Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2026 Feb 3.
doi: 10.1097/HEP.0000000000001706. Online ahead of print.

Hepatic GPR75 exacerbates MASH through GNAI2-dependent signaling

Xule Yang  1 , Na Yang  2 , Zhihao Cheng  1 , Rui Zhang  1 , Hui Fan  1 , Dongsheng Liu  1 , Jiye Aa  1 , Guangji Wang  1   3 , Yuan Xie  1
Affiliations

Hepatic GPR75 exacerbates MASH through GNAI2-dependent signaling

Xule Yang et al. Hepatology. .

Abstract

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.

Keywords: GNAI2; GPR75; MASH; VPS35; de novo lipogenesis.

PubMed Disclaimer

References

    1. Raza S, Rajak S, Yen PM, Sinha RA. Autophagy and hepatic lipid metabolism: Mechanistic insight and therapeutic potential for MASLD. NPJ Metab Health Dis. 2024;2:19.
    1. Hutchison AL, Tavaglione F, Romeo S, Charlton M. Endocrine aspects of metabolic dysfunction-associated steatotic liver disease (MASLD): Beyond insulin resistance. J Hepatol. 2023;79:1524–1541.
    1. Wallstab C, Eleftheriadou D, Schulz T, Damm G, Seehofer D, Borlak J, et al. A unifying mathematical model of lipid droplet metabolism reveals key molecular players in the development of hepatic steatosis. FEBS J. 2017;284:3245–3261.
    1. Mashek DG. Hepatic lipid droplets: A balancing act between energy storage and metabolic dysfunction in NAFLD. Mol Metab. 2021;50:101115.
    1. El-Ashmawy NE, Khedr EG, Al-Ashmawy GM, Kamel AA. Emerging role of natural lipophagy modulators in metabolic dysfunction-associated steatotic liver disease. Nutrition. 2024;126:112517.

LinkOut - more resources