title: PPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis.
abstract: 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 α (PPARα)-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 PPARα-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 PPARα and treatment with recombinant FGF19 markedly attenuate DSS-induced colitis. Thus, we propose that intestinal PPARα-UGTs and downstream FXR-FGF15 signalling play vital roles in control of bile acid homeostasis and the pathological development of colitis.
authors.affiliation: 1] State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 21009, China [2] School of Pharmacy, Xuzhou Medical College, Xuzhou 221004, Jiangsu, China [3].
authors.forename: Xueyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 1] State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 21009, China [2].
authors.forename: Lijuan
authors.initials: L
authors.lastname: Cao
authors.affiliation: 1] Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2].
authors.forename: Changtao
authors.initials: C
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 21009, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 21009, China.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.affiliation: 1] Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 21009, China.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Tongjiaxiang 24, Nanjing 21009, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D016264:Dextran Sulfate; D005346:Fibroblast Growth Factors; D014453:Glucuronosyltransferase; D047493:PPAR alpha; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C108526:fibroblast growth factor 15, mouse; C502772:Cyp7a1 protein, mouse