FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway

Dongju Jung, J. Philippe York, Li Wang, Chaofeng Yang, Aijun Zhang, Heather L. Francis, Paul Webb, Wallace L. McKeehan, Gianfranco Alpini, Gene D. LeSage, David D. Moore, Xuefeng Xia

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Cholangiocytes, bile duct lining cells, actively adjust the amount of cholesterol and bile acids in bile through expression of enzymes and channels involved in transportation and metabolism of the cholesterol and bile acids. Herein, we report molecular mechanisms regulating bile acid biosynthesis in cholangiocytes. Among the cytochrome p450 (Cyp) enzymes involved in bile acid biosynthesis, sterol 27-hydroxylase (Cyp27) that is the rate-limiting enzyme for the acidic pathway of bile acid biosynthesis expressed in cholangiocytes. Expression of other Cyp enzymes for the basic bile acid biosynthesis was hardly detected. The Cyp27 expression was negatively regulated by a hydrophobic bile acid through farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. Activated FXR exerted the negative effects by inducing an expression of fibroblast growth factor 15/19 (FGF15/19). Similar to its repressive function against cholesterol 7α-hydroxylase (Cyp7a1) expression in hepatocytes, secreted FGF15/19 triggered Cyp27 repression in cholangiocytes through interaction with its cognate receptor fibroblast growth factor receptor 4 (FGFR4). The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 repression were confirmed in vivo using knockout mouse models. Different from the signaling in hepatocytes, wherein the FGF15/19-induced repression signaling is mediated by c-Jun N-terminal kinase (JNK), FGF15/19-induced Cyp27 repression in cholangiocytes was mediated by p38 kinase. Thus, the results collectively suggest that cholangiocytes may be able to actively regulate bile acid biosynthesis in cholangiocytes and even hepatocyte by secreting FGF15/19. We suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in addition to the enterohepatic feedback loop against bile acid biosynthesis in the liver.

Original languageEnglish (US)
Pages (from-to)1011-1019
Number of pages9
JournalPflugers Archiv European Journal of Physiology
Volume466
Issue number5
DOIs
StatePublished - May 2014
Externally publishedYes

Keywords

  • Cholangiocyte
  • Cyp27
  • p38 kinase

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Physiology (medical)

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    Jung, D., York, J. P., Wang, L., Yang, C., Zhang, A., Francis, H. L., Webb, P., McKeehan, W. L., Alpini, G., LeSage, G. D., Moore, D. D., & Xia, X. (2014). FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway. Pflugers Archiv European Journal of Physiology, 466(5), 1011-1019. https://doi.org/10.1007/s00424-013-1364-3