Intestinal stearoyl-coenzyme A desaturase-inhibition improves obesity-associated metabolic disorders  

作　　者：Yangliu Xia Yang Zhang Zhipeng Zhang Nana Yan Vorthon Sawaswong Lulu Sun Wanwan Guo Ping Wang Kristopher W.Krausz Oksana Gavrilova James M.Ntambi Haiping Hao Tingting Yan Frank J.Gonzalez 

机构地区：[1]Cancer Innovation Laboratory,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD 20892,USA [2]State Key Laboratory of Natural Medicines,Laboratory of Metabolic Regulation and Drug Target Discovery,China Pharmaceutical University,Nanjing 210009,China [3]Section on Human Iron Metabolism,Eunice Kennedy Shriver National Institute of Child Health and Human Development,National Institutes of Health,Bethesda,MD 20892,USA [4]Department of General Surgery,Cancer Center,Third Hospital,Peking University,Beijing 100191,China [5]State Key Laboratory of Female Fertility Promotion,Department of Endocrinology and Metabolism,Third Hospital,Peking University,Beijing 100191,China [6]Mouse Metabolism Core Laboratory,National Institute of Diabetes and Digestive and Kidney Diseases,National Institutes of Health,Bethesda,MD 20892,USA [7]Department of Biochemistry,University of WisconsineMadison,Madison,WI 53706,USA

出　　处：《Acta Pharmaceutica Sinica B》2025年第2期892-908,共17页药学学报(英文版)

基　　金：supported by the National Cancer Institute Intramural Research Program,CCR,CIL,the Natural Science Foundation of Jiangsu Province(BK20241592,China)to Tingting Yan;National Natural Science Foundation of China(No.82404732 to Tingting Yan,No.81930109 and 82321005 to Haiping Hao,No.82370848 and HY2022-7 to Lulu Sun,No.62173005 to Zhipeng Zhang);the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(SKLNMZZ202402 to Haiping Hao,China);National Institutes of Health,National Institute of Diabetes and Digestive and Kidney Diseases(DK118093 to James N.Ntambi,USA);supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development(NICHD,USA).

摘　　要：Stearoyl-coenzyme A desaturase 1(SCD1)catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis.Although numerous SCD1 inhibitors were tested for treating metabolic disorders both in preclinical and clinic studies,the tissue-specific roles of SCD1 in modulating obesity-associated metabolic disorders and determining the pharmacological effect of chemical SCD1 inhibition remain unclear.Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered.Intestinal SCD1 was found to be induced during obesity progression both in humans and mice.Intestine-specific,but not liver-specific,SCD1 deficiency reduced obesity and hepatic steatosis.A939572,an SCD1-specific inhibitor,ameliorated obesity and hepatic steatosis dependent on intestinal,but not hepatic,SCD1.Mechanistically,intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 in intestinal epithelial cells.These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.

关 键 词：OBESITY SCD1 MT1 Intestinal epithelium High-fat diet Oxidative stress STEATOSIS Metabolic disorders 

分 类 号：R589.2[医药卫生—内分泌]