Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis.
Sangwon ByunDong-Hyun KimDaniel RyersonYoung-Chae KimHao SunBo KongPeter YauGrace GuoH Eric XuByron KemperJongsook Kim KemperPublished in: Nature communications (2018)
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.
Keyphrases
- tyrosine kinase
- drug induced
- liver injury
- epidermal growth factor receptor
- end stage renal disease
- newly diagnosed
- poor prognosis
- genome wide
- blood pressure
- blood glucose
- cell proliferation
- binding protein
- intensive care unit
- chronic kidney disease
- adverse drug
- type diabetes
- risk assessment
- high glucose
- prognostic factors
- dna methylation
- endothelial cells
- skeletal muscle
- protein kinase
- transcription factor
- weight loss
- heat shock protein
- liver fibrosis
- patient reported outcomes