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

Nat Commun. 2014 Sep 3;5:4573. doi: 10.1038/ncomms5573.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / metabolism*
  • Cholesterol 7-alpha-Hydroxylase / genetics
  • Cholesterol 7-alpha-Hydroxylase / metabolism
  • Colon / metabolism*
  • Colon / pathology
  • Dextran Sulfate
  • Disease Models, Animal
  • Feedback, Physiological
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Fibroblast Growth Factors / pharmacology
  • Gene Expression Regulation
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism*
  • Homeostasis
  • Inflammatory Bowel Diseases / chemically induced
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / genetics*
  • Inflammatory Bowel Diseases / pathology
  • Intestine, Small / metabolism
  • Intestine, Small / pathology
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PPAR alpha / antagonists & inhibitors
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Signal Transduction

Substances

  • Bile Acids and Salts
  • PPAR alpha
  • RNA, Small Interfering
  • Receptors, Cytoplasmic and Nuclear
  • fibroblast growth factor 15, mouse
  • farnesoid X-activated receptor
  • Fibroblast Growth Factors
  • Dextran Sulfate
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse
  • Glucuronosyltransferase