254 AKR1B10 inhibition in keratinocytes as a strategy to improve retinaldehyde efficacy and increase endogenous atRA

Abstract

Retinoic acid (RA) is a potent regulator of numerous physiological processes in the skin and controls keratinocyte proliferation and differentiation. The RA biosynthesis pathway is tightly regulated by enzymes that increase intracellular RA through oxidation of retinaldehyde to RA and decrease intracellular RA through reduction of retinaldehyde (RAL) to retinol (ROL), respectively. Aldo-keto reductase enzymes (AKRs), specifically AKR1B10, is responsible for the reduction of RAL to ROL thereby acting to limit the synthesis of intracellular RA. This makes the selective inhibition of AKR1B10 a highly promising mechanism for increasing endogenous RA. We hypothesized that a select panel of natural fatty acids and synthetic compounds evaluated through molecular docking studies would reduce AKR1B10 activity and increase intracellular atRA. Using healthy adult keratinocytes, we found that AKR1B10 RNA and protein is significantly upregulated differentiated keratinocytes, and AKR1B10 inhibitors modulate keratinocyte expression of differentiation and proliferation markers. Further studies using molecular docking simulations have identified optimized orientation of AKR1B10 ligands to generate potential adduct structures with increased AKR1B10 binding affinity, and LC/MS was used to measure the concentration of retinoids in keratinocytes following AKR1B10 inhibitor exposure. Together, this in-depth understanding of structural features and bioassay validation enables specific AKR1B10 inhibitors to increase endogenous atRA.