Download or read book Transcriptional Regulation of the Rat Hepatic Bile Acid Transporters Ntep and Bsep by Nuclear Receptors FXR and PXR written by and published by . This book was released on 2013 with total page 536 pages. Available in PDF, EPUB and Kindle. Book excerpt: Furthermore, sandwich cultured rat hepatocytes were used to ascertain if the above in vivo findings are reproducible in vitro. Treatment of hepatocytes with FXR ligand, CDCA, and PXR ligand, PCN, caused greater than 5-fold increase in the respective mRNA levels whereas respective siRNA treatment caused >79% knocked in their transcript levels. FXR induction decreased Ntcp mRNA levels that were ablated in FXR knockdown cultures. FXR induction resulted in a 6-fold increase in Bsep mRNA levels that disappeared in FXR knockdown cultures. On the contrary, PXR induction did not influence the expression levels of Ntcp and Bsep. Taken together these data demonstrate that both FXR and PXR are inducible at mRNA and protein levels in vivo and their expression can be knocked down in the rat liver. Moreover, FXR negatively regulate Ntcp and positively regulate Bsep while PXR does not influence Ntcp and Bsep expression. Finally, the data shows that these in vivo findings can be successfully reproduced in sandwich cultured rat hepatocytes. To conclude, sandwich cultured rat hepatocytes mimic the in vivo situation and provide a good model for bile acid transport studies.

Download or read book Transcriptional Regulation of the Rat Hepatic Bile Acid Transporters Ntep and Bsep by Nuclear Receptors FXR and PXR written by Muhammad Farooq and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Regulation of Hepatic Transporter Expression by the Pregnane X Receptor written by Shirley Hsueh Li Teng and published by . This book was released on 2007 with total page 402 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hepatic transporters play a fundamental role in the disposition of drugs and endogenous compounds. Understanding how transporters are regulated is critical because changes in transporter expression and/or activity are linked to diseases and altered drug disposition. The pregnane X receptor (PXR) is a ligand-activated nuclear receptor that regulates numerous genes involved in drug transport and metabolism. We sought to further elucidate the role of PXR in transporter regulation and in the mechanisms behind changes in transporter expression during inflammation and cholestasis. In vitro experiments with human hepatoma cell lines and in vivo studies comparing wild-type (PXR+/+) and PXR-knockout mice (PXR -/- ) demonstrated that MDR1a, MRP2, MRP3, BSEP, OATP2 and CYP3A are induced in liver following treatment with various PXR activators, indicating PXR-dependent regulation. Conversely, most of these genes were down-regulated in endotoxin and interleukin (IL)-6 treated mice. Endotoxin and IL-6 also reduced hepatic PXR mRNA and protein expression. Endotoxin-mediated changes in the expression of most transporters were similar between PXR +/+ and PXR-/- mice, with the exception of MRP2 as the decrease in PXR-/- mice was significantly less-extensive than in PXR+/+ mice. On the other hand, the suppression of MRP2, BSEP and CYP3A11 by IL-6 was seen in PXR+/+ but not PXR -/- mice. These findings suggest an involvement of PXR in inflammation-mediated transporter down-regulation and suggest that IL-6 may be the principle inflammatory mediator involved. In a cholic acid (CA) model of cholestatic hepatotoxicity, we found a PXR-dependent induction of many bile acid transporters and CYP3A11. Co-administration of the PXR activator PCN to CA-fed PXR+/+ mice prevented induced liver injury and was associated with an increase in CYP3A11 and MRP3 expression. Unexpectedly, hepatotoxicity was much less severe in PXR-/- mice, which had higher basal expression of numerous efflux transporters and CYP3A11. These findings suggest that PXR activation can protect against bile acid hepatotoxicity by inducing metabolic detoxification and basolateral efflux, particularly by MRP3. Together, these studies illustrate that PXR is an important regulator of hepatic transporter expression under both normal and inflammatory conditions, and that targeting PXR may be a worthwhile strategy to treat transporter-related diseases.