In addition to being positively regulated by prandial activity, bile acid production is also negatively
controlled by the endocrine fibroblast growth factor 19 (FGF19) or the mouse ortholog FGF15 from the ileum
that represses hepatic cholesterol 7 α-hydroxylase (Cyp7a1) expression through activating FGF receptor four
(FGFR4). However, how these two regulatory mechanisms interplay to control bile acid homeostasis in the
body and the downstream pathways by which FGFR4 regulates Cyp7a1 expression are not fully understood.
Here we report that hepatocyte FGFR substrate 2α (FRS2α), a scaffold protein essential for canonical FGFRs
to activate the ERK and AKT pathways, was required for the regulation of bile acid production by the
FGF15/19-FGFR4 signaling axis. This occurred through limiting the extent of increases in Cyp7a1 expression
induced by prandial activity. Excess FGFR4 kinase activity reduced the amplitude of the increase whereas a
lack of FGFR4 augmented the increase of Cyp7a1 expression in the liver. Ablation of Frs2α alleles in
hepatocytes abrogated the regulation of Cyp7a1 expression by FGFR4. Together, the results demonstrate that
FRS2α-mediated pathways are essential for the FGF15/FGF19-FGFR4 signaling axis to control bile acid
Keywords: Bile acid, CYP7A1, FGF15/FGF19, FGFR4, FRS2α.
Rights & PermissionsPrintExport