice were accompanied by increased oxidative stress, TNFα and TGFβ, and excessive fibrosis; WT mice increased TNFα but did not develop fibrosis. Hepatic ALR was also lower in humans with advanced alcoholic liver disease (ALD) and frequency of several single nucleotide polymorphisms was increased in ALD subjects compared to normal population. Our findings indicate that ALR protein deficiency causes exacerbation of alcohol‐induced liver injury and excessive fibrosis, and abnormality in ALR protein or deficiency may be an important mechanism of advanced ALD in humans, which occurs in about 30% of the populationGrant support: Supported by a VA Merit Review Award (1IO1BX001174) and NIH (PO1AIO81678 and R21AA020846).