出版社：American Society for Biochemistry and Molecular Biology
摘要：Bile acid concentrations are controlled by a feedback regulatorypathway whereby activation of the farnesoid X receptor (FXR)represses transcription of both the CYP7A1 gene, encoding therate-limiting enzyme in the classic bile acid synthesis pathway,and the CYP8B1 gene, required for synthesis of cholic acid.The tissue-specific roles of FXR were examined using liver-and intestine-specific FXR-null models. FXR deficiency in eitherliver (FxrL) or intestine (FxrIE) increased bile acid pool size.Treatment with the FXR-selective agonist GW4064 significantlyrepressed CYP7A1 in FxrL mice but not FxrIE mice, demonstratingthat activation of FXR in intestine but not liver is requiredfor short-term repression of CYP7A1 in liver. This intestinal-specificeffect of FXR is likely mediated through induction of the hormoneFGF15, which suppresses CYP7A1. In comparison to CYP7A1, FXR-mediatedrepression of CYP8B1 was more dependent on the presence of FXRin liver and less dependent on its presence in intestine. Consistentwith these findings, recombinant FGF15 repressed CYP7A1 mRNAlevels without affecting CYP8B1 expression. These data provideevidence that FXR-mediated repression of bile acid synthesisrequires the complementary actions of FXR in both liver andintestine and reveal mechanistic differences in feedback repressionof CYP7A1 and CYP8B1.Supplementary key words FXR • FGF15 • CYP7A1 • CYP8B1 • liver-specific FXR null mice • intestine-specific FXR null mice
Abbreviations: BW, body weight; CA, cholic acid; DCA, deoxycholic acid; FXR, farnesoid X receptor; LC-MS/MS, liquid chromatography tandem mass spectrometry; MCA, murocholic acid; RT-qPCR, real-time quantitative PCR; TCA, taurocholic acid; TDCA, taurodeoxycholic acid
L) or intestine (Fxr
