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O\u2010Linked attachment of beta\u2010N\u2010acetylglucosamine (\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAc) are ubiquitous post\u2010translational modifications of proteins as \u201cnutrient sensors\u201d and \u201cstress receptors\u201d in the body that are involved in maintaining normal cellular physiological functions. Increased levels of\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAcylation have been found in the liver samples of patients with NAFLD and nonalcoholic steatohepatitis. However, the role of\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAcylation in the development and pathogenesis of NAFLD remains unclear. Here, we sought to determine the specific role of\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAcylation in NAFLD. In this study, the results demonstrated that inhibition of\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAc transferase (OGT) led to decreased expression of liver lipid synthesis genes and proteins in\u00a0vitro. In addition, we showed that fatty acid synthase (FASN) expression was positively correlated with\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAcylation levels. Immunoprecipitation and pulldown assays confirmed the interaction between FASN and OGT at the serine 1483 of FASN, to inhibit K48\u2010linked ubiquitination and degradation of FASN, thereby promoting hepatic lipid accumulation and the development of NAFLD. Administration of the OGT inhibitor OSMI\u20101 to ob\/ob mice led to decreased liver lipid accumulation, further confirming our in\u00a0vitro experimental results. Finally, we used liver\u2010specific\n                    <jats:italic>Ogt<\/jats:italic>\n                    gene knockout mice fed a high\u2010fat diet to elucidate the specific mechanism of\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAcylation on NAFLD and found that knockdown of the\n                    <jats:italic>Ogt<\/jats:italic>\n                    gene led to decreased liver lipid accumulation. In conclusion, our findings show that inhibiting the\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAcylation of FASN at the S1483 site promotes the K48\u2010linked ubiquitination and degradation of FASN and leads to inhibition of lipid accumulation in the liver. Treatment with the OGT inhibitor OSMI\u20101 leads to decreased lipid accumulation in the liver, suggesting that targeting\n                    <jats:italic>O<\/jats:italic>\n                    \u2010GlcNAcylation sites could be a potential therapeutic strategy for alleviating NAFLD.\n                  <\/jats:p>","DOI":"10.1096\/fj.202402451rr","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T04:59:51Z","timestamp":1739509191000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mechanism of\n                    <i>O<\/i>\n                    \u2010\n                    <scp>GlcNAcylation<\/scp>\n                    regulating liver lipid synthesis in mice through\n                    <scp>FASN<\/scp>"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5280-0777","authenticated-orcid":false,"given":"Xiaoshuang","family":"Li","sequence":"first","affiliation":[{"name":"College of Animal Science and Veterinary Medicine Heilongjiang Bayi Agricultural University  Daqing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3048-5858","authenticated-orcid":false,"given":"Ziyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine Heilongjiang Bayi Agricultural University  Daqing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8583-2396","authenticated-orcid":false,"given":"Meng","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine Heilongjiang Bayi Agricultural University  Daqing P.R. China"},{"name":"College of Animal Science and Veterinary Medicine Jilin University  Changchun P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7387-8349","authenticated-orcid":false,"given":"Yu","family":"Cao","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine Heilongjiang Bayi Agricultural University  Daqing P.R. China"},{"name":"Heilongjiang Academy of Agricultural Sciences Branch of Animal Husbandry and Veterinary Branch  Qiqihar Heilongjiang P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9480-2041","authenticated-orcid":false,"given":"Wanhui","family":"Zhou","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine Heilongjiang Bayi Agricultural University  Daqing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2596-307X","authenticated-orcid":false,"given":"Lele","family":"Kou","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine Heilongjiang Bayi Agricultural University  Daqing P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-7138","authenticated-orcid":false,"given":"Wenjin","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine Jilin University  Changchun P.R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6446-3747","authenticated-orcid":false,"given":"Boxi","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Animal Science and Veterinary Medicine Heilongjiang Bayi Agricultural University  Daqing P.R. 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