PERMEABILITY BARRIER DISRUPTION COORDINATELY REGULATES MESSENGER-RNA LEVELS FOR KEY ENZYMES OF CHOLESTEROL, FATTY-ACID, AND CERAMIDE SYNTHESIS IN THE EPIDERMIS

The extracellular lipids of the stratum corneum, which are comprised m ainly of cholesterol, fatty acids, and ceramides, are essential for ep idermal permeability barrier function. Moreover, disruption of the per meability barrier results in an increased cholesterol, fatty acid, and ceramide synthesis in the underlying epidermis, This increase in lipi d synthesis has been shown previously to be due to increased activitie s of HMG-CoA reductase, acetyl-CoA carboxylase, fatty acid synthase an d serine palmitoyl transferase, key enzymes of cholesterol, fatty acid , and ceramide synthesis, respectively, In the present study, we deter mined whether the mRNA levels for the key enzymes required for synthes is of these three classes of lipids increase coordinately during barri er recovery. By northern blotting, the steady-state mRNA levels for HM G-CoA reductase, HMG-CoA synthase, farnesyl pyrophosphate synthase, an d squalene synthase, key enzymes for cholesterol synthesis, all increa sed significantly after barrier disruption by either acetone or tape s tripping. Additionally, the steady-state mRNA levels of acetyl-CoA car boxylase and fatty acid synthase, required for fatty acid synthesis, a s well as serine palmitoyl transferase, the rate-limiting enzyme of de novo ceramide synthesis, also increased. Furthermore, artificial rest oration of the permeability barrier by occlusion after barrier disrupt ion prevented the increase in mRNA levels for all of these enzymes, ex cept farnesyl pyrophosphate synthase, indicating a specific link of th e increase in mRNA levels to barrier requirements. The parallel increa se in epidermal mRNA levels for the enzymes required for cholesterol, fatty acid, and ceramide synthesis may be due to one or more transcrip tion factors that regulate lipid requirements for permeability barrier function in keratinocytes.