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Mechanism of O-GlcNAcylation regulating liver lipid synthesis in mice through FASN

文献类型： 外文期刊

作者： Li, Xiaoshuang 1 ; Zhang, Ziyang 1 ; Zhang, Meng 1 ; Cao, Yu 1 ; Zhou, Wanhui 1 ; Kou, Lele 1 ; Guo, Wenjin 2 ; Zhang, Boxi 1 ; Li, Shize 1 ; Xu, Bin 1 ;

作者机构： 1.Heilongjiang Bayi Agr Univ, Coll Anim Sci & Vet Med, Daqing 163319, Peoples R China

2.Jilin Univ, Coll Anim Sci & Vet Med, Changchun, Peoples R China

3.Heilongjiang Acad Agr Sci, Branch Anim Husb & Vet Branch, Qiqihar, Heilongjiang, Peoples R China

关键词： fatty acid synthase; liver lipid synthesis; mice; O-GlcNAcylation; ubiquitination

期刊名称：FASEB JOURNAL （ 影响因子：4.2； 五年影响因子：4.5 ）

ISSN： 0892-6638

年卷期： 2025 年 39 卷 4 期

页码：

收录情况： SCI

摘要： Nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases. O-Linked attachment of beta-N-acetylglucosamine (O-GlcNAc) are ubiquitous post-translational modifications of proteins as "nutrient sensors" and "stress receptors" in the body that are involved in maintaining normal cellular physiological functions. Increased levels of O-GlcNAcylation have been found in the liver samples of patients with NAFLD and nonalcoholic steatohepatitis. However, the role of O-GlcNAcylation in the development and pathogenesis of NAFLD remains unclear. Here, we sought to determine the specific role of O-GlcNAcylation in NAFLD. In this study, the results demonstrated that inhibition of O-GlcNAc transferase (OGT) led to decreased expression of liver lipid synthesis genes and proteins in vitro. In addition, we showed that fatty acid synthase (FASN) expression was positively correlated with O-GlcNAcylation levels. Immunoprecipitation and pulldown assays confirmed the interaction between FASN and OGT at the serine 1483 of FASN, to inhibit K48-linked ubiquitination and degradation of FASN, thereby promoting hepatic lipid accumulation and the development of NAFLD. Administration of the OGT inhibitor OSMI-1 to ob/ob mice led to decreased liver lipid accumulation, further confirming our in vitro experimental results. Finally, we used liver-specific Ogt gene knockout mice fed a high-fat diet to elucidate the specific mechanism of O-GlcNAcylation on NAFLD and found that knockdown of the Ogt gene led to decreased liver lipid accumulation. In conclusion, our findings show that inhibiting the O-GlcNAcylation of FASN at the S1483 site promotes the K48-linked ubiquitination and degradation of FASN and leads to inhibition of lipid accumulation in the liver. Treatment with the OGT inhibitor OSMI-1 leads to decreased lipid accumulation in the liver, suggesting that targeting O-GlcNAcylation sites could be a potential therapeutic strategy for alleviating NAFLD.

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