Crosstalk between CYP2E1 and PPARα substrates and agonists modulate adipose browning and obesity

作     者：Youbo Zhang Tingting Yan Tianxia Wang Xiaoyan Liu Keisuke Hamada Dongxue Sun Yizheng Sun Yanfang Yang Jing Wang Shogo Takahashi Qiong Wang Kristopher W.Krausz Changtao Jiang Cen Xie Xiuwei Yang Frank J.Gonzalez Youbo Zhang;Tingting Yan;Tianxia Wang;Xiaoyan Liu;Keisuke Hamada;Dongxue Sun;Yizheng Sun;Yanfang Yang;Jing Wang;Shogo Takahashi;Qiong Wang;Kristopher W.Krausz;Changtao Jiang;Cen Xie;Xiuwei Yang;Frank J.Gonzalez

作者机构：State Key Laboratory of Natural and Biomimetic Drugs and Department of Natural MedicinesSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China Laboratory of MetabolismCenter for Cancer ResearchNational Cancer InstituteNational Institutes of HealthBethesdaMD 20892USA School of Life Science and EngineeringLanzhou University of TechnologyLanzhou 730050China Department of Physiology and PathophysiologySchool of Basic Medical SciencesPeking Universitythe Key Laboratory of Molecular Cardiovascular ScienceMinistry of EducationBeijing 100191China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第5期

页      面：2224-2238页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 100706[医学-药理学] 1001[医学-基础医学(可授医学、理学学位)] 100602[医学-中西医结合临床] 10[医学] 

基　　金：funded by National Cancer Institute Intramural Research Program and the National Natural Science Foundation of China (81891011) 

主　　题：CYP2E1 PPARa FGF21 Metabolic enzyme Nuclear receptor Obesity 

摘      要：Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been *** ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2 E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2 E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha(PPARa) target genes,including fibroblast growth factor(FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2 e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2 E1 and to serve as PPARa agonists, thus explaining how CYP2 E1 deficiency causes hepatic PPARa activation through increasing cellular levels of endogenous PPARa agonists. Translationally, a CYP2 E1 inhibitor was found to activate the PPARa-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Pparanull mice. The present results establish a metabolic crosstalk between PPARa and CYP2 E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2 E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.