Inhibition of estrogen related receptor a blocks liver steatosis and steatohepatitis and attenuates triglyceride biosynthesis Chien-yu Chen, Yang Li, Lina He, and Bangyan Stiles Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angles, CA 90089 The ERR family of orphan nuclear receptors are transcriptional activators for genes involved in mitochondrial bioenergetics and metabolism. The goal of this study is to explore the role of estrogen-related receptor a (ERRa) in lipid metabolism and explore the potential effect of inhibiting ERRa on the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In the current study, we used three experimental mouse models: high fat diet, high carbohydrate diet, and a genetic model of hepatic insulin resistance where the liver hyperinsulinemia signal is mimicked via hepatic deletion of Pten (phosphatase and tensin homolog deleted on chromosome 10), the negative regulator of the insulin/PI3K signaling pathway. Using a recently developed small molecule inhibitor for ERRα, we demonstrate that inhibiting ERRα blocks NAFLD development induced by either HCD or HFD feeding. ERRα inhibition also diminishes lipid accumulation and attenuates NASH development in the Pten null mice. We discovered glycerolipid synthesis as an additional mechanism for ERRa regulated NAFLD/NASH development and identified glycerophosphate acyltransferase 4 (GPAT4) as a novel transcriptional target of ERRa. In summary, these results establish ERRa as a major transcriptional regulator of lipid biosynthesis in addition to its characterized primary function as a regulator for mitochondrial function. This study recognizes ERRα as a potential target for NAFLD/NASH treatment and elucidates novel signaling pathways regulated by ERRα.