Nuclear receptors, including the pregnane x receptor (PXR) and the farnesoid x
receptor (FXR), regulate the expression of genes that maintain bile acid (BA)
homeostasis. Intrahepatic cholestasis of pregnancy (ICP) is a common gestational
liver disease and BAs are implicated in its pathogenesis.
Rodents exhibit maternal liver growth in order to meet the metabolic demands of
pregnancy. This process is found to precede changes in body weight, occur in the
presence of raised serum BAs and is likely to be driven by a placental lactogen.
While the growth is normally achieved by hepatocyte hypertrophy, potentially
harmful hyperplasia makes a major contribution in mice lacking Fxr.
Consistent with reports of raised serum BAs in normal pregnant women, hepatic BAs
are found in association with pro-cholestatic gene expression in normal pregnant
mice. Gestation could be a state of reduced Fxr function because BA-fed and Fxr-/-
mice do not develop raised hepatic BAs during pregnancy. Sequencing and
functional assessment of PXR variants revealed that polymorphisms in this gene are
unlikely to contribute to the aetiology of ICP.
Surprisingly, Pxr-/- mice have enhanced hepatic metabolism and are resistant to
toxicity caused by lithocholic acid (LCA). Furthermore, while hepatic Pxr is
activated by intraperitoneal injection of LCA, it is not activated by physiologically
relevant LCA-feeding.
Summary: Pregnancy causes liver growth, raised hepatic BA and pro-cholestatic
gene expression in normal mice. In humans, these adaptations may expose
predisposed individuals to gestational liver disease. Genetic variation in PXR does
not contribute to ICP and Pxr may play only a limited role in mediating hepatic
responses to toxic BAs
