Role of FXR in the adaptive response to bile acids during pregnancy

The bile acid receptor FXR maintains bile acid homeostasis through the dynamic regulation of transporters, detoxification and biosynthesis enzymes. Intrahepatic cholestasis of pregnancy (ICP) is caused by disturbance in bile acid homeostasis in predisposed individuals. The first genetic variants in FXR, identified in an ICP population, are investigated in this thesis using in vitro approaches and a functional effect is demonstrated. Reproductive hormones are implicated in the aetiology of ICP but experiments in mice suggest that estrogen and progesterone alone are unlikely to be the cause of gestational cholestasis. Pregnancy increases the metabolic demand on the maternal liver and, in mice, causes maternal hepatomegaly that is associated with pro-cholestatic gene expression and raised serum and hepatic bile acids. Gestational hepatomegaly is characterised in detail for the first time and Fxr is shown to be required to maintain the normal mechanisms driving this process. Furthermore, pro-cholestatic gene expression and the fact that hepatic bile acids do not accumulate in pregnant Fxr-/- or cholate-fed mice suggest that for unknown reasons, gestation could be a period of reduced Fxr function. Conclusions: Pregnancy causes perturbed bile acid homeostasis in mice. This may be a result of Fxr playing a complex role in mediating, or responding to, the metabolic demands of gestation. Furthermore, FXR protects individuals from developing pregnancy-specific cholestatic disease.EThOS - Electronic Theses Online ServiceGBUnited Kingdo