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

Sangwon Byun,Byron Kemper,H Eric Xu,Peter Yau,Grace Guo,Jongsook Kim Kemper,Dong-Hyun Kim,Daniel Ryerson,Hao Sun,Bo Kong,Young-Chae Kim

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.

Highlights

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 Bile acids (BAs) synthesis
Genomics, metabolomics analyses, as well as, metabolic analyses, we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase Src upon postprandial FGF19 signaling in hepatocytes, and that the FGF19-induced Y67-FXR phosphorylation is critical for its transcriptional regulation of BA levels
Y67 is the most highly predicted Tyr phosphorylation site in FXR by bioinformatics analysis with NetPhos 3.1 (Supplementary Fig. 1b). Consistent with these findings, FGF19 treatment led to transient increases in phosphorylated (p)-Tyr-FXR levels that peaked at 10 min and returned to basal levels after 30–60 min (Fig. 1b) while treatment of hepatocytes with insulin or a synthetic FXR agonist, GW4064, did not significantly increase Tyr-FXR phosphorylation (Fig. 1c)

Summary

Introduction

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. Bile acids (BAs) are amphipathic steroid molecules that aid in digestion of dietary lipids, and function as signaling molecules that profoundly impact metabolism and energy balance by activating the nuclear receptor, farnesoid X receptor (FXR, NR1H4), and a membrane G-protein-coupled receptor, TGR51–5 Due to their detergent-like nature, excess levels of BAs are toxic and lead to cellular injury, which can further progress to fatal diseases, such as liver fibrosis and cirrhosis, and liver and intestinal cancer[6,7]. While FXR induces the expression of FGF15/19, it remains unknown whether transcriptional activity of FXR can be physiologically modulated in a feedback manner by FGF19 signal-induced PTMs

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Conclusion