Journal Facts

Journal
BoneKEy Knowledge Environment
ISSN
1533-4368
Volume
Year
2002

Article Facts

Title
Secondary bile acids and the vitamin D receptor: Novel interactions and insights into gastrointestinal physiology
DOI
10.1138/2002045
Author

Online Date
06/24/2002

Article Links

BoneKEy-Osteovision | Commentary

Secondary bile acids and the vitamin D receptor: Novel interactions and insights into gastrointestinal physiology


DOI:10.1138/2002045

Commentary on: Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR, Mangelsdorf DJ. Vitamin D receptor as an intestinal bile acid sensor. Science. 2002 May 17;296(5571):1313-6.

Colorectal cancer is the 4th most common malignancy in the U.S. (ca. 135,000 new cases per year) and annually afflicts approximately 1 million individuals worldwide (). It causes about 60,000 deaths in the U.S. every year, and represents the 2nd most common deadly malignancy in Westernized societies. Specific cancer-family syndromes (e.g, familial adenomatous polyposis), inflammatory bowel disease, obesity with insulin resistance, genetic variations in specific phase I biotransformation enzymes, high fat diet, and protective non-steroidal anti-inflammatory agents have been identified as factors modifying risk for colonic neoplasia (). High fat diets stimulate colonic bacterial growth and metabolism of secreted bile acids that generate lumenal accumulation of genotoxic secondary bile acids. Secondary bile acids such as lithocholic acid (LCA) potentially promote the accrual of mutations that activate proto-oncogenes (H-Ras) or diminish tumor suppressors (APC, p53) in intestinal epithelial cells (). Importantly, vitamin D metabolites are thought to play a protective role in colorectal cancer through multifactorial mechanisms that are only now beginning to emerge (vide infra). Makishima and colleagues now identify a truly novel and unanticipated role for the vitamin D receptor (VDR) in bile acid physiology: they show that the carcinogenic bile acid LCA up-regulates expression of CYP3A genes involved in bile acid catabolism - in large part via LCA actions as a VDR agonist (). Mammalian two - hybrid assays of ligand - induced protein-protein interactions between the VDR and the p160 co-activator SRC1 reveal that LCA and key oxidized metabolites induce this interaction characteristic of VDR agonists. In competition assays using tritiated calcitriol as the radioligand, they demonstrate that LCA and 3-keto-LCA bind to the VDR with IC50 values in the 10- to 30- micromolar range, in excellent agreement with the EC50 values obtained from cell-based two-hybrid assays. Importantly, these interactions occur at concentrations of LCA 10 fold lower than those necessary to activate the pregnane X receptor (PXR), the nuclear receptor classically invoked in xenobiotic regulation of P450 genes (). Moreover, they demonstrate that vitamin D response elements (VDREs) present in CYP3A genes are recognized and regulated by the VDR in response to LCA. Finally, they show that CYP3A11 gene expression in small intestine and hepatic tissues is upregulated in PXR -/- mice by subcutaneous injection of LCA, thus demonstrating that another receptor - most probably the VDR - mediates this transcriptional response. However, VDR-dependent actions in colonic epithelial cells of the large intestine were not examined. The authors point to an epidemiological relationship between rickets and colonic neoplasia; they suggest that vitamin D - dependent catabolism of bile acids may contribute to protective actions, presumably via hepatic and intestinal CYP3A gene activation that also processes bile salts during enterohepatic circulation. Excessive fat intake may saturate this system and result in increased exposure of colonic epithelium to carcinogenic bile acids ().

Notably, VDR signaling exerts direct, cell-autonomous actions that inhibit proliferation, promote differentiation, and activate apoptosis - best described in hematopoietic and epithelial cells (). Topical calcitriol has clinically useful activity in treatment of psoriasis, a cutaneous hyperproliferative syndrome (). Freedman and colleagues were among the first to provide mechanistic insight, identifying that VDR activation by both classical ligands and non-calcemic analogs upregulates expression of the cyclin dependent kinase inhibitors (CKIs) p21 and p27 in myelomonocytic cells (). Detailed analyses of the p21 promoter have identified a tetra-partite element encoded by nucleotides -565 to -822 that confers VDR responses. Protein-protein interactions with specific co-regulators (e.g., DRIP205, BAG1L:Hsp70) other than the p160 family of co-activators likely confer VDR activation of p21 transcription (). Of note, transcriptional activation by nuclear receptors is both promoter and cell context specific; it remains to be tested whether LCA can mimic the anti-proliferative actions of calcitriol or induce recruitment of co-activators other than the p160 family (). Perhaps more germane to colorectal neoplasia, such bile acids may function as antagonists of VDR-dependent induction of growth arrest and terminal differentiation necessary for normal colonic epithelial function. The VDR is expressed throughout the colon; calcitriol suppresses tumor load in the APC (min) mouse () - a murine model of APC-dependent colonic neoplasia — and inhibits colonic neoplasia induced by genotoxic agents (). Given the high prevalence of p53 mutations in colon cancer (), the p53-independent mechanisms that mediate VDR-dependent up-regulation of CKIs and cellular apoptosis () are predicted to be therapeutically advantageous. Should LCA derivatives antagonize homeostatic functions of VDR signaling - as may be suggested from recent in vivo studies in pre-malignant epithelia ()- perturbed VDR regulation of colonic epithelial growth, differentiation, and apoptosis could contribute to the deleterious actions of secondary bile salts. I am unaware of reports linking vitamin D dependent rickets type II or VDR polymorphisms to colorectal cancer risk; however, mice lacking the VDR exhibit augmented intestinal epithelial proliferation rates in the colon (), and VDR allelic variants may be associated with other common epithelial malignancies (). It would be of interest to determine whether VDR -/- mice still exhibit enhanced susceptibility to LCA that is unmodified by agonists of PXR that promote CYP3A expression. Moreover, VDR signaling decreases pro-inflammatory Th1 T-cells and augments production of IL10 producing Th2 subsets — actions that may diminish cancer risk arising from colonic inflammation (). Future studies will no doubt address the influences of LCA on VDR signaling in colonic epithelial cells, T-cell immunomodulation, and intracellular vitamin D catabolism by CYP24. Finally, given the authors’ discovery that LCA can weakly up-regulate calbindin 9K in the small intestine of rodents - a gut segment involved in VDR-regulated calcium absorption - it will be interesting to see if secondary bile acid metabolites actively contribute to abnormalities in bone homeostasis that arise in states of chronic gastrointestinal fat malabsorption ().

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