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APOCAROTENOIDS MODULATE RETINOID RECEPTORS

Eroglu, Abdulkerim
http://rave.ohiolink.edu/etdc/view?acc_num=osu1338314466

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Biochemistry.
β-carotene (BC) is the major dietary source of provitamin A. Central cleavage of BC 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 BC at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are β-apocarotenals and β-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the β-apocarotenoids significantly activated RARs and RXRα. β-Apo-13-carotenone was found to antagonize the activation of RXRα by 9-cis-retinoic acid and was effective at concentrations as low as 1 nM. Molecular modeling studies revealed that β-apo-13-carotenone makes molecular interactions like an antagonist of RXRα. The results suggest a possible function of BACs on RXRα signaling. Moreover, β-apo-14’-carotenal, β-apo-14’-carotenoic acid, and β-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 β-apo-13-carotenone can directly interact with the ligand binding site of the retinoid receptors. β-Apo-13-carotenone and the β-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 β-apo-13-carotenone was present in human plasma. These findings suggest that β-apocarotenoids function as naturally-occurring retinoid antagonists. We have also tested apo-lycopenoids that have a structural resemblance to β-apo-13-carotenone to see if they exert a similar action as β-apo-13-carotenone in modulating retinoid receptor activation. We found that apo-13-lycopenone was able to block ATRA induced expression of RARβ and CYP26A1 like the action of β-apo-13-carotenone. This suggests that the ionone ring may not be prerequisite for β-apo-13-carotenone’s binding to RARs. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary β-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer.
Earl H. HARRISON, PhD (Advisor)
Robert W. CURLEY, PhD (Committee Member)
Ouliana ZIOUZENKOVA, PhD (Committee Member)
Jeanette W. MARKETON, PhD (Committee Member)
129 p.
Biochemistry
Beta-apocarotenoids; Retinoic acid; Vitamin A; Beta-apo-13-carotenone; Retinoic Acid Receptors (RARs); Retinoid X Receptor alpha (RXR&945; ); Retinoid Signaling; Beta-apo-14&8217; -carotenal; Beta-apo-14&8217; -carotenoic acid; Apo-lycopenoids; Apo-13-lyc

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Citations

  • Eroglu, A. (2012). APOCAROTENOIDS MODULATE RETINOID RECEPTORS [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338314466

    APA Style (7th edition)

  • Eroglu, Abdulkerim. APOCAROTENOIDS MODULATE RETINOID RECEPTORS. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1338314466.

    MLA Style (8th edition)

  • Eroglu, Abdulkerim. "APOCAROTENOIDS MODULATE RETINOID RECEPTORS." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338314466

    Chicago Manual of Style (17th edition)

osu1338314466
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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.