TY - JOUR
T1 - Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis
AU - Byun, Sangwon
AU - Kim, Dong Hyun
AU - Ryerson, Daniel
AU - Kim, Young Chae
AU - Sun, Hao
AU - Kong, Bo
AU - Yau, Peter
AU - Guo, Grace
AU - Eric Xu, H.
AU - Kemper, Byron
AU - Kemper, Jongsook Kim
N1 - Funding Information:
We thank Johan Auwerx and Kristina Schoonjans at Ecole Polytechnique Fédérale de Lausanne, Switzerland, for kindly providing FXR-floxed mice. We also thank the Liver Tissue Cell Distribution System, Minneapolis, University of Minnesota (NIH Contract # HHSN276201200017C) for providing human liver specimens of PBC patients. Petri dish, mouse, and liver images in the figures are unmodified images provided by Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License [https://creativecommons.org/licenses/by/3.0/legalcode]. This study was supported by an American Heart Association Postdoctoral Fellowship to S.B. (17POST33410223), an American Heart Association Scientist Development Award (16SDG27570006) to Y.-C.K., and by R01 grants from the National Institutes of Health (DK062777 and DK095842) and an Innovative Basic Science grant from the American Diabetes Association (1-16-IBS-156) to J.K.K.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85049506499&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049506499&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04697-5
DO - 10.1038/s41467-018-04697-5
M3 - Article
C2 - 29968724
AN - SCOPUS:85049506499
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2590
ER -