The regulation of epidermal lipid synthesis by permeability barrier requirements

A major function of the skin is to prevent the loss of fluids. The barrier to fluid loss resides in the intercellular lipids (primarily sterols, fatty acids, and sphingolipids) of the stratum corneum. The epidermis is a very active site of lipid synthesis and when the permeability barrier is disrupted by topical solvents or detergents a marked stimulation of sterol, fatty acid, and sphingolipid synthesis occurs. Essential fatty acid deficient mice, with a chronic disturbance in barrier function, also have an increase in epidermal lipid synthesis. When the defect in barrier function is artificially corrected by occlusion with a water vapor impermeable membrane the increase in epidermal lipid synthesis is prevented, suggesting that water flux may be a regulatory factor. The activity of the key rate limiting enzyme in cholesterol synthesis, HMG CoA reductase is increased following barrier disruption due to both an increased quantity of enzyme and an increase in activation state. Similarly, the activity of serine palmitoyl transferase, the rate limiting enzyme in sphingolipid synthesis is also increased following barrier disruption. Occlusion prevents the increase in HMG CoA reductase and serine palmitoyl transferase activity. When the increase in epidermal lipid synthesis is inhibited by occlusion the characteristic rapid return of stratum corneum lipids and recovery of barrier function is prevented. Moreover, when epidermal cholesterol synthesis is inhibited by lovastatin, an inhibitor of HMG CoA reductase, the rate of recovery of barrier structure and function is delayed. Similarly, B chloroalanine, an inhibitor of serine palmitoyl transferase and sphingolipid synthesis, also impairs barrier recovery. Thus, disruption of the barrier stimulates epidermal lipid synthesis which provides the lipids necessary for the repair of the barrier. The signals that initiate and coordinate this response are yet to be defined, but the understanding of this process may allow for pharmacological interventions that will specifically disrupt the barrier and allow for the transcutaneous delivery of drugs.