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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bile Acids and Salts / metabolism*
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Cholesterol 7-alpha-Hydroxylase / genetics
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Cholesterol 7-alpha-Hydroxylase / metabolism
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Colon / metabolism*
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Colon / pathology
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Dextran Sulfate
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Disease Models, Animal
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Feedback, Physiological
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Fibroblast Growth Factors / genetics
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Fibroblast Growth Factors / metabolism*
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Fibroblast Growth Factors / pharmacology
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Gene Expression Regulation
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Glucuronosyltransferase / genetics
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Glucuronosyltransferase / metabolism*
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Homeostasis
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Inflammatory Bowel Diseases / chemically induced
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Inflammatory Bowel Diseases / drug therapy
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Inflammatory Bowel Diseases / genetics*
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Inflammatory Bowel Diseases / pathology
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Intestine, Small / metabolism
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Intestine, Small / pathology
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Liver / metabolism
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Liver / pathology
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Male
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Mice
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Mice, Inbred C57BL
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PPAR alpha / antagonists & inhibitors
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PPAR alpha / genetics
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PPAR alpha / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Signal Transduction
Substances
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Bile Acids and Salts
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PPAR alpha
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RNA, Small Interfering
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Receptors, Cytoplasmic and Nuclear
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fibroblast growth factor 15, mouse
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farnesoid X-activated receptor
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Fibroblast Growth Factors
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Dextran Sulfate
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Cholesterol 7-alpha-Hydroxylase
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Cyp7a1 protein, mouse
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Glucuronosyltransferase