Biochemical pathways of retinoid transport, metabolism, and signal transduction

Retinoids control the processes of differentiation, proliferation, and apoptosis from the conception of vertebrates through their deaths. It may seem improbable that a few small, simple lipids could contain and communicate such extensive and disparate information as the retinoids, but the permutations possible make this notion plausible. Retinoid actions result from coordinated interplay among more than one hormone and multiple binding proteins, biosynthetic and catabolic enzymes, receptors (acting alone or in combination not only with retinoid but also with other lipophilic hormone receptors), and receptor-response elements. This symphony is conducted in all vertebrates in deliberate spatially and temporally specific patterns. This article reviews the absorption and formation of retinol, the parent and major circulating naturally occurring retinoid; the role of retinol as substrate for biosynthesis of two hormones, i.e., all-trans-retinoic acid (atRA) and 9-cis-retinoic acid (9cRA); the integrated operations of retinoid metabolism and the intracellular retinoid-binding proteins, cellular retinol-binding protein (CRBP), and cellular RA-binding protein (CRABP), which protect (retinoids), serve (as substrate), and control (metabolic reactions); and the mechanism of RA and 9cRA action as activators of the transcription factors RA-receptor (RAR) and the retinoid X receptor (RXR). The discussion offers a mechanistic rationale for the pleiotropic actions of retinoids.