Targeting GPR68 Alleviates Inflammation and Lipid Accumulation in Metabolic Dysfunction-Associated Steatohepatitis

Area of Science:

• Hepatology
• Molecular Biology
• Metabolic Diseases

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a growing liver disease with limited treatments.
• Tissue acidification is implicated in metabolic diseases, but its role in MASH is unclear.

Purpose of the Study:

• To investigate the role of proton-sensing G protein-coupled receptor GPR68 in MASH pathogenesis.
• To evaluate GPR68 as a potential therapeutic target for MASH.

Main Methods:

• Utilized a high-fat diet-induced mouse model of MASH.
• Assessed hepatic GPR68 expression and MASH pathology.
• Administered the GPR68 inhibitor ogremorphin to evaluate therapeutic effects.

Main Results:

• Hepatic GPR68 expression was significantly upregulated in MASH progression.
• GPR68 inhibition with ogremorphin ameliorated MASH, reducing inflammation and lipid accumulation.
• Inhibition of GPR68 decreased pro-inflammatory cytokines (IL-6, TNF-α) and dampened acidification-associated signaling.

Conclusions:

• GPR68 acts as a key regulator in diet-induced MASH, linking tissue acidification to liver injury.
• Targeting GPR68 represents a promising therapeutic strategy for managing MASH.