High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate
Peng Zhou (周鹏), Wen-yi Chang（常文译）, De-ao Gong（龚德敖）, Jie Xia（夏杰）, Wei Chen, Lu-yi Huang, Rui Liu, Yi Liu, Chang Chen, Kai Wang*, Ni Tang*, Ai-long Huang*
Summary
Emerging studies have addressed the tumor-promoting role of fructose in different cancers. The effects and pathological mechanisms of high dietary fructose on hepatocellular carcinoma (HCC) remain unclear. Here, we examined the effects of fructose supplementation on HCC progression in wild-type C57BL/6 mice using a spontaneous and chemically induced HCC mouse model. We show that elevated uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and O-GlcNAcylation levels induced by high dietary fructose contribute to HCC progression. Non-targeted metabolomics and stable isotope tracing revealed that under fructose treatment, microbiota-derived acetate upregulates glutamine and UDP-GlcNAc levels and enhances protein O-GlcNAcylation in HCC. Global profiling of O-GlcNAcylation revealed that hyper-O-GlcNAcylation of eukaryotic elongation factor 1A1 promotes cell proliferation and tumor growth. Targeting glutamate-ammonia ligase or O-linked N-acetylglucosamine transferase (OGT) remarkably impeded HCC progression in mice with high fructose intake. We propose that high dietary fructose promotes HCC progression through microbial acetate-induced hyper-O-GlcNAcylation.
Highlights
•High fructose promotes HCC by enhancing O-GlcNAcylation via microbiota-derived acetate
•GLUL overexpression contributes to hyper-O-GlcNAcylation and HCC progression
•Elevated O-GlcNAcylation of eEF1A1 at T279 accelerates liver cancer growth
•Targeting GLUL or OGT impeded HCC progression in a high-fructose diet
Keywords: fructose, hepatocellular carcinoma, acetate, O-GlcNAcylation, GLUL, eEF1A1
DOI： https://doi.org/10.1016/j.cmet.2023.09.009
PubMed: https://pubmed.ncbi.nlm.nih.gov/37797623/
Full text: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00340-6
