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.