Chapter 88 - Bile Acid-Derived Vitamin D Receptor Ligands

Abstract

The active form of vitamin D3, 1,25-dihydroxyvitmain D3, acts as a ligand for the vitamin D receptor (VDR), and regulates calcium homeostasis, cell differentiation and proliferation, and immunity. VDR is a promising drug target in the treatment of cancer, autoimmune disease, inflammation, infection, and cardiovascular disease as well as bone and mineral disorders. Hypercalcemia, the major adverse effect of administration of vitamin D derivatives, limits their clinical application. The secondary bile acid lithocholic acid (LCA) is an additional physiological ligand for VDR. Together with farnesoid X receptor and pregnane X receptor, VDR senses and regulates bile acid metabolism. Synthetic LCA derivatives, such as LCA acetate and LCA propionate, are potent VDR ligands and induce tissue VDR activation without inducing hypercalcemia in mice. X-ray crystal structures of VDR complexed with LCA and its derivatives and a coactivator peptide provide insight into the structure–function relationships of LCA derivatives and VDR. LCA derivatives have the potential to function as selective VDR modulators and should be useful in the further development of noncalcemic VDR ligands.