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 HepG2 cells with c11, the synthetic GPR52 agonist, increased fatty acid biosynthesis, and GPR52-knockdown (KD) abolished the lipogenic action of c11 without affecting its basal level. In addition, c11 induced gene expressions of lipogenic enzymes (SCD1, ELOVL6, and ACC1), while 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 lipogenic gene induction was absent in Gpr52-/- mice with a partially decreased hepatosteatosis. Our present study showed that hepatic GPR52 promotes biosynthesis of fatty acid and cholesterol in a ligand-dependent and a constitutive manner, respectively, and murine Gpr52 participates in HFD-induced fatty acid synthesis in liver.