G protein-coupled receptor 119 regulates hepatic lipid homeostasis in zebrafish (Danio rerio)

Hepatic lipid homeostasis is crucial for overall liver health, necessitating an understanding of its underlying physiological mechanisms. While G protein-coupled receptor 119 (GPR119) has emerged as a key receptor in lipid metabolism, its physiological role in the liver remains poorly explored. We investigated the role of GPR119 in hepatic lipid homeostasis using the zebrafish hepatocyte cell line (ZFL), alongside both high-fat diet (HFD)-induced and genetic knockout (GPR119^-/-) zebrafish models. We demonstrated that pharmacological activation of GPR119 by the agonist MBX-2982 attenuated HFD-induced hepatic steatosis and liver injury. Conversely, endogenous GPR119 deficiency induced spontaneous hepatic lipid accumulation and elevated serum transaminase activities under basal physiological conditions. Mechanistically, GPR119 signaling limits lipid accumulation by coordinately downregulating de novo lipogenesis while promoting lipolysis and very-low-density lipoprotein (VLDL)-dependent lipid clearance. Collectively, our findings indicate that GPR119 is a regulator of hepatic lipid homeostasis, functioning to restrict lipid supply and accelerate lipid clearance. This study provides in vivo genetic evidence highlighting the role of GPR119 in hepatic lipid homeostasis, thereby advancing our physiological understanding of liver function and lipid handling.