Hepatic GPR75 exacerbates MASH through GNAI2-dependent signaling

Area of Science:

• Hepatology
• Metabolic Diseases
• Molecular Biology

Background:

• Metabolic-dysfunction-associated steatotic liver disease (MASLD) and its severe form, MASH, are significant global health concerns.
• The role of hepatic G protein-coupled receptor 75 (GPR75) in MASH pathogenesis is under investigation.

Purpose of the Study:

• To investigate the role of hepatic GPR75 in the progression of metabolic dysfunction-associated steatohepatitis (MASH).

Main Methods:

• Examined GPR75 protein levels in MASH conditions.
• Utilized Gpr75 knockout and overexpression models in mice fed a high-fat diet.
• Investigated the GNAI2-cAMP-PKA signaling pathway and SREBP-1c maturation.
• Assessed the role of VPS35 in GPR75 stabilization and degradation.

Main Results:

• GPR75 protein levels significantly increase in MASH.
• Gpr75 depletion protected against diet-induced hepatic steatosis and MASH.
• Hepatocyte-specific GPR75 overexpression exacerbated MASH and liver fibrosis.
• GPR75 deficiency activated the GNAI2-cAMP-PKA pathway, reducing de novo lipogenesis.
• VPS35 stabilizes GPR75, decreasing its degradation during MASH progression.

Conclusions:

• GPR75 is a novel regulator of MASLD/MASH, modulating hepatic fatty acid metabolism.
• GPR75 suppression presents a potential therapeutic strategy for MASLD/MASH.