Abstract
After permeability barrier perturbation there is an increase in the mRNA levels for key enzymes necessary for lipid synthesis in the epidermis. The mechanism(s) responsible for this regulation is unknown. Sterol regulatory element binding proteins-1a, 1c, and -2 (SREBPs) control the transcription of enzymes required for cholesterol and fatty acid synthesis in response to modulations of sterol levels. We now demonstrate that SREBP-2 is the predominant SREBP in human keratinocytes and murine epidermis, while SREBP-1 is not detected. Sterols regulate SREBP-2 mRNA levels in keratinocytes and the epidermis and the proteolytic cleavage of SREBP-2 to the mature active form in keratinocytes. In parallel to the increase in mature active SREBP, there is a coordinate increase in mRNA levels for cholesterol (HMG-CoA reductase, HMG-CoA synthase, farnesyl diphosphate synthase, and squalene synthase) and fatty acid (acetyl-CoA carboxylase, fatty acid synthase) synthetic enzymes. However, mRNA levels for serine palmitoyl transferase (SPT), the first committed step for ceramide synthesis, do not increase in parallel. The increase of mRNA for enzymes required for epidermal cholesterol and fatty acid synthesis is consistent with both the previously described early increase of cholesterol and fatty acid synthesis after barrier disruption and a role for SREBP-2 in the regulation of cholesterol and fatty acid synthesis for epidermal barrier homeostasis. In contrast, SPT appears to be regulated by different mechanisms, consistent with the different time course of its stimulation after barrier disruption.—Harris, I. R., A. M. Farrell, W. M. Holleran, S. Jackson, C. Grunfeld, P. M. Elias, and K. R. Feingold. Parallel regulation of sterol regulatory element binding protein-2 and the enzymes of cholesterol and fatty acid synthesis but not ceramide synthesis in cultured human keratinocytes and murine epidermis.
Highlights
After permeability barrier perturbation there is an increase in the mRNA levels for key enzymes necessary for lipid synthesis in the epidermis
Recent studies have demonstrated that mRNA levels for HMG-CoA reductase, HMG-CoA synthase, farnesyl diphosphate synthase (FPPS), squalene synthase, acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and serine palmitoyl transferase (SPT) all increase after barrier disruption [9, 10]
As permeability barrier requirements regulate the mRNA levels for many enzymes required for lipid synthesis [9, 10], and transepidermal water loss increases with repeated fluindostatin treatment [24, 25], mice were studied prior to development of a barrier abnormality
Summary
After permeability barrier perturbation there is an increase in the mRNA levels for key enzymes necessary for lipid synthesis in the epidermis. Parallel regulation of sterol regulatory element binding protein-2 and the enzymes of cholesterol and fatty acid synthesis but not ceramide synthesis in cultured human keratinocytes and murine epidermis. Within 1–2 h after barrier abrogation, in parallel with increased activities of HMG-CoA reductase, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), key enzymes of cholesterol and fatty acid synthesis, respectively [4,5,6,7]. With the exception of FPPS, the increase in mRNA levels for these enzymes is prevented by immediate occlusion with a Latex wrap which provides an artificial permeability barrier [10]. These data indicate that the increase in mRNA levels for these enzymes is regulated by barrier function rather than representing an injury response
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