Cellular metabolism and activation of retinoids: roles of cellular retinoid-binding proteins

Vitamin A and related molecules--the retinoids--play essential roles in vision, growth, reproduction, and cellular differentiation beginning in early development. Retinoic acid, a key regulatory retinoid formed intracellularly through the oxidation of retinol, functions as ligand for a family of nuclear retinoic acid receptors that regulate transcription from target genes. Metabolic events are critical to maintaining physiological concentrations of retinoic acid. In the cytoplasm, retinol, retinaldehyde, and retinoic acid are associated with retinoid-binding proteins, most of which are approximately 15-kDa proteins belonging to the fatty acid-binding protein/cellular retinol-binding protein family. The ligand binding properties and molecular features of these proteins have been well characterized. Recent experiments have highlighted the importance of the cellular retinoid-binding proteins in controlling the concentration of free retinoids and in directing protein-bound retinoids to key enzymes responsible for their metabolism. For example, the cellular retinol-binding protein, CRBP, has been implicated in retinol uptake, retinol esterification, mobilization of retinyl esters, and the initial oxidation of retinol to retinaldehyde. The ligands bound to other retinoid-binding proteins have also been shown to be available for enzymatic transformation. The new knowledge of the various ways these cytoplasmic proteins buffer the concentration of ligand, control their distribution, and determine their metabolism by specific enzymes is contributing to an improved understanding of the physiological control of retinoid action.