Promoter demethylation and protein O-GlcNAcylation synergistically regulate fatty acid synthase, promoting MASLD-associated hepatic steatosis and inflammatory responses

Dysregulation of hepatic lipid metabolism is closely associated with the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Fatty acid synthase (FAS) is a key enzyme regulating hepatic lipogenesis, and its expression is significantly elevated in MASLD patients, suggesting that FAS may play a role in disease progression and may serve as a potential therapeutic target. However, the regulatory mechanisms governing FAS expression during MASLD progression, its post-translational modifications, and whether it further contributes to hepatic steatosis and inflammatory responses remain incompletely understood.

In this study, we found that ten-eleven translocation 2 (TET2), thymine DNA glycosylase (TDG), FAS, and glutamine synthetase (GS) were all significantly upregulated in both in vitro and in vivo hepatic steatosis models induced by lipid mixtures or high-fat diets. Lipid mixtures increased FAS and GS expression through TDG-mediated promoter demethylation, accompanied by enhanced lipid droplet accumulation and inflammatory responses in hepatocytes.

Furthermore, lipid mixture-induced upregulation of GS promoted O-linked N-acetylglucosaminylation (O-GlcNAcylation) of FAS, thereby increasing FAS protein stability in hepatocytes and enhancing lipid droplet formation and inflammation. Collectively, these results demonstrate that TDG-mediated promoter demethylation and GS-regulated O-GlcNAcylation synergistically regulate FAS expression and protein stability, thereby promoting MASLD-associated hepatic steatosis and inflammatory responses. These findings highlight this regulatory pathway as a key molecular mechanism in MASLD progression and suggest its potential as a therapeutic target.

Zou-Han Lin, Pin-I Chou (co-first author), Jia-Wei Chang, Zong-Chen Lin, Yuan-Ting Sun, Ming-Hui Chang, Shih-En Huang, Yu-Min Yeh, Chien-Chin Chen, and I-Chen Peng*. (2025 Dec) Promoter demethylation and protein O-GlcNAcylation-mediated enhancement of fatty acid synthase contributes to hepatic steatosis and inflammation in MASLD. The Journal of Nutritional Biochemistry. 2025 Dec 6:110227. Online ahead of print. https://doi.org/10.1016/j.jnutbio.2025.110227