The multifaceted nature of retinoid transport and metabolism

Abstract

Since their discovery over a century ago, retinoids have been the most studied of the fat-soluble vitamins. Unlike most vitamins, retinoids are stored at relatively high concentrations in the body to buffer against nutritional insufficiency. Until recently, it was thought that the sole important retinoid delivery pathway to tissues involved retinol bound to retinol-binding protein (RBP4). More recent findings, however, indicate that retinoids can be delivered to tissues through multiple overlapping delivery pathways, involving chylomicrons, very low density lipoprotein (VLDL) and low density lipoprotein (LDL), retinoic acid bound to albumin, water soluble β-glucuronides of retinol and retinoic acid, and provitamin A carotenoids. This review will focus on explaining this evolving understanding of retinoid metabolism and transport within the body.

Keywords: Vitamin A; beta-carotene; hypervitaminosis A; hypovitaminosis A; metabolic disease; retinol-binding protein (RBP4); transthyretin (TTR).

Figure 1

Generalized scheme for retinoid metabolism. Dietary retinyl esters, retinol, and provitamin A carotenoids (such as β-carotene) are taken into the body. Vitamin A (by definition all-trans-retinol) may be esterified into retinyl esters and stored. In times of dietary retinoid insufficiency, retinyl ester stores are hydrolyzed to retinol for delivery to peripheral tissues. Both all-trans-retinol and β-carotene may be converted enzymatically to all-trans-retinal. However, as noted in the text, the visual chromophore 11-cis-retinal, owing to energetic considerations, is formed via the coupled enzymatic hydrolysis of all-trans-retinyl ester with the isomerization of the all-trans-retinoid to the 11-cis-isomer (19). Retinal either can be enzymatically oxidized to retinoic acid, which regulates transcription of over 500 retinoid-responsive genes, or reduced enzymatically to retinol. When retinoic acid is no longer needed, it is catabolized and eliminated from the body.

Figure 2

Retinoid transport in the form of retinyl esters. Dietary retinoid, in the form of retinol, retinyl esters, and provitamin A carotenoids, are absorbed in the small intestine, where they are packaged into chylomicrons and secreted into the lymphatic system. Retinyl esters in chylomicrons undergo lipolysis and remodeling while traversing the circulation. From there, retinyl esters may take one of two paths—(I) they may either be hydrolyzed into retinol (via the actions of LPL), which may be taken up by peripheral tissues (in rodents, 25-33% of chylomicron retinyl ester is delivered directly to peripheral tissues); or (II) they may be transported to the liver (in rodents, 66-75% of chylomicron retinyl ester is transported to the liver). Retinyl esters are stored in the liver. The liver can secrete some retinyl ester bound to VLDL into circulation. Upon metabolism of VLDL, some retinyl esters may be found in LDL or transferred to high density lipoprotein (HDL). Retinyl esters bound to these lipoprotein particles may also be taken up into peripheral tissues.

Figure 3

Overview of the classical understanding of retinoid delivery. Until recently, it was widely accepted that the primary mechanism of retinoid transport involved retinol circulating bound to RBP4. While other pathways had also been known at the time, such as retinoid transport as retinyl ester in chylomicrons and as provitamin A carotenoids, retinol-RBP4 was regarded as the sole important delivery pathway to tissues. As noted in the text, two recent experimental studies show that for mice totally lacking Stra6 no significant differences were detected for retinol or retinyl ester levels in adipose tissue, brain, heart, kidney, liver, lungs, muscle, pancreas, spleen, testis, or thymus, only those present in the eye (45,46). Another study concluded that STRA6 is not the only pathway for retinol uptake into the eye (47). Collectively, this raises a question as to how physiologically important STRA6 may be for mediating tissue uptake and accumulation of retinoid, especially outside of the eye (46). Consequently, we have not drawn in STRA6 into this overview, although earlier publications have argued in favor of STRA6 inclusion (48-50).

Figure 4

Overview of the modern understanding of retinoid delivery. Retinoids and provitamin A carotenoids are delivered to cells and tissues through a number of pathways, as depicted in this figure. Retinyl esters are delivered to cells and tissues either (1) packaged in chylomicrons/chylomicron remnants (after dietary retinoid intake) or (2) bound to VLDL, LDL, or HDL (in the fasting circulation). Retinol bound to RBP4 in the retinol-RBP4-TTR complex is taken in by cells (3), possibly via the actions of STRA6. Retinol may also be delivered to cells in the form of its water-soluble retinyl-β-glucuronide (4), although these are present at very low concentrations in the circulation. Retinoic acid is present at lower concentrations (as compared with retinol and retinyl esters) in both fasting and postprandial circulation, and may be delivered to cells bound to albumin (7) or transported as its water-soluble retinoyl-β-glucuronide. Provitamin A carotenoids, such as β-carotene, are present in the postprandial circulation at low concentrations in chylomicrons or hepatic lipoproteins (5). Once inside the cell, retinol may be esterified to retinyl esters, a storage form of vitamin A, or oxidized to retinal. Provitamin A carotenoids may be converted to retinal. Retinal serves as an intermediate in the oxidation of retinol to retinoic acid. Retinoic acid is transported to the nucleus of the cell, where it activates transcription of retinoid-responsive genes. As noted in the text, two recent experimental studies show that for mice totally lacking Stra6 no significant differences were detected for retinol or retinyl ester levels in adipose tissue, brain, heart, kidney, liver, lungs, muscle, pancreas, spleen, testis, or thymus, only those present in the eye (45,46). Another study concluded that STRA6 is not the only pathway for retinol uptake into the eye (47). Collectively, this raises a question as to how physiologically important STRA6 may be for mediating tissue uptake and accumulation of retinoid, especially outside of the eye (46). Based on these new findings, we have not drawn STRA6 into this overview, although earlier publications have argued in favor of STRA6 inclusion (48-50).