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

Sangwon Byun, Dong-Hyun Kim, Daniel Ryerson, Young-Chae Kim, Hao Sun, Bo Kong, Peter Yau, Grace Guo, H. Eric Xu, Byron Kemper and Jongsook Kim Kemper ()
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Sangwon Byun: University of Illinois at Urbana-Champaign
Dong-Hyun Kim: University of Illinois at Urbana-Champaign
Daniel Ryerson: University of Illinois at Urbana-Champaign
Young-Chae Kim: University of Illinois at Urbana-Champaign
Hao Sun: University of Illinois at Urbana-Champaign
Bo Kong: Rutgers University
Peter Yau: University of Illinois at Urbana-Champaign
Grace Guo: Rutgers University
H. Eric Xu: Van Andel Research Institute
Byron Kemper: University of Illinois at Urbana-Champaign
Jongsook Kim Kemper: University of Illinois at Urbana-Champaign

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04697-5

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