Pharmacological Activation of Fxr Attenuates Pregnancy‐Induced Repression of Hepatic and Ileal Bile Acid Transporters in Mice

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The Farnesoid X Receptor (Fxr) controls bile acid homeostasis by coordinately regulating the expression of bile acid synthesis enzymes (Cyp7a1) and transporters in the intestine (Asbt, Ostβ) and liver (Ntcp, Oatp1a4, Bsep, Mrp3, Ostβ), as well as endocrine (Fgf15) and transcription (Shp) factors. We have demonstrated that expression of bile acid synthesis enzymes and transporters is dysregulated in pregnant mice. To determine the role of Fxr in the adaptive gene responses of pregnancy, mRNA and protein expression were quantified in livers and intestines from wild‐type and Fxr‐null mice, as well as wild‐type mice administered the Fxr agonist GW4064 (GW). In response to pregnancy, ileal Fgf15, Asbt and Ostβ mRNAs decreased by 25 to 57% in wild‐type mice. Expression of these genes was also constitutively reduced 40 to 99% in Fxr‐null mice, although unchanged by pregnancy. In the liver, pregnancy‐mediated repression of Bsep mRNA was observed in wild‐type, but not Fxr‐null mice. Similar to wild‐types, pregnancy further reduced hepatic Shp, Ntcp, Oatp1a4 and Mrp3 mRNA levels of Fxr‐null mice. Treatment of pregnant mice with GW induced hepatic Shp, Ntcp, Bsep, Mrp3 and Ostβ, and ileal Fgf15 and Ostβ mRNA levels by 20 to 300%. GW also enhanced protein levels of Ntcp and Bsep in pregnant mice. Likewise, the induction of Cyp7a1 in pregnant mice was reduced by GW to levels lower than virgin controls. Collectively, these data implicate both intestinal and hepatic Fxr signaling in pregnancy‐related procholestatic gene changes, and suggest that Fxr activation may restore bile acid homeostasis in maternal cholestasis. Supported by AFPE, R01ES020522, GM104037 and T32ES007148.