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

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.

MicroRNA‐210 Promotes Bile Acid–Induced Cholestatic Liver Injury by Targeting Mixed‐Lineage Leukemia‐4 Methyltransferase in Mice

“…Because miR‐210 inhibits MLL4 expression, we examined whether miR‐210 is up‐regulated in cholestatic mice. Cholestatic liver injury was induced by BDL, feeding CA‐chow for 1 week, or treatment with ANIT, a chemical inducer of intrahepatic cholestasis . In each of these models, hepatic miR‐210 levels were increased and Mll4 mRNA levels were decreased (Fig.…”

“…MLL4 then acts as a coactivator of BA‐activated FXR and induces SHP expression, which further up‐regulates MLL4 through inhibition of miR‐210 . In contrast, in cholestatic liver (bottom), defective FGF15/19 signaling impairs nuclear localization of SHP, which increases KLF4 activity and miR‐210 expression. The elevated miR‐210 then inhibits MLL4 expression with decreased SHP expression, resulting in increased hepatic BA levels, toxicity, and inflammation.…”

“…These findings from previous and current studies together reveal an intriguing positive feedback loop in which BA‐activated FXR, together with its coactivator MLL4, induces Shp , which leads to increased MLL4 expression through inhibition of KLF4‐mediated transactivation of miR‐210 , resulting in sustained expression of SHP. In contrast, in cholestatic liver, impaired FGF15/19 signaling results in defective nuclear localization of SHP and subsequently increased the activity of KLF4 and miR‐210 expression. The elevated miR‐210 levels inhibit expression of MLL4, which further inhibits FXR‐mediated induction of SHP and, thus, forms a negative feedback loop that reinforces reduced SHP function and elevated miR‐210 levels (model, Fig.…”

“…Nearly every aspect of BA synthesis, transport, and metabolism is regulated transcriptionally by FXR‐dependent pathways, including induction of SHP; FGF19; β‐Klotho (β‐KL); the essential coreceptor for FGF19 musculoaponeurotic fibrosarcoma oncogene homolog G, a transcriptional repressor of BA synthesis; and lysine‐specific histone demethylase 1, an SHP‐interacting epigenetic repressor of BA synthesis . BA levels are further regulated through FGF19 signaling–induced posttranslational modifications of FXR and SHP . Recently, a role for the FXR‐induced RNA binding protein ZFP36L1 in posttranscriptional regulation of Cyp7a1 was also shown .…”

“…Nuclear localization and activity of SHP in mice requires FGF15/19 signaling–induced posttranslational modifications, including phosphorylation . In patients with PBC, hepatic expression of β‐KL, the essential coreceptor of FGF19, was dramatically reduced, phosphorylated extracellular signal‐regulated kinase levels were reduced, and circulating FGF19 levels increased, indicative of impaired FGF19 signaling. Thus, impaired FGF19 signaling in patients with PBC may result in defective nuclear localization of SHP, which together with elevated KLF4 expression, in part, explains elevated miR‐210 expression.…”