AUTOREGULATION OF RETINOIC ACID BIOSYNTHESIS THROUGH REGULATION OF RETINOL ESTERIFICATION IN HUMAN KERATINOCYTES

In this report, we describe an auto-reguIatory loop in human keratinoc ytes, whereby all-trans retinoic acid (retinoic acid) regulates its ow n biosynthesis from all-trans retinol (retinol) through regulation of retinol esterification. Retinol esterification activity was low in nor mal proliferating human keratinocytes, cultured in retinoid-free media . Treatment of keratinocytes with retinoic acid induced retinol esteri fying activity (8-fold). Induction of retinol esterifying activity was blocked by either actinomycin D or cycloheximide. Based an substrate specificity and inhibitor sensitivity, lecithin:retinol acyltransferas e (LRAT) was identified as the retinoic acid-inducible retinol esterif ying enzyme, Induction of LRAT by retinoic acid reduced conversion of retinol to retinoic acid by 50%. This reduction in retinoic acid synth esis resulted from sequestration of retinol as retinyl esters, since i nhibition of LRAT restored retinoic acid synthesis to control levels. In normal human skin, undifferentiated keratinocytes, in the lowest ce ll layer, esterified retinol 4 times greater, than differentiating ker atinocytes, in upper cell layers, reflecting an induced state, under c onditions of retinol sufficiency, Regulation of LRAT activity by retin oic acid provides a novel mechanism through which retinoic acid can re gulate its own level by controlling availability of retinol for conver sion to retinoic acid. In human skin in vivo, retinyl esters synthesiz ed in basal keratinocytes could undergo hydrolysis during differentiat ion and thus serve as a source of retinol for keratinocytes in upper l ayers of skin.