The prevalence of obesity is a global concern with nearly 2 in 5 adults (42.4%) in the US having obesity. Rapid and sustained increases in weight gain result in various obesity-driven complications and health outcomes including non- alcoholic fatty liver disease (NAFLD). Recently, several predicted loss of function variants of the understudied orphan G protein- coupled receptor (GPCR), GPR75 were identified to be associated with leanness and a protective phenotype against obesity in a world-wide multi-ethnic exome sequencing of over 640,000 individuals. Our group was instrumental in these studies and our proposal seeks to examine the role of GPR75 in obesity and NAFLD. Specifically, we hypothesize that the pairing of GPR75 to its high-affinity ligand, 20-HETE, a vasoactive and proinflammatory lipid, exacerbating diet-induced obesity, driving NAFL and nonalcoholic steatohepatitis (NASH) which is characterized by pronounced inflammation, cell damage and fibrosis. To test this hypothesis, we propose two specific aims. Aim 1 seeks to determine the degree to which the pairing of 20-HETE/GPR75 contributes to the pathogenesis of obesity-driven NAFLD/NASH. This aim will evaluate the severity of obesity, diabetes/insulin resistance and liver damage in mice deficient in GPR75 and exposed to elevations in 20-HETE and a high-fat diet feeding protocol across time. A novel water-soluble GPR75 receptor blocker, AAA, will be used to assess the dependency of the disease development and progression on 20-HETE-GPR75 pairing. Aim 2 looks to identify the cellular mechanism by which the 20-HETE-GPR75 pairing drives increases in fatty acid uptake and inflammation which contribute to NAFLD. Specifically, it will determine how the activation of GPR75 via 20-HETE stimulates the activity of the fatty acid transporter 2 (FATP2) in hepatocytes. We will also evaluate how the combination of 20-HETE and fatty acid influx drive various proinflammatory and profibrotic signals. This particular aim will also incorporate the use of AAA (GPR75 receptor blocker) and hepatocytes deficient in GPR75. The implications behind the proposed research are highly innovative as they will lay the foundation and fundamentals as we continue to learn more about the role of GPR75 in obesity and NAFLD/NASH. Our preliminary data strongly suggest that GPR75 is a druggable target with translational applications for the prevention and treatment of obesity and NAFLD/NASH, diseases that presently plague the global healthcare system. Therefore, we believe that this application fits strongly with the IDG’s initiative to support studies pertaining to poorly characterized GPCRS in human health and disease.

This project addresses the NIH’s Illuminating the Druggable Genome (IDG) initiative by focusing on the poorly understood GPCR, GPR75 and its endogenous high-affinity ligand 20-HETE, a vasoactive lipid, in the context of obesity and non-alcoholic fatty liver disease (NAFLD). The proposed research will uncover the pathological consequences and molecular mechanisms that are activated by the paring of GPR75 to 20-HETE as well as how to best block this interaction in order to alleviate and prevent the damage associated with obesity and NAFLD. Obesity and obesity-associated complications like NAFLD are a major and ever-growing public health concern and our proposal will reveal how promising GPR75 is as a novel target for the treatment of these diseases.