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

作者全名："Zhou, Peng; Chang, Wen-yi; Gong, De-ao; Xia, Jie; Chen, Wei; Huang, Lu-yi; Liu, Rui; Liu, Yi; Chen, Chang; Wang, Kai; Tang, Ni; Huang, Ai-long"

作者地址："[Zhou, Peng; Chang, Wen-yi; Gong, De-ao; Xia, Jie; Huang, Lu-yi; Liu, Rui; Liu, Yi; Wang, Kai; Tang, Ni; Huang, Ai-long] Chongqing Med Univ, Affiliated Hosp 2, Key Lab Mol Biol Infect Dis, Minist Educ,Inst Viral Hepatitis,Dept Infect Dis, Chongqing 400016, Peoples R China; [Chen, Wei] Shanghai Appl Prot Technol Co Ltd, Shanghai 201109, Peoples R China; [Chen, Chang] Chongqing Med Univ, Inst Life Sci, Chongqing 400016, Peoples R China"

通信作者："Wang, K; Tang, N; Huang, AL (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Key Lab Mol Biol Infect Dis, Minist Educ,Inst Viral Hepatitis,Dept Infect Dis, Chongqing 400016, Peoples R China."

来源：CELL METABOLISM

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001116553200001

JCR分区：Q1

影响因子：27.7

年份：2023

卷号：35

期号：11

开始页：1961

结束页：+

文献类型：Article; Early Access

关键词：　

摘要："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-ace-tylglucosamine (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 treat-ment, 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 eukary-otic 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."

基金机构："National Natural Science Foundation of China [U20A20392, 82072286, 82272975, 82073251]; The 111 Project [D20028]; Chongqing Medical Scientific Research Project (joint project of Chongqing Health Commission and Science and Technology Bureau) [2023DBXM007]; Senior Medical Talents Program of Chongqing for Young and Middle-aged; Innovative and Entrepreneurial Team of Chongqing Talents Plan; Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0036, W0101]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University"

基金资助正文："The authors acknowledge Prof. Dr. T. -C. He (University of Chicago, USA) for providing the pAdEasy system. We also thank Prof. Bing Sun (Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, China) for kindly providing pLL3.7 and pMSCV2.2-IRES-GFP vectors. This study was supported by the National Natural Science Foundation of China (grant no. U20A20392, A.-l.H.; 82072286 and 82272975, N.T.; 82073251, K.W.) , the 111 Project (no. D20028, A.-l.H.) , Chongqing Medical Scientific Research Project (joint project of Chongqing Health Commission and Science and Technology Bureau, 2023DBXM007, N.T.) , Senior Medical Talents Program of Chongqing for Young and Middle-aged, the Innovative and Entrepreneurial Team of Chongqing Talents Plan, Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0036, N.T.; W0101, K.W.) , and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University."