• Potentiating the differentiation of specialized epithelial cells. Vitamin A and retinoids play an important role in the orderly differentiation of mucus-secreting columnar epithelium; when a deficiency state exists, the epithelium undergoes squamous metaplasia, differentiating into a keratinizing epithelium. Activation of retinoic acid receptors (RARs) by their ligands causes the release of corepressors and the obligatory formation of heterodimers with another retinoid receptor, known as the retinoic X receptor (RXR). Both RAR and RXR have three isoforms, α, β, and γ. The RAR/RXR heterodimers bind to retinoic acid response elements located in the regulatory regions of genes that encode receptors for growth factors, tumor suppressor genes, and secreted proteins. Through these effects, retinoids regulate cell growth and differentiation, cell-cycle control, and other biologic responses. All-trans-retinoic acid, a potent acid derivative of vitamin A, has the highest affinity for RARs compared with other retinoids.
Metabolic effects of retinoids. The RXR, believed to be activated by 9-cis retinoic acid, can form heterodimers with other nuclear receptors, such as receptors involved in drug metabolism, the peroxisome proliferator-activated receptors (PPARs), and vitamin D receptors. PPARs are key regulators of fatty acid metabolism, including fatty acid oxidation in fat and muscle, adipogenesis, and lipoprotein metabolism. The association between RXR and PPARγ provides an explanation for the metabolic effects of retinoids on adipogenesis.
Enhancing immunity to infections. Vitamin A supplementation can reduce morbidity and mortality rates for some forms of diarrhea. Similarly, supplementation in preschool children with measles, particularly those who are malnourished, can reduce mortality and complications of the disease, including eye damage and blindness. The effects of vitamin A on infections probably derive in part from its ability to stimulate the immune system through unclear mechanisms. Infections may reduce the bioavailability of vitamin A, possibly by inducing the acute phase response, which appears to inhibit RBP synthesis in the liver. The drop in hepatic RBP causes a decrease in circulating retinol, which reduces the tissue availability of vitamin A. The beneficial effect of vitamin A in diarrheal diseases may be related to the maintenance and restoration of the integrity of the epithelium of the gut.
In addition, the retinoids, β-carotene, and some related carotenoids can function as photoprotective and antioxidant agents. Retinoids have broad biologic effects, including effects on embryonic development, cellular differentiation and proliferation, and lipid metabolism.
Retinoids are used clinically to treat skin disorders such as severe acne and certain forms of psoriasis, and also to treat acute promyelocytic leukemia. As discussed in Chapter 6, all-trans-retinoic acid induces the differentiation and subsequent apoptosis of acute promyelocytic leukemia cells through its ability to bind to a PML-RARα fusion protein that characterizes this form of cancer.
Deficiency States. Vitamin A deficiency occurs worldwide as a consequence of either poor nutrition or fat malabsorption. In children, stores of vitamin A are depleted by infections, and the absorption of the vitamin is poor in newborn infants. In adults, vitamin A deficiency, in conjunction with depletion of other fat-soluble vitamins, may develop in patients with malabsorption syndromes, such as celiac disease, Crohn disease, and colitis. Bariatric surgery and the continuous use of mineral oil laxatives also may lead to deficiency. The multiple effects of vitamin A deficiency are as follows: