357 Deciphering biosynthesis of all-trans-retinoic acid from retinaldehyde and the regulation of retinoid homeostasis in skin

All-trans-retinoic acid (atRA), the biologically active metabolite of vitamin A, regulates numerous physiological processes in the skin and controls proliferation and differentiation of keratinocytes. The concentration of atRA in skin is tightly regulated and involves multiple enzymes responsible for its degradation and biosynthesis. One of the key intermediates in the biosynthesis of atRA is all-trans-retinaldehyde (RAL). RAL can be irreversibly oxidized to atRA by aldehyde dehydrogenases or reversibly reduced to retinol by retinaldehyde reductases. Retinol can then be converted to retinyl esters that become stored in cells. Hence, the control of retinaldehyde levels is essential in the regulation of atRA concentration and, therefore, of its availability to modulate retinoid-signaling pathways. The clearance of atRA is predominantly mediated by hydroxylations catalyzed by cytochrome P450 family 26 enzymes (CYP26). In this study, we have compared the effects of RAL and atRA on the expression of the enzymes involved in atRA metabolism and biosynthesis, as well as on differentiation markers in keratinocyte cultures and in reconstructed human epidermis (RHE). Expression of differentiation markers and CYP26s were similarly modulated by atRA and RAL via endogenous atRA synthesis, whereas expression of the enzymes possibly involved in the biosynthesis of atRA from RAL such as the retinaldehyde reductase AKR1B10 or aldehyde dehydrogenases were differentially modulated by RAL and atRA. These preliminary results may lead to a novel therapeutic strategy for controlling the endogenous concentration of atRA, and provide insights into the mechanisms underlying atRA homeostasis in the skin.