High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate.

Cell metabolism Pub Date : 2023-11-07 Epub Date: 2023-10-04 DOI:10.1016/j.cmet.2023.09.009
Peng Zhou, Wen-Yi Chang, De-Ao Gong, Jie Xia, Wei Chen, Lu-Yi Huang, Rui Liu, Yi Liu, Chang Chen, Kai Wang, Ni Tang, Ai-Long Huang
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引用次数: 1

Abstract

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.

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高膳食果糖通过微生物群衍生的乙酸盐增强O-GlcNAcylation,从而促进肝细胞癌的进展。
新出现的研究已经解决了果糖在不同癌症中的促肿瘤作用。高果糖对肝细胞癌(HCC)的影响和病理机制尚不清楚。在这里,我们使用自发和化学诱导的HCC小鼠模型研究了补充果糖对野生型C57BL/6小鼠HCC进展的影响。我们发现,高果糖诱导的尿苷二磷酸-N-乙酰葡糖胺(UDP-GlcNAc)和O-GlcNAcylation水平升高有助于HCC的进展。非靶向代谢组学和稳定同位素追踪显示,在果糖治疗下,微生物群衍生的乙酸盐上调谷氨酰胺和UDP-GlcNAc水平,并增强HCC中的蛋白质O-GlcNAcylation。O-GlcNAcylation的全局分析显示,真核延伸因子1A1的高O-GlcNA cylation促进细胞增殖和肿瘤生长。在高果糖摄入的小鼠中,靶向谷氨酸氨连接酶或O-连接的N-乙酰葡糖胺转移酶(OGT)显著阻碍HCC的进展。我们提出,高膳食果糖通过微生物乙酸盐诱导的高-O-GlcNA酰化来促进HCC的进展。
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