Amelioration of non-alcoholic fatty liver disease by targeting GPR110 in a diet-induced obese mouse model

Abstract

Recent research has shown that the G protein-coupled receptor 110 (GPR110) is an oncogene evidenced by the increased expression of this receptor in numerous cancer types. Cell migration, invasion, and proliferation can all be reduced by GPR110 knockdown. GPR110 is, however, mostly expressed in the liver of healthy individuals. The precise physiological role of hepatic GPR110 in metabolism has not been revealed. In this study, I identified the unique role of GPR110 in association with the liver function in a mouse model of diet-induced obesity using a comprehensive metabolic phenotyping approach. The expression of GPR110 in the liver was shown to be strictly regulated by nutritional availability using RT-qPCR and Western blot analyses. In both mice and humans, a high hepatic GPR110 level was strongly linked to the probability of developing liver steatosis. The disease severity of mice with non-alcoholic fatty liver disease (NAFLD) induced by a high-fat diet was alleviated when GPR110 was knocked down using antisense oligonucleotides. Stearoyl-coA desaturase 1 (SCD1), a crucial enzyme in hepatic de novo lipogenesis, has been identified as a downstream target of GPR110 by RNA-sequencing analysis. Treatment with the liver-specific SCD1 inhibitor MK8245 greatly improved the lipid profiles of GPR110-overexpressing mice and selective shRNAs against SCD1 in GPR110 infected primary hepatocytes In my thesis work, I hereby provide the first evidence demonstrating that GPR110 plays a physiological role in regulating hepatic lipid metabolism through controlling the expression of SCD1. In obese individuals, down-regulation of GPR110 expression can potentially serve as a protective mechanism to stop the over-accumulation of lipids in the liver. My work has shed light on the future development of a rational therapeutic approach by inhibiting GPR110 for the management of NAFLD.