The Role Of Shp/Rev-Erb Alpha/Cyp4a Axis In The Pathogenesis Of Alcohol-Associated Liver Disease

Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid omega-hydroxylation of medium-and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp(-/-) mice were fed with a modified ethanol-binge. National institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERE alpha agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp(-/-) mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERB alpha is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erb alpha(-/-) hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBu agonist 5R9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERB alpha/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV- ERB alpha or CYP4A as the potential therapeutic targets for ALD.