Hepatic GPR75 exacerbates MASH through GNAI2-dependent signaling

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD), including its more severe form, metabolic dysfunction-associated steatohepatitis (MASH), is increasingly recognized as a critical global health challenge. This study investigates the role of hepatic GPR75 in MASH progression. APPROACH AND RESULTS: Although GPR75 is not abundantly expressed in the liver in healthy individuals, its protein levels significantly increase during MASH. Depletion of Gpr75 in either the whole liver or specifically in hepatocytes protected mice from diet-induced hepatic steatosis, while hepatocyte-specific overexpression of Gpr75 exacerbated diet-induced MASH and liver fibrosis. The deficiency of hepatic Gpr75 activated the GNAI2-cAMP-PKA signaling pathway in the livers of MASLD mice, reducing SREBP-1c maturation and de novo lipogenesis. Mechanistically, VPS35 stabilized GPR75 by recycling it to the hepatocyte membrane, thereby decreasing its degradation during MASH progression. CONCLUSIONS: This study demonstrates that GPR75 serves as a novel regulator of MASLD/MASH by modulating hepatic fatty acid metabolism. These findings suggest that GPR75 suppression may represent a potential therapeutic strategy for MASLD/MASH treatment.