Figure 2

Ilustration of RA and paracrine RA signaling. In serum, retinol is bound to retinol-binding protein 4 (RBP-4) synthesized in the liver. Although retinol is lipid soluble, it enters cells mainly through the interaction with its receptor STRA. In the cell, retinol can either be converted into retinyl esters for storage via lecithin retinol acyltransferase (LRAT) or bind to the cellular retinol binding protein (CRBP). The CRBP-bound retinol is oxidized to retinal by either alcohol dehydrogenase (ADH) or retinol dehydrogenase (RDH), and retinal is oxidized to retinoic acid (RA) by retinaldehyde dehydrogenases (RALDH1/2/3). All-trans retinoic acid (atRA) is the major bioactive component among the retinoids. CYP26 can further oxidize atRA to 4-oxo-RA for degradation. Cellular retinoic acid-binding protein (CRABP) facilitates transportation of atRA into the nucleus where atRA binds its receptors. The ternary complex of ligand-bound RAR and RXR binds to the retinoic acid response element (RARE) and activates the RA target genes. atRA can diffuse to adjacent cells to activate target gene expression in these cells. RAR can also bind to the liver X receptor (LXR), farnesoid X receptor (FXR), and peroxisome proliferator-activated receptor (PPAR) for multiple functions.