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

We recently showed that topically applied PPAR alpha activators promote epi dermal differentiation in intact adult mouse skin. In this study we determi ned the effect of clofibrate and Wy-14,643, activators of PPAR alpha, on hy perproliferative epidermis in hairless mice, induced either by repeated bar rier abrogation (subacute model) or by essential fatty acid deficiency (chr onic model). The hyperproliferative epidermis was characterized by an incre ased number of proliferating cells expressing proliferating cell nuclear an tigen. Topical treatment with PPAR alpha activators resulted in a substanti al decrease in epidermal hyperplasia in both the subacute and chronic model s of hyperproliferation, Following topical treatment, proliferating cell nu clear antigen-expressing cells were restricted to the basal layer, similar to normal epidermis, In hyperproliferative epidermis there was decreased ex pression 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 towar ds normal levels. Finally, topically applied clofibrate also increased apop tosis, This study demonstrates that topical PPAR activators have profound e ffects on epidermal gene expression in hyperproliferative skin disorders. T reatment with PPAR alpha activators normalizes cell proliferation and promo tes epidermal differentiation, correcting the cutaneous pathology. This stu dy identifies PPAR alpha activators as potential skin therapeutic agents.