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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #209790
Title: Asymmetric Cleavage of B-Carotene Yields a Transcriptional Repressor of Retinoid X Receptor and Peroxisome Proliferator-Activated Receptor Responses

Author
item ZIOUZENKOVA, OULIANA - HARVARD UNIVERSITY
item ORASANU, GABRIELA - HARVARD UNIVERSITY
item SUKHOVA, GALINA - HARVARD UNIVERSITY
item LAU, EVAN - HARVARD UNIVERSITY
item BERGER, JOEL - MERCK RESEARCH LAB
item Tang, Guang-Wen
item KRINSKY, NORMAN - HNRCA-TUFTS
item Dolnikowski, Gregory
item PLUTZKY, JORGE - HARVARD UNIVERSITY

Submitted to: Molecular Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/15/2006
Publication Date: 9/28/2006
Citation: Ziouzenkova, O., Orasanu, G., Sukhova, G., Lau, E., Berger, J.P., Tang, G., Krinsky, N.I., Dolnikowski, G., Plutzky, J. 2006. Asymmetric Cleavage of B-Carotene Yields a Transcriptional Repressor of Retinoid X Receptor and Peroxisome Proliferator-Activated Receptor Responses.. Molecular Endocrinology. 21(1):77-88.

Interpretive Summary: This research work reported a research study on the beta-carotene cleavage products. It was found that one of the asymmetric cleavage products, called 14-apo-carotenal, showed inhibition effects on the gene expression of peroxisome proliferator-activated receptors (PPAR) that is essential for adipogenisis both in vitro and in vivo. In addition, it also showed anti-inflammatory effects in association of PPAR target gene expression and adipogenesis. Thus, beta-carotene may have anti-adipogenisis and anti-inflammatory effects through its excentric cleavage products.

Technical Abstract: B-Carotene and its metabolites exert a broad range of effects, in part by regulating transcriptional responses through specific nuclear receptor activation. Symmetric cleavage of B-carotene can yield 9-cis retinoic acid (9-cisRA), the natural ligand for the nuclear receptor RXR, the obligate heterodimeric partner for numerous nuclear receptor family members. A significant portion of B-carotene can also undergo asymmetric cleavage to yield apocarotenals, a series of poorly understood naturally occurring molecules whose biologic role, including their transcriptional effects, remains essentially unknown. We show here that B-apo-14'-carotenal (apo14), but not other structurally related apocarotenals, represses peroxisome proliferator-activated receptors (PPAR) and RXR activation and biologic responses induced by their respective agonists both in vitro and in vivo. During adipocyte differentiation, apo14 inhibited PPAR target gene expression and adipogenesis, even in the presence of the potent PPAR agonist BRL49653. Apo14 also suppressed known PPAR responses, including target gene expression and its known antiinflammatory effects, but not if PPAR agonist stimulation occurred before apo14 exposure and not in PPAR-deficient cells or mice. Other apocarotenals tested had none of these effects. These data extend current views of B-carotene metabolism to include specific apocarotenals as possible biologically active mediators and identify apo14 as a possible template for designing PPAR and RXR modulators and better understanding modulation of nuclear receptor activation. These results also suggest a novel model of molecular endocrinology in which metabolism of a parent compound, B-carotene, may alternatively activate (9-cisRA) or inhibit (apo14) specific nuclear receptor responses.