Nuclear receptors play significant roles in the regulation of transporters and enzymes to balance the level of endogenous molecules and to protect the body from foreign molecules. The vitamin D receptor (VDR) and its natural ligand, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], was shown to upregulate rat ileal apical sodium dependent bile acid transporter (Asbt) to increase the reclamation of bile acids, ligands of the farnesoid X receptor (FXR). FXR is considered to be an important, negative regulator of the cholesterol metabolizing enzyme, Cyp7a1, which metabolizes cholesterol to bile acids in the liver. In rats, decreased Cyp7a1 and increased P-glycoprotein/multidrug resistance protein 1 (P-gp/Mdr1) expressions pursuant to 1,25(OH)2D3 treatment was viewed as FXR effects in which hepatic VDR protein is poorly expressed. In contrast, changes in rat intestinal and renal transporters such as multidrug resistance associated proteins (Mrp2, Mrp3, and Mrp4), Asbt, and P-gp after administration of 1,25(OH)2D3 were attributed directly as VDR effects due to higher VDR levels expressed in these tissues. Higher VDR expressions were found among mouse hepatocytes compared to those in rats. Hence, fxr(-/-) and fxr(+/+) mouse models were used to discriminate between VDR vs. FXR effects in murine livers. Hepatic Cyp7a1 in mice was found to be upregulated with 1,25(OH)2D3 treatment, via the derepression of the short heterodimer partner (SHP). Putative VDREs, identified in mouse and human SHP promoters, were responsible for the inhibitory effect on SHP. The increase in hepatic Cyp7a1 expression and decreased plasma and liver cholesterol were observed in mice prefed with a Western diet. A strong correlation was found between tissue Cyp7a1 and P-gp changes and 1,25(OH)2D3 plasma and tissue concentrations, confirming that VDR plays an important role in the disposition of xenobiotics and cholesterol metabolism. Moreover, renal and brain Mdr1a/P-gp were found to be directly upregulated by the VDR in mice, and concomitantly, increased renal and brain secretion of digoxin, a P-gp substrate, in vivo. The important observations: the cholesterol lowering and increased brain P-gp efflux activity properties suggest that VDR is a therapeutic target for treatment of hypercholesterolemia and Alzheimer’s diseases, since beta amyloid, precursors of plague, are P-gp substrates.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/36277 |
| Date | 15 August 2013 |
| Creators | Chow, Edwin C. Y. |
| Contributors | Pang, K. Sandy |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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