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

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Yao-Geng Wang, Chang-Pei Gan, Joke Beukers-Korver, Hilde Rosing, Wen-Long Li, Els Wagenaar, Maria C Lebre, Ji-Ying Song, Colin Pritchard, Rahmen Bin Ali, Ivo Huijbers, Jos H Beijnen, Alfred H Schinkel
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Abstract

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.

肠道人羧基酯酶2(CES2)的表达可挽救全基因组Ces2基因敲除小鼠的药物代谢和大多数代谢综合征表型。
羧基酯酶 2(CES2)主要在肝脏和肠道中表达,但在肠道中表达量最大。它能水解许多外源性和内源性化合物(包括脂质)中的羧酸酯、硫酯和酰胺键。因此,CES2 不仅在许多(原)药物、毒素和杀虫剂的代谢中发挥重要作用,直接影响人体的药理学和毒理学,而且还参与能量平衡,影响脂质和葡萄糖的代谢。在本研究中,我们研究了 CES2 的药理和生理功能。我们构建了缺乏全部八个 Ces2 基因的 Ces2 群体基因敲除小鼠(Ces2-/-品系),以及在此 Ces2/- 背景下的人源化肝脏或肠道 CES2 转基因品系。我们的研究表明,Ces2-/-小鼠口服卡培他滨的可利用性和组织处置能力大幅提高,而组织特异性地降低了肠道和肝脏人CES2(hCES2)的活性。在 Ces2-/-小鼠体内,化疗药物维诺瑞宾的新陈代谢强烈减弱,但 hCES2 的表达只能在一定程度上缓解这种情况。另一方面,Ces2-/-小鼠表现出脂肪肝、脂肪变性、高胆固醇血症、糖耐量和胰岛素敏感性降低,但体重没有变化。矛盾的是,肝脏表达 hCES2 可挽救这些代谢表型,但肝脏体积、脂肪组织质量和总体体重却增加了,这表明存在 "健康 "肥胖表型。相比之下,肠道 hCES2 的表达有效地挽救了所有表型,甚至相对于野生型基线值改善了一些参数,包括体重。我们的研究结果表明,诱导肠道 hCES2 可能会对抗代谢综合征的大部分(如果不是全部)不利影响。这些 CES2 小鼠模型将提供强大的临床前工具,用于加强药物开发、提高生理洞察力以及探索代谢综合征相关疾病的潜在解决方案。
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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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