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. 2024 Sep 25;25(19):10303. doi: 10.3390/ijms251910303

Figure 2.

Figure 2

Metabolism and mode of action of retinoids. In the intestine, retinyl esters (RE) undergo hydrolysis to retinol (ROL) and fatty acids before they can be absorbed by the enterocytes. Retinol in the enterocytes can be oxidized to all-trans-retinoic acid (RA) but predominantly binds to cellular retinol-binding protein-2 (CRBP2) and is re-esterified mainly by lecithin–retinol acyltransferase (LRAT). The retinyl esters enter the circulation via the mesenteric lymph in the form of chylomicrons. In the intestinal epithelial cells, β-carotene is converted to retinaldehyde (RAL) by beta-carotene 15,15’-monooxygenase 1 (BCMO1). Retinaldehyde can then either be oxidized to retinoic acid (RA) or reduced to give retinol and, finally, retinyl esters. The chylomicrons containing the retinyl esters and carotenoids are secreted into the general circulation via the lymphatic system and are delivered to the liver or to the target organs and their respective cells. The hepatocytes uptake the chylomicrons containing retinyl esters and, using retinly ester hydrolases (REH), hydrolyze the esters to retinol, which is bound to CRBP1. Subsequently, retinol can be either released in the circulation bound to RBP4 and transthyretin (TTR) or transferred to hepatic stellate cells and stored in the form of retinyl esters. The target cells uptake RBP4-bound all-trans-retinol with the vitamin A receptor, stimulated by retinoic acid 6 (STRA6). Subsequently, retinol is bound to CRBP1 and undergoes oxidation in two steps: first to retinaldehyde by aldehyde dehydrogenase (ALDH) and finally to retinoic acid. After binding with cellular retinoic acid-binding protein (CRABP), RA is transferred into the nucleus and binds to retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), causing conformational changes that activate these receptors. After activation, RAR/RXR heterodimers or RXR-RXR/RAR-RAR homodimers can be formed and bind to a promoter region known as the retinoic acid response element (RARE), resulting finally in an increase or decrease in the expression of specific genes. The catabolism of retinoids begins with cytochrome P450 cyp26-catalyzed hydroxylation of ATRA.