title: Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects.
abstract: 1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey; and Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Christakos
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey; and Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Puneet
authors.initials: P
authors.lastname: Dhawan
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey; and Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey; and Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Verlinden
authors.affiliation: Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey; and Laboratory of Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D019587:Dietary Supplements; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008822:Mice, Transgenic; D010641:Phenotype; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D014808:Vitamin D Deficiency / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014807:Vitamin D; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol