Retinol and retinyl esters: biochemistry and physiology

Abstract

By definition, a vitamin is a substance that must be obtained regularly from the diet. Vitamin A must be acquired from the diet, but unlike most vitamins, it can also be stored within the body in relatively high levels. For humans living in developed nations or animals living in present-day vivariums, stored vitamin A concentrations can become relatively high, reaching levels that can protect against the adverse effects of insufficient vitamin A dietary intake for six months, or even much longer. The ability to accumulate vitamin A stores lessens the need for routinely consuming vitamin A in the diet, and this provides a selective advantage to the organism. The molecular processes that underlie this selective advantage include efficient mechanisms to acquire vitamin A from the diet, efficient and overlapping mechanisms for the transport of vitamin A in the circulation, a specific mechanism allowing for vitamin A storage, and a mechanism for mobilizing vitamin A from these stores in response to tissue needs. These processes are considered in this review.

Keywords: DGAT1; RBP4; Stra6; adipocyte; anhydro-retinoids; enterocyte; hepatic stellate cell; hepatocyte; lipid droplets; retinoic acid; retro-retinoids; vitamin A.

Fig. 1.

Chemical structures of different retinoid chemical species. The chemical structure of the major proretinoid carotenoid, β-carotene, is shown at the top. The chemical structures for all-trans-retinol (which by definition is vitamin A), an all-trans-retinyl ester, 11-cis-retinal (the active retinoid in vision), and the all-trans-, 9-cis-, and 13-cis-isomers of retinoic acid are shown.

Fig. 2.

The metabolism of β-carotene and retinoids. All retinoid is originally derived from proretinoid carotenoids such as β-carotene (1). Retinal (2) can be formed by the central cleavage of β-carotene by the enzyme BCMO1. Retinol (3) is formed by the reversible reduction of retinal (2) by one of the retinal reductase family members. The enzyme LRAT synthesizes retinyl esters (4) by transferring a fatty acyl moiety from the sn-1 position of membrane phosphatidyl choline to retinol. Unesterified retinol is liberated from retinyl ester stores through the action of a REH. Retinol is oxidized to retinal by one of several RDHs, which is then irreversibly oxidized (by one of three RALDHs) to form transcriptionally active retinoic acid (5). Retinoic acid is oxidized/catabolized to more water-soluble hydroxy- and oxo- forms by one of several cytochrome P450 enzyme family members.

Fig. 3.

The delivery of retinoids and carotenoids through the circulation to cells. Retinoids and proretinoid carotenoids are delivered to cells and tissues through a number of alternative delivery pathways. In the fasting circulation, retinol delivered via RBP4 (1) accounts for most delivery to cells/tissues. However, in the postprandial state, retinyl esters present in chylomicrons and their remnants (2) can contribute substantially to the retinoid taken up by cells. Similarly, proretinoid carotenoids, such as β-carotene, are present in the postprandial circulation (4) and this can be taken up by cells/tissues and converted to retinoid. Retinyl esters and carotenoids (3) are also present in VLDL, LDL, and HDL in the fasting circulation. Retinoic acid is present in both the fasting and postprandial circulation (7), albeit at relatively low levels compared with retinol and retinyl esters. The water-soluble retinyl- (5) and retinoyl-β-glucuronides (6) are also present at relatively low levels in the circulation.

Fig. 4.

The genetic ablation of Lrat results in the total absence of lipid droplets in HSCs. Electron micrographs of liver sections obtained from age-, gender-, and genetic background matched wild-type (left panel) and Lrat-deficient (right panel) mice maintained throughout life on a retinoid-sufficient chow diet. The large lipid droplets, indicated by the arrow in the left panel, are a characteristic morphological feature of HSCs, which are clearly present in the wild-type liver, whereas but totally absent in liver from Lrat-deficient mice. H, hepatocyte.