GPR52 accelerates fatty acid biosynthesis in a ligand-dependent manner in hepatocytes and in response to excessive fat intake in mice

Gpr52 is an orphan G-protein-coupled receptor of unknown physiological function. We found that Gpr52-deficient (Gpr52(−/−)) mice exhibit leanness associated with reduced liver weight, decreased hepatic de novo lipogenesis, and enhanced insulin sensitivity. Treatment of the hepatoma cell line HepG2 cells with c11, the synthetic GPR52 agonist, increased fatty acid biosynthesis, and GPR52 knockdown (KD) abolished the lipogenic action of c11. In addition, c11 induced the expressions of lipogenic enzymes (SCD1 and ELOVL6), whereas these inductions were attenuated by GPR52-KD. In contrast, cholesterol biosynthesis was not increased by c11, but its basal level was significantly suppressed by GPR52-KD. High-fat diet (HFD)-induced increase in hepatic expression of Pparg2 and its targets (Scd1 and Elovl6) was absent in Gpr52(−/−) mice with alleviated hepatosteatosis. Our present study showed that hepatic GPR52 promotes the biosynthesis of fatty acid and cholesterol in a ligand-dependent and a constitutive manner, respectively, and Gpr52 participates in HFD-induced fatty acid synthesis in liver.