Sodium butyrate activates HMGCS2 to promote ketone body production through SIRT5-mediated desuccinylation  

作　　者：Yanhong Xu Xiaotong Ye Yang Zhou Xinyu Cao Shiqiao Peng Yue Peng Xiaoying Zhang Yili Sun Haowen Jiang Wenying Huang Hongkai Lian Jiajun Yang Jia Li Jianping Ye 

机构地区：[1]Neurology Department,Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,Shanghai 201306,China [2]National Demonstration Center for Experimental Fisheries Science Education,Shanghai Ocean University,Shanghai 201306,China [3]Shanghai Diabetes Institute,Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,Shanghai 200233,China [4]School of Physical Education,Jiangxi Normal University,Nanchang 330022,China [5]Metabolic Disease Research Center,Zhengzhou University Affiliated Zhengzhou Central Hospital,Zhengzhou 450007,China [6]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [7]Center for Advanced Medicine,College of Medicine,Zhengzhou University,Zhengzhou 450007,China

出　　处：《Frontiers of Medicine》2023年第2期339-351,共13页医学前沿（英文版）

基　　金：supported by the National Key Research and Development Program of China(No.2018YFA0800603);a project(No.19ZR1439000)of the Shanghai Association for Science and Technology to Jianping Ye.

摘　　要：Ketone bodies have beneficial metabolic activities,and the induction of plasma ketone bodies is a health promotion strategy.Dietary supplementation of sodium butyrate(SB)is an effective approach in the induction of plasma ketone bodies.However,the cellular and molecular mechanisms are unknown.In this study,SB was found to enhance the catalytic activity of 3-hydroxy-3-methylglutaryl-CoA synthase 2(HMGCS2),a rate-limiting enzyme in ketogenesis,to promote ketone body production in hepatocytes.SB administrated by gavage or intraperitoneal injection significantly induced bloodβ-hydroxybutyrate(BHB)in mice.BHB production was induced in the primary hepatocytes by SB.Protein succinylation was altered by SB in the liver tissues with down-regulation in 58 proteins and up-regulation in 26 proteins in the proteomics analysis.However,the alteration was mostly observed in mitochondrial proteins with 41%down-and 65%up-regulation,respectively.Succinylation status of HMGCS2 protein was altered by a reduction at two sites(K221 and K358)without a change in the protein level.The SB effect was significantly reduced by a SIRT5 inhibitor and in Sirt5-KO mice.The data suggests that SB activated HMGCS2 through SIRT5-mediated desuccinylation for ketone body production by the liver.The effect was not associated with an elevation in NAD+/NADH ratio according to our metabolomics analysis.The data provide a novel molecular mechanism for SB activity in the induction of ketone body production.

关 键 词：sodium butyrate SUCCINYLATION HMGCS2 KETOGENESIS SIRT5 

分 类 号：O63[理学—高分子化学]