Genetic and Pharmacological Regulation of Hepatic and lleal FXR During Pregnancy

Rutgers, The State Univ Of N.J., New Brunswick NJ

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Abstract

? DESCRIPTION (provided by applicant): Bile acid homeostasis is often dysregulated in pregnancy and can present as asymptomatic hypercholemia (40% of pregnancies) to the more severe disease, intrahepatic cholestasis of pregnancy (ICP, 0.5-2% of pregnancies). Recent research in humans and mice suggests that women with ICP have a greater susceptibility to future hepatobiliary disease, while offspring born to mothers with ICP are at higher risk of developing metabolic disorders. While the mechanisms by which pregnancy leads to cholestatic disease are still being explored, altered hepatic transport of biliary constituents and xenobiotics has emerged as a potential contributing factor. The Farnesoid X Receptor (human FXR/mouse Fxr) is a bile acid-activated transcription factor belonging to the nuclear receptor superfamily, and one of its functions is to promote the enterohepatic recirculation of bile acids by regulating the transcription of critical transporter and metabolic genes. Prior research has proposed that pregnancy represents a state of Fxr inactivation, with hepatic gene changes in pregnant mice that mirror those of naïve Fxr knockout mice. We hypothesize that loss of hepatic and intestinal FXR/Fxr signaling during pregnancy reduces the expression of bile acid metabolic enzymes and transporters, and that pharmacological activation of FXR/Fxr during pregnancy can reestablish these pathways and restore bile acid homeostasis. Aim 1 will determine the degree to which Fxr is necessary for the adaptive hepatic and intestinal gene responses of pregnant mice, using mice lacking or overexpressing Fxr. Aim 2 will investigate the extent to which activation of Fxr using the pharmacological agonist GW4064 (GW) can reverse the down- regulation of transporters in pregnant mice. The expected outcome is that the absence of Fxr will prevent repression of key bile acid and xenobiotic transporters, as well as additional regulatory genes in the Fxr pathway, while pharmacological and genetic activation of Fxr during pregnancy may restore expression in mice. It is anticipated that this research will contribute to our understanding of the mechanisms underlying ICP and serve as a critical first step in identifying a novel therapeutic target to treat pregnant women with cholestatic liver disease. At the completion of this research and the F31 Fellowship, the Principal Investigator will be prepared to conduct independent biomedical research in the fields of Obstetric Pharmacology and Reproductive Toxicology.