Asymmetric Cleavage of β-Carotene Yields a Transcriptional Repressor of Retinoid X Receptor and Peroxisome Proliferator-Activated Receptor Responses

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β-Carotene and its metabolites exert a broad range of effects, in part by regulating transcriptional responses through specific nuclear receptor activation. Symmetric cleavage of β-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 β-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 β-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 PPARγ target gene expression and adipogenesis, even in the presence of the potent PPARγ agonist BRL49653. Apo14 also suppressed known PPARα responses, including target gene expression and its known antiinflammatory effects, but not if PPARα agonist stimulation occurred before apo14 exposure and not in PPARα-deficient cells or mice. Other apocarotenals tested had none of these effects. These data extend current views of β-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, β-carotene, may alternatively activate (9-cisRA) or inhibit (apo14) specific nuclear receptor responses.

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