Intestinal human carboxylesterase 2(CES2)expression rescues drug metabolism and most metabolic syndrome phenotypes in global Ces2 cluster knockout mice  

作　　者：Yao-geng Wang Chang-pei Gan Joke Beukers-Korver Hilde Rosing Wen-long Li Els Wagenaar Maria CLebre Ji-ying Song Colin Pritchard Rahmen Bin Ali Ivo Huijbers Jos H.Beijnen Alfred H.Schinkel 

机构地区：[1]Division of Pharmacology,The Netherlands Cancer Institute,1066 CX,Amsterdam,The Netherlands [2]Department of Pharmacy&Pharmacology,The Netherlands Cancer Institute,1066 CX,Amsterdam,The Netherlands [3]Division of Experimental Animal Pathology,The Netherlands Cancer Institute,1066 CX,Amsterdam,the Netherlands [4]Transgenic Core Facility,Mouse Clinic for Cancer and Aging(MCCA),The Netherlands Cancer Institute,1066 CX,Amsterdam,The Netherlands [5]Faculty of Science,Department of Pharmaceutical Sciences,Division of Pharmacoepidemiology&Clinical Pharmacology,Utrecht University,3584 CG,Utrecht,The Netherlands

出　　处：《Acta Pharmacologica Sinica》2025年第3期777-793,共17页中国药理学报(英文版)

基　　金：funded in part by the Chinese Scholarship Council(CSC Scholarships No.201506240107 to Yao-geng Wang,No.201506240145 to Chang-pei Gan and No.201606220081 to Wen-long Li);by the National Natural Science Foundation of China(82304647)of which Yao-geng Wang is a beneficiary.

摘　　要：Carboxylesterase 2(CES2)is expressed mainly in liver and intestine,but most abundantly in intestine.It hydrolyzes carboxylester,thioester,and amide bonds in many exogenous and endogenous compounds,including lipids.CES2 therefore not only plays an important role in the metabolism of many(pro-)drugs,toxins and pesticides,directly influencing pharmacology and toxicology in humans,but it is also involved in energy homeostasis,affecting lipid and glucose metabolism.In this study we investigated the pharmacological and physiological functions of CES2.We constructed Ces2 cluster knockout mice lacking all eight Ces2 genes(Ces2^(-/-)strain)as well as humanized hepatic or intestinal CES2 transgenic strains in this Ces2^(-/-)background.We showed that oral availability and tissue disposition of capecitabine were drastically increased in Ces2^(-/-)mice,and tissue-specifically decreased by intestinal and hepatic human CES2(hCES2)activity.The metabolism of the chemotherapeutic agent vinorelbine was strongly reduced in Ces2^(-/-)mice,but only marginally rescued by hCES2 expression.On the other hand,Ces2^(-/-)mice exhibited fatty liver,adipositis,hypercholesterolemia and diminished glucose tolerance and insulin sensitivity,but without body mass changes.Paradoxically,hepatic hCES2 expression rescued these metabolic phenotypes but increased liver size,adipose tissue mass and overall body weight,suggesting a“healthy”obesity phenotype.In contrast,intestinal hCES2 expression efficiently rescued all phenotypes,and even improved some parameters,including body weight,relative to the wild-type baseline values.Our results suggest that the induction of intestinal hCES2 may combat most,if not all,of the adverse effects of metabolic syndrome.These CES2 mouse models will provide powerful preclinical tools to enhance drug development,increase physiological insights,and explore potential solutions for metabolic syndrome-associated disorders.

关 键 词：metabolic syndrome carboxylesterase 2 CAPECITABINE VINORELBINE lipid metabolism glucose homeostasis 

分 类 号：R363[医药卫生—病理学] R965[医药卫生—基础医学]