RA metabolism and signaling. (A) Vitamin A and its precursors (β-carotene) obtained from diet are absorbed by intestinal epithelium cells and esterified in retinyl esters by the enzyme lecithin retinol acyltransferase (LRAT). (B) Retinyl esters are packed with chylomicrons and enter general circulation where they are captured by hepatocytes and stored as retinol. (C) The retinol binds to retinol binding protein (RBP) in the liver and is carried through the bloodstream. This complex is recognized via the stimulated by retinoic acid 6 (STRA6) receptor, which mediates the absorption of extracellular retinol to cytosol. (D) After uptake, RA is generated from retinol by two sequential reactions. First, retinol is oxidized into retinal by enzyme alcohol dehydrogenase (ADH). Subsequently, in CD103+ DCs, retinal is oxidized by the enzyme retinal dehydrogenase (RALDH) to generate RA. (E) Intestinal epithelium cells can also metabolize vitamin A after absorption into retinal and RA, which can be directly released into the intestinal mucosa. (F) RA interacts with nuclear receptors, such as the retinoic acid receptor (RAR) and retinoid receptor X (RXR), to regulate the transcription of several target genes by binding the retinoic acid-responsive elements (RAREs) in DNA. (G) Control of the RA concentration in tissues is performed by a group of enzymes that belong to the cytochrome P450 family 26 (CYP26), which catalyzes RA present in the cytosol to generate the oxidized forms.