Stimulation of PPARα promotes epidermal keratinocyte differentiation In vivo

Abstract

Our recent studies have demonstrated that PPARα activators stimulate differentiation and inhibit proliferation in cultured human keratinocytes and accelerate epidermal development and permeability barrier formation in fetal rat skin explants. As the role of PPARα activation in adult epidermis is not known, the aim of this study was to determine if topically applied PPARα ligands regulate keratinocyte differentiation in murine epidermis. Topical treatment with PPARα activators resulted in decreased epidermal thickness. Expression of structural proteins of the upper spinous/granular layers (involucrin, profilaggrin-filaggrin, loricrin) increased following topical treatment with PPARα activators. Furthermore, topically applied PPARα activators also increased apoptosis, decreased cell proliferation, and accelerated recovery of barrier function following acute barrier abrogation. Experiments with PPARα(-/-) knockout mice showed that these effects are specifically mediated via PPARα. Compared with the epidermis of PPARα(+/+) mice, involucrin, profilaggrin-filaggrin, and loricrin expression were slightly decreased in PPARα(-/-) mice. Moreover, topical clofibrate treatment did not increase epidermal differentiation in PPARα(-/-) mice. Furthermore, in cultured human keratinocytes we have demonstrated that PPARα activators induce an increase in involucrin mRNA levels. We have also shown that this increase in gene expression requires an intact AP-1 response element at -2117 to -2111bp. Thus, stimulation of PPARα stimulates keratinocyte/epidermal differentiation and inhibits proliferation.