{"title":"Mechanism of O-GlcNAcylation regulating liver lipid synthesis in mice through FASN","authors":"Xiaoshuang Li, Ziyang Zhang, Meng Zhang, Yu Cao, Wanhui Zhou, Lele Kou, Wenjin Guo, Boxi Zhang, Shize Li, Bin Xu","doi":"10.1096/fj.202402451RR","DOIUrl":null,"url":null,"abstract":"<p>Nonalcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases. O-Linked attachment of beta-N-acetylglucosamine (<i>O</i>-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 <i>O</i>-GlcNAcylation have been found in the liver samples of patients with NAFLD and nonalcoholic steatohepatitis. However, the role of <i>O</i>-GlcNAcylation in the development and pathogenesis of NAFLD remains unclear. Here, we sought to determine the specific role of <i>O</i>-GlcNAcylation in NAFLD. In this study, the results demonstrated that inhibition of <i>O</i>-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 <i>O</i>-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 <i>Ogt</i> gene knockout mice fed a high-fat diet to elucidate the specific mechanism of <i>O</i>-GlcNAcylation on NAFLD and found that knockdown of the <i>Ogt</i> gene led to decreased liver lipid accumulation. In conclusion, our findings show that inhibiting the <i>O</i>-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 <i>O</i>-GlcNAcylation sites could be a potential therapeutic strategy for alleviating NAFLD.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 4","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The FASEB Journal","FirstCategoryId":"99","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1096/fj.202402451RR","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.