ETV5 regulates hepatic fatty acid metabolism through PPAR signaling pathway

ETV5 is an ETS transcription factor which has been associated with obesity in genomic association studies. However, little is known about the role of ETV5 in hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD). In the present study, we found that ETV5 protein expression was increased in diet- and genetic-induced steatotic liver. ETV5 responded to the nutrient status in an mTORC1 dependent manner and in turn regulated mTORC1 activity. Both viral-mediated and genetic depletion of ETV5 in mice led to increased lipid accumulation in the liver. RNA sequencing analysis revealed that PPAR signaling and fatty acid degradation/metabolism pathways were significantly downregulated in ETV5 deficient hepatocytes in vivo and in vitro. Mechanistically, ETV5 could bind to the PPRE region of PPAR downstream genes and enhance its transactivity. Collectively, our study identifies ETV5 as a novel transcription factor for the regulation of hepatic fatty acid metabolism which is required for the optimal β oxidation process. ETV5 may provide a therapeutic target for the treatment of hepatic steatosis.