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
. 2025 Feb 28;39(4):e70359.
doi: 10.1096/fj.202402451RR.

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

Xiaoshuang Li  1 , Ziyang Zhang  1 , Meng Zhang  1   2 , Yu Cao  1   3 , Wanhui Zhou  1 , Lele Kou  1 , Wenjin Guo  2 , Boxi Zhang  1 , Shize Li  1 , Bin Xu  1
Affiliations

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

Xiaoshuang Li et al. FASEB J. .

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.

Keywords: O‐GlcNAcylation; fatty acid synthase; liver lipid synthesis; mice; ubiquitination.

PubMed Disclaimer

Similar articles

See all similar articles

References

REFERENCES

    1. Sayuti NH, Muhammad Nawawi KN, Goon JA, Mokhtar NM, Makpol S, Tan JK. A review of the effects of fucoxanthin on NAFLD. Nutrients. 2023;15(8):1954.
    1. Gonzalez‐rellan MJ, Parracho T, Heras V, et al. Hepatocyte‐specific O‐GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function. Mol Metab. 2023;75:101776.
    1. Gastaldelli A, Cusi K. From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep. 2019;1(4):312‐328.
    1. Harrison SA, Gawrieh S, Roberts K, et al. Prospective evaluation of the prevalence of non‐alcoholic fatty liver disease and steatohepatitis in a large middle‐aged US cohort. J Hepatol. 2021;75(2):284‐291.
    1. Gorg B, Karababa A, Schutz E, et al. O‐GlcNAcylation‐dependent upregulation of HO1 triggers ammonia‐induced oxidative stress and senescence in hepatic encephalopathy. J Hepatol. 2019;71(5):930‐941.

LinkOut - more resources