PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis

被引：182

作者：

Zhou, Xueyan ^{[1
,2
]}

Cao, Lijuan ^{[1
]}

Jiang, Changtao ^{[3
]}

Xie, Yang ^{[1
]}

Cheng, Xuefang ^{[1
]}

Krausz, Kristopher W. ^{[3
]}

Qi, Yunpeng

Sun, Lu ^{[3
]}

Shah, Yatrik M. ^{[4
,5
]}

Gonzalez, Frank J. ^{[3
]}

Wang, Guangji ^{[1
]}

Hao, Haiping ^{[1
]}

机构：

[1] China Pharmaceut Univ, Key Lab Drug Metab & Pharmacokinet, State Key Lab Nat Med, Nanjing 21009, Jiangsu, Peoples R China

[2] Xuzhou Med Coll, Sch Pharm, Xuzhou 221004, Jiangsu, Peoples R China

[3] Natl Canc Inst, Ctr Canc Res, Lab Metab, NIH, Bethesda, MD 20892 USA

[4] Univ Michigan, Sch Med, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Sch Med, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

FARNESOID-X-RECEPTOR; BILE-ACID-HOMEOSTASIS; INFLAMMATORY BOWEL DISEASES; UDP-GLUCURONOSYLTRANSFERASE; ULCERATIVE-COLITIS; LIPID HOMEOSTASIS; EPITHELIAL-CELLS; COLON-CANCER; MICE; EXPRESSION;

D O I：

10.1038/ncomms5573

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Bile acids play a pivotal role in the pathological development of inflammatory bowel disease (IBD). However, the mechanism of bile acid dysregulation in IBD remains unanswered. Here we show that intestinal peroxisome proliferator-activated receptor alpha (PPAR alpha)-UDP-glucuronosyltransferases (UGTs) signalling is an important determinant of bile acid homeostasis. Dextran sulphate sodium (DSS)-induced colitis leads to accumulation of bile acids in inflamed colon tissues via activation of the intestinal peroxisome PPAR alpha-UGTs pathway. UGTs accelerate the metabolic elimination of bile acids, and thereby decrease their intracellular levels in the small intestine. Reduced intracellular bile acids results in repressed farnesoid X receptor (FXR)-FGF15 signalling, leading to upregulation of hepatic CYP7A1, thus promoting the de novo bile acid synthesis. Both knockout of PPAR alpha and treatment with recombinant FGF19 markedly attenuate DSS-induced colitis. Thus, we propose that intestinal PPAR alpha-UGTs and downstream FXR-FGF15 signalling play vital roles in control of bile acid homeostasis and the pathological development of colitis.

引用

页数：15

共 59 条

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