Stimulation of PPARα promotes epidermal keratinocyte differentiation in vivo

Our recent studies have demonstrated that PPAR alpha 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 PPAR alpha activation in adult epidermis is not known, the aim of this study was to determine if topically applied PPAR alpha ligands regulate keratinocyte differentiation in murine epidermis. Topical treatment with PPAR alpha 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 PPAR alpha activators. Furthermore, topically applied PPAR alpha activators also increased apoptosis, decreased cell proliferation, and accelerated recovery of barrier function following acute barrier abrogation. Experiments with PPAR alpha(-/-) knockout mice showed that 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. Moreover, 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 mRNA levels. We have also shown that this increase in gene expression requires an intact AP-1 response element at -2117 to -2111 bp. Thus, stimulation of PPAR alpha stimulates keratinocyte/epidermal differentiation and inhibits proliferation.