Estrogen-related receptor (ERR) plays critical roles in the transcriptional regulation of genes involved in mitochondrial bioenergetics, TCA cycle, mitochondrial oxidative phosphorylation, and fatty acid β-oxidation. This project intends to discover the roles of ERR as novel transcriptional factor for lipid metabolism its involvement in lipid pathology development in the liver. To address the function of ERR in dyslipidemia, we developed a novel small molecule inhibitor (ERR-PA) that can block the binding of ERRs to the promoters of its target genes. Using this compound in diet and genetic models of liver steatosis (NAFLD/ALD) and steatohepatitis (NASH/ASH), our preliminary studies showed that inhibiting ERR robustly blocks the development of steatosis and reverses the lipid accumulation in models where liver steatosis is induced by diet and ethanol feeding as well as genetic alterations. ERR-PA also significantly reduced the fibrosis and inflammation occurring in established steatohepatitis. Using these in vivo as well as in vitro systems, we will explore the molecular mechanisms by which ERR inhibition suppresses the progression of liver disease. The hypothesis to be tested is that ERRs positively regulate transcription of genes encoding enzymes for anabolic lipid metabolism and inhibiting this action blocks steatosis and associated inflammation and fibrosis in NASH/ASH. We will address this hypothesis with the following three aims. Aim1 will investigate the regulation of lipid metabolism via the transcriptional activity of ERRs. This aim will explore the transcriptional complex by which ERRα regulates de novo lipogenesis, glycerolipid biosynthesis and fatty acid β-oxidation. Aim2 will explore the regulation of ERRs by insulin signaling based on our previous discover that ERRα is a downstream target of insulin/PI3K/AKT signaling signal regulated via AKT phosphorylation on CREB and upregulation of PGC-1α. Aim3 will determine the effect of ERR inhibition on oxidative lipid damage in during ASH/NASH development. This aim will investigate lipid, oxidized lipid and other derivatives, ROS production and their contribution to liver damage. The proposed project will explore ERRα as a potential target for inhibiting and reversing fatty liver diseases. The mechanistic and translations approaches will uncover novel biology for lipid metabolism as well as test the therapeutic effect of a small molecule polyamide.