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Naturally occurring eccentric cleavage products of provitamin A ?-carotene function as antagonists of retinoic acid receptors.

ABSTRACT: ?-Carotene is the major dietary source of provitamin A. Central cleavage of ?-carotene catalyzed by ?-carotene oxygenase 1 yields two molecules of retinaldehyde. Subsequent oxidation produces all-trans-retinoic acid (ATRA), which functions as a ligand for a family of nuclear transcription factors, the retinoic acid receptors (RARs). Eccentric cleavage of ?-carotene at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are ?-apocarotenals and ?-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the ?-apocarotenoids significantly activated RARs. Importantly, however, ?-apo-14'-carotenal, ?-apo-14'-carotenoic acid, and ?-apo-13-carotenone antagonized ATRA-induced transactivation of RARs. Competitive radioligand binding assays demonstrated that these putative RAR antagonists compete directly with retinoic acid for high affinity binding to purified receptors. Molecular modeling studies confirmed that ?-apo-13-carotenone can interact directly with the ligand binding site of the retinoid receptors. ?-Apo-13-carotenone and the ?-apo-14'-carotenoids inhibited ATRA-induced expression of retinoid responsive genes in Hep G2 cells. Finally, we developed an LC/MS method and found 3-5 nm ?-apo-13-carotenone was present in human plasma. These findings suggest that ?-apocarotenoids function as naturally occurring retinoid antagonists. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary ?-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer.

SUBMITTER: Eroglu A

PROVIDER: S-EPMC3346154 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Naturally occurring eccentric cleavage products of provitamin A β-carotene function as antagonists of retinoic acid receptors.

Eroglu Abdulkerim A Hruszkewycz Damian P DP dela Sena Carlo C Narayanasamy Sureshbabu S Riedl Ken M KM Kopec Rachel E RE Schwartz Steven J SJ Curley Robert W RW Harrison Earl H EH

The Journal of biological chemistry 20120314 19

β-Carotene is the major dietary source of provitamin A. Central cleavage of β-carotene catalyzed by β-carotene oxygenase 1 yields two molecules of retinaldehyde. Subsequent oxidation produces all-trans-retinoic acid (ATRA), which functions as a ligand for a family of nuclear transcription factors, the retinoic acid receptors (RARs). Eccentric cleavage of β-carotene at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are ...[more]

PMID: 22418437

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Project description:BackgroundWe investigated the roles of Toll-like receptors (TLRs) in naturally occurring influenza.MethodsA prospective, case - control study was conducted. Adults hospitalized with virologically confirmed influenza A infections (onset <48 hours, before treatment) were compared with age-/gender-matched controls. TLRs (2, 3, 4, 7, 8, 9) expression in monocytes and dendritic cells (DCs - total, myeloid, plasmacytoid) was quantitated using flow cytometry. Gene expression of RLRs (RIG-1, MDA-5) was evaluated using real-time PCR. Concomitant signaling molecules expression, plasma cytokine/chemokine concentrations, and respiratory tract viral loads were measured. PBMCs were cultured and stimulated ex vivo with TLR-specific ligands for cytokine responses.ResultsForty two patients with influenza (24 A/H3N2, 18 A/H1N1pdm09) and 20 controls were studied. Patients' mean age was 68 ± 16 years; 81% had respiratory/cardiovascular complications. There were increased cellular expressions of TLR9, TLR8, TLR3, and TLR7 during influenza; TLR2 and TLR4 were suppressed. Results were similar for both virus strains. Higher TLR expression levels at presentation significantly correlated with lower viral loads (Spearman's rho: -0.46 to -0.69 for TLR9, TLR8, and TLR3; P-values <0.05). Multivariate regression models (adjusted for age, comorbidity, disease severity, time from onset) confirmed their independent associations. Increased signaling molecules (phospho-MAPKs, I?B) and inflammatory cytokines (IL-6, sTNFR-1, CCL2/MCP-1; CXCL10/IP-10, IFN-?) correlated with increased TLR expression. RLRs were upregulated simultaneously. PBMCs of patients with influenza showed significant, dynamic changes in their cytokine responses upon TLR stimulation, compared with controls.ConclusionsOur results suggest that TLRs play an important role in early, innate viral inhibition in naturally occurring influenza. Inflammatory cytokine responses are concomitantly induced. These findings support investigation of TLR targeting as a novel intervention approach for prophylaxis against influenza.

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Naturally occurring eccentric cleavage products of provitamin A ?-carotene function as antagonists of retinoic acid receptors.

Publications

Naturally occurring eccentric cleavage products of provitamin A β-carotene function as antagonists of retinoic acid receptors.

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