Restoration of enterohepatic bile acid pathways in pregnant mice following short term activation of Fxr by GW4064

Sep 10, 2016Toxicology and applied pharmacology

Recovery of bile acid circulation in pregnant mice after brief activation of a liver and gut receptor

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Abstract

Pregnant mice exhibited a 2.5-fold increase in Cyp7a1 mRNA compared to virgin controls.

Short-term treatment with GW4064 restored Fxr signaling in pregnant mice to levels observed in virgin mice.
Ileal Fgf15, Shp, and Ostα/β mRNAs were induced following GW4064 treatment in pregnant mice.
Hepatic Shp, Bal, Ntcp, and Bsep levels returned to those of virgin mice after GW4064 treatment.
Treatment with plasma from pregnant mice increased Cyp7a1 mRNA by nearly 3-fold in primary hepatocytes.
GW4064 or recombinant FGF19 protein co-treatment could reduce the elevated Cyp7a1 mRNA levels induced by pregnant plasma.

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The farnesoid X receptor (Fxr) controls bile acid homeostasis by coordinately regulating the expression of synthesizing enzymes (Cyp7a1, Cyp8b1), conjugating enzymes (Bal, Baat) and transporters in the ileum (Asbt, Ostα/β) and liver (Ntcp, Bsep, Ostβ). Transcriptional regulation by Fxr can be direct, or through the ileal Fgf15/FGF19 and hepatic Shp pathways. Circulating bile acids are increased during pregnancy due to hormone-mediated disruption of Fxr signaling. While this adaptation enhances lipid absorption, elevated bile acids may predispose women to develop maternal cholestasis. The objective of this study was to determine whether short-term treatment of pregnant mice with GW4064 (a potent FXR agonist) restores Fxr signaling to the level observed in virgin mice. Plasma, liver and ilea were collected from virgin and pregnant mice administered vehicle or GW4064 by oral gavage. Treatment of pregnant mice with GW4064 induced ileal Fgf15, Shp and Ostα/β mRNAs, and restored hepatic Shp, Bal, Ntcp, and Bsep back to vehicle-treated virgin levels. Pregnant mice exhibited 2.5-fold increase in Cyp7a1 mRNA compared to virgin controls, which was reduced by GW4064. Similarly treatment of mouse primary hepatocytes with plasma isolated from pregnant mice induced Cyp7a1 mRNA by nearly 3-fold as compared to virgin plasma, which could be attenuated by co-treatment with either GW4064 or recombinant FGF19 protein. Collectively, these data reveal that repressed activity of intestinal and hepatic Fxr in pregnancy, as previously demonstrated, may be restored by pharmacological activation. This study provides the basis for a novel approach to restore bile acid homeostasis in patients with maternal cholestasis.

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Restoration of enterohepatic bile acid pathways in pregnant mice following short term activation of Fxr by GW4064

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