Arid1a loss drives non‐alcoholic steatohepatitis in mice via epigenetic dysregulation of hepatic lipogenesis and fatty acid oxidation

Abstract

Nonalcoholic steatohepatitis (NASH) is a rapidly growing cause of chronic liver damage, cirrhosis, and hepatocellular carcinoma (HCC). How fatty liver pathogenesis is subject to epigenetic regulation is unknown. We hypothesized that chromatin remodeling is important for the pathogenesis of fatty liver disease. ARID1A, a DNA‐binding component of the SWI/SNF ATP‐dependent chromatin‐remodeling complex, contributes to nucleosome repositioning and access by transcriptional regulators. Liver‐specific deletion of Arid1a (Arid1a LKO) caused the development of age‐dependent fatty liver disease in mice. Transcriptome analysis revealed upregulation of lipogenesis and down‐regulation of fatty acid oxidation genes. As evidence of direct regulation, ARID1A demonstrated direct binding to the promoters of many of these differentially regulated genes. Additionally, Arid1a LKO mice were more susceptible to high‐fat diet‐induced liver steatosis and fibrosis. We deleted Pten in combination with Arid1a to synergistically drive fatty liver progression. Inhibition of lipogenesis using CAT‐2003, a potent SREBP inhibitor, mediated improvements in markers of fatty liver disease progression in this Arid1a/Pten double knockout model.

Conclusion

ARID1A plays a role in the epigenetic regulation of hepatic lipid homeostasis, and its suppression contributes to fatty liver pathogenesis. Combined Arid1a and Pten deletion shows accelerated fatty liver disease progression and is a useful mouse model for studying new therapeutic strategies for NASH.

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