This article is available online at http://www.jlr.org super family ( 15 ). When 1,25(OH) 2 D 3 is bound to VDR, it activates it by inducing conformational changes. The activated complex, VDR/1,25(OH) 2 D 3 , binds as a heterodimer with the retinoid X receptor (RXR) to vitamin D response elements located in the promoter region of the target genes. Recruitment of coactivator proteins to this heterodimer is also essential to the transactivation. However, clinical use of 1,25(OH) 2 D 3 is limited because therapeutic doses can give rise to signifi cant hypercalciuria and hypercalcemia ( 16 ). A number of synthetic ligands to VDR have been developed for medical use; however, most of them can also cause similar problems because they are derived from 1,25(OH) 2 D 3 .Several synthetic compounds without the vitamin D 3 scaffold have been reported to bind to VDR and have VDR-modulating activities, including growth inhibition of cancer cells and keratinocytes and induction of leukemic cell differentiation, with less calcium mobilization side effects than 1,25(OH) 2 D 3 ( 17 ). Therefore, these synthetic compounds are expected to be therapeutics for cancer, leukemia, and psoriasis. Subsequently, Makishima et al. discovered that secondary bile acids, including lithocholic acid (LCA) and its derivatives, also behaved as VDR agonists (18)(19)(20). LCA acts as a detergent to stabilize fats for absorption, and it has been implicated in human and experimental animal carcinogenesis. However, the agonistic behavior of LCA as a ligand recognized by VDR was not common knowledge because the structure of LCA is completely different from that of vitamin D 3 . Additional studies showed that VDR had dual functions as a metabolic sensor of bile acids and as an endocrine receptor for 1,25(OH) 2 D 3 . , regulates calcium homeostasis ( 1 ). It also promotes cellular differentiation, inhibits cellular proliferation, and suppresses the immune system ( 2-7 ). It has been used clinically to treat renal osteodystrophy, vitamin D-dependent rickets type I, and X-linked hypophosphatemic rickets, among other conditions (8)(9)(10)(11)(12)(13)(14). Most of its effects are mediated by its specifi c binding to the vitamin D receptor (VDR), which is a member of nuclear receptor (NR)
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