RPA1 controls chromatin architecture and maintains lipid metabolic homeostasis.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease, with a prevalence of 25% worldwide. However, the underlying molecular mechanism involved in the development and progression of the NAFLD spectrum remains unclear. Single-stranded DNA-binding protein replication protein A1 (RPA1) participates in DNA replication, recombination, and damage repair. Here, we show that Rpa1+/- mice develop fatty liver disease during aging and in response to a high-fat diet. Liver-specific deletion of Rpa1 results in downregulation of genes related to fatty acid oxidation and impaired fatty acid oxidation, which leads to hepatic steatosis and hepatocellular carcinoma. Mechanistically, RPA1 binds gene regulatory regions, chromatin-remodeling factors, and HNF4A and remodels chromatin architecture, through which RPA1 promotes HNF4A transcriptional activity and fatty acid β oxidation. Collectively, our data demonstrate that RPA1 is an important regulator of NAFLD through controlling chromatin accessibility.