Stimulation of PPAR alpha promotes epidermal keratinocyte differentiation in vivo

Our recent studies have demonstrated that PPAR alpha activators stimulate d ifferentiation and inhibit proliferation in cultured human keratinocytes an d accelerate epidermal development and permeability barrier formation in fe tal rat skin explants. As the role of PPAR alpha activation in adult epider mis is not known, the aim of this study was to determine if topically appli ed PPAR alpha ligands regulate keratinocyte differentiation in murine epide rmis. Topical treatment with PPAR alpha activators resulted in decreased ep idermal thickness. Expression of structural proteins of the upper spinous/g ranular layers (involucrin, profilaggrin-filaggrin, loricrin) increased fol lowing topical treatment with PPAR alpha activators. Furthermore, topically applied PPAR alpha activators also increased apoptosis, decreased cell pro liferation, and accelerated recovery of barrier function following acute ba rrier abrogation. Experiments with PPAR alpha(-/-) knockout mice showed tha t these effects are specifically mediated via PPAR alpha. Compared with the epidermis of PPAR alpha(+/+) mice, involucrin, profilaggrin-filaggrin, and loricrin expression were slightly decreased in PPAR alpha-/- mice. Moreove r, topical clofibrate treatment did not increase epidermal differentiation in PPAR alpha-/- mice. Furthermore, in cultured human keratinocytes we have demonstrated that PPAR alpha activators induce an increase in involucrin m RNA levels. We have also shown that this increase in gene expression requir es an intact AP-1 response element at -2117 to -2111 bp. Thus, stimulation of PPAR alpha stimulates keratinocyte/epidermal differentiation and inhibit s proliferation.