Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis

Nat Commun. 2018 Jul 3;9(1):2590. doi: 10.1038/s41467-018-04697-5.

Abstract

Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates FXR function remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho-defective Y67F-FXR or Src downregulation in mice results in impaired homeostatic responses to acute BA feeding, and exacerbates cholestatic pathologies upon drug-induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis (PBC) patients. This study identifies Src-mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Naphthylisothiocyanate / toxicity
  • Animals
  • Bile Acids and Salts / metabolism*
  • Biomarkers / metabolism
  • Cell Nucleus / metabolism
  • Disease Models, Animal
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Healthy Volunteers
  • Hepatocytes
  • Humans
  • Intestinal Mucosa / metabolism
  • Isoxazoles / pharmacology
  • Liver / cytology
  • Liver / drug effects
  • Liver / pathology
  • Liver Cirrhosis, Biliary / chemically induced
  • Liver Cirrhosis, Biliary / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Phosphorylation / physiology
  • Postprandial Period / physiology
  • Primary Cell Culture
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Signal Transduction / physiology
  • Tyrosine / metabolism
  • src-Family Kinases / metabolism*

Substances

  • Bile Acids and Salts
  • Biomarkers
  • FGF19 protein, human
  • Isoxazoles
  • Receptors, Cytoplasmic and Nuclear
  • fibroblast growth factor 15, mouse
  • farnesoid X-activated receptor
  • Tyrosine
  • 1-Naphthylisothiocyanate
  • Fibroblast Growth Factors
  • src-Family Kinases
  • GW 4064