β-carotene is the most abundant provitamin A carotenoid in human diet and tissues. It exerts a number of beneficial functions in mammals, including humans, owing to its ability to generate vitamin A as well as to emerging crucial signaling functions of its metabolites. Even though β-carotene is generally considered a safer form of vitamin A due to its highly regulated intestinal absorption, detrimental effects have also been ascribed to its intake, at least under specific circumstances. A better understanding of the metabolism of β-carotene is still needed to unequivocally discriminate the conditions under which it may exert beneficial or detrimental effects on human health and thus to enable the formulation of dietary recommendations adequate for different groups of individuals and populations worldwide. Here we provide a general overview of the metabolism of this vitamin A precursor in mammals with the aim of identifying the gaps in knowledge that call for immediate attention. We highlight the main questions that remain to be answered in regards to the cleavage, uptake, extracellular and intracellular transport of β-carotene as well as the interactions between the metabolism of β-carotene and that of other macronutrients such as lipids.

Apocarotenoids are cleavage products of C40 isoprenoid pigments, named carotenoids, synthesized exclusively by plants and microorganisms. The colors of flowers and fruits and the photosynthetic process are examples of the biological properties conferred by carotenoids to these organisms. Mammals do not synthesize carotenoids but obtain them from foods of plant origin. Apocarotenoids are generated upon enzymatic and nonenzymatic cleavage of the parent compounds both in plants and in the tissues of mammals that have ingested carotenoid-containing foods. The best-characterized apocarotenoids are retinoids (vitamin A and its derivatives), generated upon central oxidative cleavage of provitamin A carotenoids, mainly β-carotene. In addition to the well-known biological actions of vitamin A, it is becoming apparent that nonretinoid apocarotenoids also have the potential to regulate a broad spectrum of critical cellular functions, thus influencing mammalian health. This review discusses the current knowledge about the generation and biological activities of nonretinoid apocarotenoids in mammals.

The developing mammalian embryo is entirely dependent on the maternal circulation for its supply of retinoids (vitamin A and its metabolites). The mechanisms through which mammalian developing tissues maintain adequate retinoid levels in the face of suboptimal or excessive maternal dietary vitamin A intake have not been established. We investigated the role of retinyl ester formation catalyzed by lecithin:retinol acyltransferase (LRAT) in regulating retinoid homeostasis during embryogenesis. Dams lacking both LRAT and retinol-binding protein (RBP), the sole specific carrier for retinol in serum, were maintained on diets containing different amounts of vitamin A during pregnancy. We hypothesized that the lack of both proteins would make the embryo more vulnerable to changes in maternal dietary vitamin A intake. Our data demonstrate that maternal dietary vitamin A deprivation during pregnancy generates a severe retinoid-deficient phenotype of the embryo due to the severe retinoid-deficient status of the double mutant dams rather than to the lack of LRAT in the developing tissues. Moreover, in the case of excessive maternal dietary vitamin A intake, LRAT acts together with Cyp26A1, one of the enzymes that catalyze the degradation of retinoic acid, and possibly with STRA6, the recently identified cell surface receptor for retinol-RBP, in maintaining adequate levels of retinoids in embryonic and extraembryonic tissues. In contrast, the pathway of retinoic acid synthesis does not contribute significantly to regulating retinoid homeostasis during mammalian development except under conditions of severe maternal retinoid deficiency.

The mammalian embryo relies on maternal circulating retinoids (vitamin A derivatives) for development. β‐Carotene is the major human dietary provitamin A. β‐Carotene‐15,15′‐oxygenase (CMOI) has been proposed as the main enzyme generating retinoid from β‐carotene in vivo. CMOI is expressed in embryonic tissues, suggesting that β‐carotene provides retinoids locally during development. We performed loss of CMOI function studies in mice lacking retinol‐binding protein (RBP), an established model of embryonic vitamin A deficiency (VAD). We show that, unexpectedly, lack of CMOI in the developing tissues further exacerbates the severity of VAD and thus the embryonic malformations of RBP ^−/− mice. Since β ‐carotene was not present in any of the mouse diets, we unveiled a novel action of CMOI independent from its β ‐carotene cleavage activity. We also show for the first time that CMOI exerts an additional function on retinoid metabolism by influencing retinyl ester formation via modulation of lecithin:retinol acyltransferase (LRAT) activity, at least in developing tissues. Finally, we demonstrate unequivocally that β‐carotene can serve as an alternative vitamin A source for the in situ synthesis of retinoids in developing tissues by the action of CMOI.—Kim, Y.‐K., Wassef, L., Chung, S., Jiang, H., Wyss, A., Blaner, W. S., Quadro, L. β‐Carotene and its cleavage enzyme β‐carotene‐15,15′‐oxygenase (CMOI) affect retinoid metabolism in developing tissues. FASEB J. 25, 1641–1652 (2011). www.fasebj.org