Crosstalk between CYP2E1 and PPAR alpha substrates and agonists modulate adipose browning and obesity

doi:10.1016/j.apsb.2022.02.004

CORC > 兰州理工大学 > 兰州理工大学

	Crosstalk between CYP2E1 and PPAR alpha substrates and agonists modulate adipose browning and obesity
	Zhang, Youbo 1,2,3; Yan, Tingting 3; Wang, Tianxia 1,2,4; Liu, Xiaoyan 1,2; Hamada, Keisuke 3; Sun, Dongxue 3; Sun, Yizheng 1,2; Yang, Yanfang 1,2; Wang, Jing 1,2; Takahashi, Shogo 3
刊名	ACTA PHARMACEUTICA SINICA B
	2022-05-01
卷号	12 期号:5 页码:2224-2238
关键词	CYP2E1 PPAR alpha FGF21 Metabolic enzyme Nuclear receptor Obesity
ISSN号	2211-3835
DOI	10.1016/j.apsb.2022.02.004
英文摘要	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 explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 Cyp2e1-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 CYP2E1 and to serve as PPAR alpha agonists, thus explaining how CYP2E1 deficiency causes hepatic PPAR alpha activation through increasing cellular levels of endogenous PPAR alpha agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPAR alpha-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 PPAR alpha and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
WOS记录号	WOS:000810889400006
内容类型	期刊论文
源URL	[http://ir.lut.edu.cn/handle/2XXMBERH/158946]
专题	兰州理工大学
作者单位	1.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China; 2.Peking Univ, Sch Pharmaceut Sci, Dept Nat Med, Beijing 100191, Peoples R China; 3.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA; 4.Lanzhou Univ Technol, Sch Life Sci & Engn, Lanzhou 730050, Peoples R China; 5.Peking Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Key Lab Mol Cardiovasc Sci,Minist Educ, Beijing 100191, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Youbo,Yan, Tingting,Wang, Tianxia,et al. Crosstalk between CYP2E1 and PPAR alpha substrates and agonists modulate adipose browning and obesity[J]. ACTA PHARMACEUTICA SINICA B,2022,12(5):2224-2238.
APA	Zhang, Youbo.,Yan, Tingting.,Wang, Tianxia.,Liu, Xiaoyan.,Hamada, Keisuke.,...&Gonzalez, Frank J..(2022).Crosstalk between CYP2E1 and PPAR alpha substrates and agonists modulate adipose browning and obesity.ACTA PHARMACEUTICA SINICA B,12(5),2224-2238.
MLA	Zhang, Youbo,et al."Crosstalk between CYP2E1 and PPAR alpha substrates and agonists modulate adipose browning and obesity".ACTA PHARMACEUTICA SINICA B 12.5(2022):2224-2238.