荷兰癌症研究所Alfred H. Schinkel研究团队发现，肠道人类羧酸酯酶2（CES2）表达可挽救全局性Ces2簇基因敲除小鼠的药物代谢和大多数代谢综合征表型。该研究于2024年11月4日在线发表于《中国药理学报》。

研究人员探讨了羧酸酯酶2（CES2）的药理学和生理学功能。研究人员构建了缺失所有八个Ces2基因的Ces2簇基因敲除小鼠（Ces2^–/–品系），以及在Ces2^–/–背景下的人源化肝脏或肠道CES2转基因小鼠。研究人员发现，Capecitabine的口服生物利用度和组织分布在Ces2^–/–小鼠中显著增加，而在人类肠道和肝脏CES2（hCES2）活性的作用下，组织特异性地降低。化疗药物Vinorelbine的代谢在Ces2^–/–小鼠中显著减少，但通过hCES2表达仅略有恢复。

另一方面，Ces2^–/–小鼠表现出脂肪肝、脂肪炎、高胆固醇血症、葡萄糖耐受性降低和胰岛素敏感性降低，但体重无明显变化。令人矛盾的是，肝脏hCES2表达恢复了这些代谢表型，但增加了肝脏大小、脂肪组织质量和总体体重，提示出现了“健康”的肥胖表型。相比之下，肠道hCES2表达有效地恢复了所有表型，甚至改善了一些参数，包括体重，相对于野生型基线值。

这些结果表明，诱导肠道hCES2可能对抗代谢综合症的大多数（如果不是全部）不良影响。这些CES2小鼠模型将为药物开发提供强大的临床前工具，增加生理学的见解，并探索代谢综合症相关疾病的潜在解决方案。

据介绍，CES2主要在肝脏和肠道中表达，其中以肠道表达最为丰富。它水解多种外源性和内源性化合物中的羧酸酯、硫酯和酰胺键，包括脂质。因此，CES2不仅在许多（前体）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，而且还参与能量稳态，影响脂质和葡萄糖代谢。

附：英文原文

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

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

Issue&Volume: 2024-11-04

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.

DOI: 10.1038/s41401-024-01407-4

Source: https://www.nature.com/articles/s41401-024-01407-4