The pregnane X receptor (PXR) is established to play an integral role in metabolism, endobiotic signaling and homeostasis of energy balance. Studies on the effect of endoplasmic reticulum (ER) stress, a common theme of metabolic diseases, have shown that the expression of PXR was down-regulated. The downregulation was preceded by the downregulation of hepatocyte nuclear factor-4? (HNF4?). A PXR minimal promoter was transactivated by HNF4? but repressed by activating transcription factors (ATFs) and CHOP (C/EBP homologous protein). ATFs and CHOP are ER-stress proteins. Studies on the induction of cytochrome P450 3A4 (CYP3A4) have revealed functional antagonism between rifampicin and chenodeoxycholic acid (CDCA). Rifampicin is a PXR activator and commonly used to treat cholestasis. CDCA, on the other hand, is a potent activator of the farnesoid X receptor (FXR). Interestingly, the induction of CYP3A4 by rifampicin was significantly reduced by CDCA at a concentration with no ER stress activity. PXR-directed induction of CYP3A4 by rifampicin serves as a major foundation for treating cholestasis. The central hypothesis of this project is that the functionality of PXR is a critical determinant of disease-drug interactions in wide spectrum of metabolic disorders.
The specific aims are: (1) to ascertain functional consequences of PXR downregulation; and (2) to characterize bile acid-rifampicin interactions. In order to determine whether downregulation of PXR represents a common phenomenon in ER stress-related diseases, a large number of diseased livers with metabolic abnormalities will be tested for the expression of PXR. The molecular action of the HNF4?-ATF- CHOP network on PXR suppression will be specified under ER stress and in diseased livers. To specify functional changes of PXR downregulation during ER stress, xenografts derived from cells expressing PXR will be tested for their reversal in responding to PXR activators under ER stress. The expression of PXR target genes such as carboxylesterase-2 (CES2) will be monitored. In addition, the anticancer potential of CES2 activated prodrug in xenografts will be determined under ER stress in the presence or absence of rifampicin. To elucidate the molecular actions between rifampicin and CDCA, the PXR-directed recruitment of polymerase II will be determined with or without FXR activation. Species-specific PXR activators (human versus mouse) will be evaluated for their differential anticholestatic activities. Overall, these studieswill characterize molecular interplays among PXR, FXR along with the HNF4?-ATF/CHOP network in terms of regulated expression and transactivation activity of PXR during ER stress condition and in metabolic disorders. These studies will gain important new information on transcriptional networking, disease-drug interactions and therapeutic optimization related to PXR. Therefore, this project will have direct impact not only on clinical practice but also on the basic understanding of PXR as a master transcriptional regulator.
All organisms are exposed constantly to toxic chemicals from both foreign (including medicines) and endogenous sources. Organisms such as humans have evolved several defensive systems against chemical insults. These systems operate by regulating the expression of certain genes. The pregnane X receptor (PXR) is established as a master regulator of those genes for the elimination of toxicants and drugs. This project will assess how diseases such as type II diabetes and cholestasis (elevated bile acids) alter the functions of PXR. This project will also assess how drugs and dosing regimens should be chosen according to the altered PXR functions.
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