Fatty acid oxidation-induced HIF-1α activation facilitates hepatic urate synthesis through upregulating NT5C2 and XDH  

作　　者：Ningning Liang Xuan Yuan Lili Zhang Xia Shen Shanshan Zhong Luxiao Li Rui Li Xiaodong Xu Xin Chen Chunzhao Yin Shuyuan Guo Jing Ge Mingjiang Zhu Yongzhen Tao Shiting Chen Yongbing Qian Nicola Dalbeth Tony RMerriman Robert Terkeltaub Changgui Li Qiang Xia Huiyong Yin 

机构地区：[1]CAS Key Laboratory of Nutrition,Metabolism,and Food Safety,Shanghai Institute of Nutrition and Health,Chinese Academy of Sciences(CAS),Shanghai 200031,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Department of Biomedical Sciences,Jockey Club College of Veterinary Medicine and Medicine,Tung Biomedical Science Center,State Key Laboratory of Marine Pollution(SKLMP),The Shenzhen Research Institute and Futian Research Institute,City University of Hong Kong,Hong Kong 999077,China [4]Institute of Metabolic Diseases,Qingdao University,Qingdao,Shandong 266003,China [5]Shandong Provincial Key Laboratory of Metabolic Diseases,Qingdao Key Laboratory of Gout,Affiliated Hospital of Qingdao University Medical College,Qingdao University,Qingdao,Shandong 266071,China [6]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China [7]Department of Liver Surgery,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China [8]Department of Medicine,Faculty of Medical and Health Sciences,University of Auckland,Auckland 1142,New Zealand [9]Department of Biochemistry,University of Otago,Dunedin 9016,New Zealand [10]Division of Clinical Immunology and Rheumatology,University of Alabama at Birmingham,Birmingham,Alabama 35294,United States [11]VA San Diego Healthcare System,San Diego,La Jolla,CA 92037,United States [12]School of Medicine,University of California San Diego,La Jolla,CA 92037,United States

出　　处：《Life Metabolism》2024年第5期17-31,共15页生命代谢（英文）

基　　金：funded by grants from the National Key Research and Development Program of China(2022YFC2503300 and 2018YFA0800300);the National Natural Science Foundation of China(32030053 and 32241017);the startup fund from City University of Hong Kong(9380154);the RGC Theme-based Research Scheme(8770011);the TBSC Project fund,and Shenzhen Medical Research Fund(B2302042);R.T.was supported by the VA Research Service(I01 BX005927)and NIH(PAG007996).

摘　　要：Dyslipidemia affects approximately half of all people with gout,and prior Mendelian randomization analysis suggested a causal role for elevated triglycerides in hyperuricemia(HU),but the underlying mechanisms remain elusive.We hypothesize that dyslipi-demia promotes hepatic urate biosynthesis in HU and gout and fatty acid(FA)oxidation(FAO)drives this process.Here we devel-oped a targeted metabolomics to quantify major metabolites in purine metabolic pathway in the sera of a human cohort with HU,gout,and normaluricemic controls.We found that the levels of major purine metabolites and multiple FAs were significantly elevated in HU and gout groups compared to normouricemic controls,whereas hypoxathine showed opposite trend.Furthermore,the levels of multiple serum FAs were positively correlated with urate,xanthine,and inosine but negatively with hypoxanthine,which was also observed in a murine model of high-fat diet-induced HU.Using a stable isotope-labeled metabolic flux assay,we discovered that exogenous hypoxanthine plays a key role in urate synthesis.Moreover,FAO-induced hypoxia-inducible factor 1 alpha(HIF-1α)activation upregulated 5ʹ-nucleotidase II(NT5C2)and xanthine dehydrogenase(XDH)levels to facilitate hypox-anthine uptake from the blood to the liver and activation of urate biosynthesis.Our findings were further supported by data in human hepatocytes and 50 paired serum and liver tissues from liver transplant donors.Together,this study uncovers a mecha-nism by which FAO promotes hepatic urate synthesis by activating HIF-1α-NT5C2/XDH pathways,directly linking lipid metabo-lism to HU.

关 键 词：DYSLIPIDEMIA HYPERURICEMIA PURINE HYPOXANTHINE metabolic flux 

分 类 号：R696[医药卫生—泌尿科学]