Elevated cholesterol metabolism and bile acid synthesis in mice lacking membrane tyrosine kinase receptor FGFR4

Heparan sulfate-regulated transmembrane tyrosine kinase receptor FGFR4 is t he major FGFR isotype in mature hepatocytes. Fibroblast growth factor has b een implicated in the definition of liver from foregut endoderm where FGFR4 is expressed and stimulation of hepatocyte DNA synthesis in vitro, Here we show that livers of mice lacking FGFR4 exhibited normal morphology and reg enerated normally in response to partial hepatectomy, However, the FGFR4 (- /-) mice exhibited depleted gallbladders, an elevated bile acid pool and el evated excretion of bile acids. Cholesterol- and bile acid-controlled liver cholesterol 7 alpha-hydroxylase, the limiting enzyme for bile acid synthes is, was elevated, unresponsive to dietary cholesterol, but repressed normal ly by dietary cholate, Expression pattern and cholate-dependent, cholestero l-induced hepatomegaly in the FGFR4 (-/-) mice suggested that activation of receptor interacting protein 140, a co-repressor of feed-forward activator liver X receptor alpha, may mediate the negative regulation of cholesterol - and bile acid-controlled liver cholesterol 7 alpha-hydroxylase transcript ion by FCFR4 and cholate, The results demonstrate that transmembrane sensor s interface with metabolite-controlled transcription networks and suggest t hat pericellular matrix-controlled liver FGFR4 in particular may ensure ade quate cholesterol for cell structures and signal transduction.