Keratinocyte differentiation in hyperproliferative epidermis: Topical application of PPAR alpha activators restores tissue homeostasis

We recently showed that topically applied PPAR alpha activators promote epidermal differentiation in intact adult mouse skin. In this study we determined the effect of clofibrate and Wy-14,643, activators of PPAR alpha, on hyperproliferative epidermis in hairless mice, induced either by repeated barrier abrogation (subacute model) or by essential fatty acid deficiency (chronic model). The hyperproliferative epidermis was characterized by an increased number of proliferating cells expressing proliferating cell nuclear antigen. Topical treatment with PPAR alpha activators resulted in a substantial decrease in epidermal hyperplasia in both the subacute and chronic models of hyperproliferation, Following topical treatment, proliferating cell nuclear antigen-expressing cells were restricted to the basal layer, similar to normal epidermis, In hyperproliferative epidermis there was decreased expression of involucrin, profilaggrin-filaggrin, and loricrin as assayed by in situ hybridization and immunohistochemistry. Following topical treatment with PPAR activators staining for these mRNAs and proteins increased towards normal levels. Finally, topically applied clofibrate also increased apoptosis, This study demonstrates that topical PPAR activators have profound effects on epidermal gene expression in hyperproliferative skin disorders. Treatment with PPAR alpha activators normalizes cell proliferation and promotes epidermal differentiation, correcting the cutaneous pathology. This study identifies PPAR alpha activators as potential skin therapeutic agents.