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Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol

Kwang-Hoon Song1, Tiangang Li, Erika Owsley

  • 1Department of Integrative Medical Sciences, Northeastern Ohio Universities Colleges of Medicine and Pharmacy, Rootstown, OH 44272, USA.

Hepatology (Baltimore, Md.)
|December 17, 2008
PubMed
Abstract

Insights

Bile acids induce fibroblast growth factor 19 (FGF19) in liver cells, which then inhibits bile acid synthesis by activating the FGF receptor 4 (FGFR4) and Erk1/2 pathway, independent of SHP. This pathway prevents toxic bile acid buildup in human livers.

Area of Science:

  • Hepatology
  • Endocrinology
  • Molecular Biology

Background:

  • Fibroblast growth factor 15 (FGF15) and its human ortholog FGF19 are bile acid-induced intestinal factors.
  • FGF15/FGF19 mediate feedback inhibition of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription in mouse liver.
  • The precise mechanism of FGF15/FGF19 in inhibiting bile acid synthesis in hepatocytes remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which FGF19 inhibits bile acid synthesis in human hepatocytes.
  • To investigate the role of the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/Erk1/2) pathway and FGF receptor 4 (FGFR4) in FGF19 signaling.

Main Methods:

  • Primary human hepatocytes were treated with chenodeoxycholic acid (CDCA) or a farnesoid X receptor (FXR) agonist.
  • Messenger RNA (mRNA) levels of CYP7A1 and small heterodimer partner (SHP) were measured.
  • Kinase inhibition, phosphorylation assays, siRNA knockdown, and antibody neutralization were employed to study signaling pathways.

Main Results:

  • CDCA and the FXR agonist induced FGF19 and inhibited CYP7A1 mRNA levels in hepatocytes.
  • FGF19 rapidly repressed CYP7A1 mRNA but not SHP mRNA.
  • The MAPK/Erk1/2 pathway was crucial for FGF19-mediated CYP7A1 inhibition.
  • CDCA stimulated tyrosine phosphorylation of FGFR4, and FGFR4 inhibition abrogated FGF19's effect on CYP7A1.

Conclusions:

  • Hepatic FGF19 signaling via FGFR4 and Erk1/2 inhibits CYP7A1 independently of SHP.
  • Bile acids activate an autocrine/paracrine FGF19/FGFR4/Erk1/2 pathway in hepatocytes.
  • This pathway serves to inhibit bile acid synthesis and prevent the accumulation of toxic bile acids in human livers.

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