Provitamin A metabolism and functions in mammalian biology

Abstract

Vitamin A deficiency is a major public health problem in developing countries. Some studies also implicate a suboptimal vitamin A intake in certain parts of the population of the industrialized world. Provitamin A carotenoids such as β-carotene are the major source for retinoids (vitamin A and its derivatives) in the human diet. However, it is still controversial how much β-carotene intake is required and safe. An important contributor to this uncertainty is the lack of knowledge about the biochemical and molecular basis of β-carotene metabolism. Recently, key players of provitamin A metabolism have been molecularly identified and biochemically characterized. Studies in knockout mouse models showed that intestinal β-carotene absorption and conversion to retinoids is under negative feedback regulation that adapts this process to the actual requirement of vitamin A of the body. These studies also showed that in peripheral tissues a conversion of β-carotene occurs and affects retinoid-dependent physiologic processes. Moreover, these analyses provided a possible explanation for the adverse health effects of carotenoids by showing that a pathologic accumulation of these compounds can induce oxidative stress in mitochondria and cell signaling pathways related to disease. Genetic polymorphisms in identified genes exist in humans and also alter carotenoid homeostasis. Here, the advanced knowledge of β-carotene metabolism is reviewed, which provides a molecular framework for understanding the role of this important micronutrient in health and disease.

FIGURE 1.

Transformations of carotenoids and apocarotenoids catalyzed by different metazoan carotenoid-oxygenases and all-trans-to-11-cis isomerases. A: Insect NinaB catalyzes a combined carotenoid cleavage and isomerase reaction. B, C: In mammals, carotenoid cleavage reaction and isomerase reaction are separated to 2 distinct proteins referred to as RPE65 and BCMO1. D: In mammals, a third family member is localized to mitochondria and catalyzes carotenoid breakdown by successively removing the ionone ring sites at position 9,10 and 9′,10′ in the carbon backbone of carotenoids. BCDO2, β,β-carotene-9′,10′-dioxygenase 2; BCMO1, β,β-carotene-15,15′-monooxygenase 1; RPE65, retinal pigment epithelium-specific 65-kDa protein.

FIGURE 2.

Intestinal vitamin A production is under negative feedback regulation of RA. A: In vitamin A deficiency, SR-B1 (β-carotene absorption) and BCMO1 (β-carotene conversion) are highly expressed in the intestine. β-Carotene is efficiently taken up and converted to all-trans-retinal. The primary cleavage product then is converted to all-trans-retinol and esterified to REs that are incorporated into chylomicrons for transport. B: In vitamin A sufficiency, RA is produced that activates the expression of transcription factor ISX. In turn, ISX represses intestinal expression of SR-B1 and BCMO1, thus reducing β-carotene utilization for vitamin A production. BCMO1, β,β-carotene-15,15′-monooxygenase 1; ISX, intestine-specific homeobox; RA, all-trans-retinoic acid; RAR, retinoic acid receptor; RE, retinyl ester; RXR, retinoid X receptor; SR-B1, scavenger receptor class B type 1.

FIGURE 3.

Schematic overview of the role of BCMO1 and β-carotene in mammalian biology. BCMO1, β,β-carotene-15,15′-monooxygenase 1; PPARγ, peroxisome proliferator–activated receptor γ.

FIGURE 4.

BCDO2 is a mitochondrial protein that protects these organelles against oxidative stress. In wild-type mice (BCDO2^+/+), carotenoids are catabolized by BCDO2, thus preventing mitochondrial accumulation of these compounds. In mutant mice (BCDO2^−/−), carotenoids accumulate in mitochondria and impair respiration (complexes I to IV) and cause oxidative stress. BCDO2, β,β-carotene-9′,10′-dioxygenase 2; Cyt, cytochrome C; Q, ubiquinone; ROS, reactive oxygen species.