PXR-mediated Metabolism During Pregnancy and Cholestasis

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Title: PXR-mediated Metabolism During Pregnancy and Cholestasis
Authors: Owen, Bryn Myers
Item Type: Thesis or dissertation
Abstract: 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.
Issue Date: 2009
Date Awarded: 2009
URI: http://hdl.handle.net/10044/1/4431
Author: Owen, Bryn Myers
Department: Faculty of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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