This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this proposal is to determine whether the nuclear receptors farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR), constitutive androstane receptor (CAR), and retinoid-X-receptor alpha (RXRa) protect the liver during cholestatic liver disease. The main hypothesis is that FXR, PXR, CAR, and RXRa protect the liver during cholestatic liver disease by regulating bile-acid synthesis, transport, and detoxification. Cholestatic liver disease arises when excretion of bile acids from the liver is interrupted. This causes toxic bile acids to accumulate in liver, which produces hepatocyte injury. Recent studies have identified several nuclear receptors expressed by hepatocytes that regulate bile acid homeostasis, including FXR, PXR, CAR, and RXRa. When activated, these nuclear receptors regulate expression of genes in hepatocytes that encode for proteins that reduce bile-acid uptake and synthesis, as well as increase bile-acid excretion and detoxification. Studies have shown that some of these nuclear receptors are important for regulating bile-acid toxicity in mice fed toxic quantities of bile acids. However, it is not known whether these nuclear receptors function similarly and reduce bile acid toxicity during cholestasis. This forms the basis of this proposal, which will examine the physiological role of each of these nuclear receptors in cholestatic liver disease by systematically determining whether liver injury and bile-acid synthesis, transport, and detoxification are enhanced, reduced, or unaffected in nuclear receptor-null animals with different types of cholestatic liver disease. The studies in this proposal will not only provide important information about the physiological function of each nuclear receptor in cholestasis, but will also provide important insight into whether modulation of these pathways might be beneficial for the treatment of cholestatic liver disease.
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