title: Resveratrol potentiates vitamin D and nuclear receptor signaling.
abstract: The 1,25-dihydroxyvitamin D3 (1,25D) hormone is derived from vitamin D generated in skin or obtained from the diet, and binds to and activates the vitamin D receptor (VDR) in target tissues including kidney, colon/small intestine, and bone/muscle. We tested resveratrol for its ability to modulate VDR signaling, using vitamin D responsive element (VDRE) and mammalian 2-hybrid (M2H) transcriptional system technology. Via VDRE-based assays in kidney, colon and myoblast cells, VDR-mediated transcription was activated by resveratrol, and a cooperative effect on transactivation was observed with resveratrol plus 1,25D. The M2H assay revealed a modest, resveratrol-induced dimerization of VDR with its retinoid X receptor (RXR) heteropartner. Cells treated with both resveratrol and 1,25D displayed synergistic stimulation of VDR-RXR heterodimerization, while resveratrol antagonized rexinoid-mediated RXR-RXR homodimerization. Increased transactivation in response to resveratrol was also observed with a subset of other nuclear receptors and their respective cognate responsive elements. Evaluation of wild-type versus a ligand-binding domain mutant VDR revealed that hormone-responsiveness to 1,25D was severely depressed, while the response to resveratrol was only moderately attenuated. Moreover, radiolabeled 1,25D-displacement assays demonstrated an increase in VDR-bound 1,25D in the presence of resveratrol. Thus, resveratrol may affect VDR and other nuclear receptors indirectly, likely via the ability of resveratrol to: (1) potentiate 1,25D binding to VDR; (2) activate RXR; and/or (3) stimulate SIRT1, an enzyme known to deacetylate nuclear receptors. The results of this study elucidate a possible pathway for crosstalk between two nutritionally derived lipids, vitamin D and resveratrol, both of which converge on VDR signaling.
authors.affiliation: School of Mathematical and Natural Sciences, Arizona State University, Glendale, Arizona, 85306.
authors.forename: Angelika
authors.initials: A
authors.lastname: Dampf Stone
authors.forename: Shane F
authors.initials: SF
authors.lastname: Batie
authors.forename: Marya S
authors.initials: MS
authors.lastname: Sabir
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Jacobs
authors.forename: Jamie H
authors.initials: JH
authors.lastname: Lee
authors.forename: G Kerr
authors.initials: GK
authors.lastname: Whitfield
authors.forename: Mark R
authors.initials: MR
authors.lastname: Haussler
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D047488:Retinoid X Receptors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D030181:Vitamin D Response Element / Q000235:genetics / Q000502:physiology
chemical_list: D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D013267:Stilbenes; D000077185:Resveratrol
keywords: ACETYLATION; NUTRACEUTICAL; SIRT1; TRANSACTIVATION; VITAMIN D RECEPTOR