The VDR & Beyond Vitamin D: Other Ligands
The VDR is a member of the steroid/hormone nuclear receptor superfamily that includes 48 ligand-activated transcription factors. These factors bind to conserved elements in the promoters of genes as hetero- or homodimers through a zinc-finger motif and the adjacent ligand-binding domain activates or represses transcription upon binding to a small diffusible ligand. This allows nuclear receptors to function as intracellular detectors for endocrine hormones, dietary lipids and xenobiotic metabolites or compounds.
The nuclear receptor superfamily has been split into four groups based on class of ligand bound and whether DNA binding involves a hetero- or homodimer complex.[106,107] The first class is the endocrine receptors that function as homodimers and bind steroid hormones produced by endocrine tissues, and include androgen, estrogen, progesterone, mineralocorticoid and glucocorticoid. The second group forms heterodimers with RXRs and ligands include dietary lipids, xenobiotics and various cholesterol metabolites. The third group heterodimerize with RXRs and include the thryroid hormone, retinoic-acid (vitamin A) and vitamin D receptors. The fourth group are those receptors that have unknown ligands and are referred to as orphan nuclear receptors.
Interestingly, the VDR was shown to possess characteristics of both the second and third groups with the discovery of its ability to function as an intestinal secondary bile acid receptor. Members of the second group include receptors for primary bile acids such as the farnesoid X receptor (FXR) and the xenobiotic receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Primary bile acids are major metabolites of cholesterol that are produced in the liver, excreted in the bile and subsequently reabsorbed in the intestine. Bile acids that are not reabsorbed are converted to secondary bile acids by the intestinal microflora. Secondary bile acids are toxic and must undergo detoxification by the body. FXR and PXR are receptors for secondary bile acids and promote their metabolism in the liver.[108,110,111] VDR functions as a sensor for secondary bile acid lithocholic acid (LCA) and appears to be important for the detoxification of LCA in both the liver and intestine via the induction of CYP3A, a cytochrome P450 and known target gene of vitamin D, which mediates the catabolism of LCA.[107–109,112,113] The importance of these nuclear receptors in maintaining a functional detoxification system in the intestinal tract has been nicely reviewed.
It is becoming clear that there is overlap both in the ligands that activate PXR, FXR, CAR and VDR and the genes that are regulated by them. Because vitamin D is an important immune regulator one may hypothesize that these other receptors could regulate some aspects of immunity, particularly gut immunity. Obstruction of bile flow leads to bacterial overgrowth in the small intestine, mucosal injury, barrier disruption and systemic infection. Oral administration of bile acids ameliorates the problems associated with bile-acid deficiency. Recently, in studies using mice, it was demonstrated that FXR plays a critical role in preventing bacterial overgrowth and maintaining the epithelial barrier in the intestine by upregulating several genes involved in mucosal defense of the gut. In addition, it was shown that bile salts may contribute to biliary tract sterility in humans by regulating the expression of the cathelicidin gene through the nuclear receptors VDR and FXR (Figure 4).
A role for enteric receptors in regulating the innate immune system by inducing antimicrobial gene expression. Intestinal detoxification receptors and the VDR share ligands and target genes. It has been shown that primary bile acids are capable of inducing cathelicidin gene expression in biliary epithelial cells through the FXR. Secondary bile acids that are byproducts of metabolism of primary bile acids by intestinal bacteria induce the cathelicidin gene via the VDR. The extensive crosstalk by these receptors possibly creates a system where bile acids, xenobiotic compounds and microbial byproducts can maintain critical gut immunity by inducing antimicrobial gene expression.
FXR: Farnesoid X receptor; VDR: Vitamin D receptor; RXR: Retinoid X receptor.
The accumulating evidence suggests that in the intestinal tract, the byproducts of gut microbes could be important for communicating with the epithelial cells, thus modulating the expression of the cathelicidin gene. This may be important for establishing a mucosal barrier to prevent contact of microbes and pathogens with the intestinal epithelium. This is nicely demonstrated by the ability of short-chain fatty acids such as sodium butyrate that are produced by fermentation of fiber by microbes in the colon to induce expression of the cathelicidin. The vitamin D pathway has been implicated in this induction. The production of secondary bile acids by microbes may modulate cathelicidin expression in the colon via the VDR. One could speculate that the selective force for placing the cathelicidin gene under the regulation of the VDR was so its expression could be regulated by both vitamin D and xenobiotic factors (Figure 4).
A recent study indicates that the VDR may act as a receptor for additional nutritional ligands, including curcumin and polyunsaturated fats such as α-linolenic acid, docosahexaenoic acid, eicosapentaenoic acid and arachidonic acid. The in vivo relevance of these findings remains to be elucidated, but it is intriguing to consider that numerous nutritional compounds may modulate the expression of VDR target genes such as antimicrobial peptides.
Future Microbiol. 2009;4(9):1151-1165. © 2009
Cite this: The Vitamin D–antimicrobial Peptide Pathway and Its Role in Protection against Infection - Medscape - Nov 01, 2009.