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Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis
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 transmitte...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030054/ https://www.ncbi.nlm.nih.gov/pubmed/29968724 http://dx.doi.org/10.1038/s41467-018-04697-5 |
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author | Byun, Sangwon Kim, Dong-Hyun Ryerson, Daniel Kim, Young-Chae Sun, Hao Kong, Bo Yau, Peter Guo, Grace Xu, H. Eric Kemper, Byron Kemper, Jongsook Kim |
author_facet | Byun, Sangwon Kim, Dong-Hyun Ryerson, Daniel Kim, Young-Chae Sun, Hao Kong, Bo Yau, Peter Guo, Grace Xu, H. Eric Kemper, Byron Kemper, Jongsook Kim |
author_sort | Byun, Sangwon |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6030054 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-60300542018-07-05 Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis Byun, Sangwon Kim, Dong-Hyun Ryerson, Daniel Kim, Young-Chae Sun, Hao Kong, Bo Yau, Peter Guo, Grace Xu, H. Eric Kemper, Byron Kemper, Jongsook Kim Nat Commun Article 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. Nature Publishing Group UK 2018-07-03 /pmc/articles/PMC6030054/ /pubmed/29968724 http://dx.doi.org/10.1038/s41467-018-04697-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Byun, Sangwon Kim, Dong-Hyun Ryerson, Daniel Kim, Young-Chae Sun, Hao Kong, Bo Yau, Peter Guo, Grace Xu, H. Eric Kemper, Byron Kemper, Jongsook Kim Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis |
title | Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis |
title_full | Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis |
title_fullStr | Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis |
title_full_unstemmed | Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis |
title_short | Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis |
title_sort | postprandial fgf19-induced phosphorylation by src is critical for fxr function in bile acid homeostasis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030054/ https://www.ncbi.nlm.nih.gov/pubmed/29968724 http://dx.doi.org/10.1038/s41467-018-04697-5 |
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