title: Stimulation of PPARalpha promotes epidermal keratinocyte differentiation in vivo.
abstract: Our recent studies have demonstrated that PPARalpha 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 PPARalpha activation in adult epidermis is not known, the aim of this study was to determine if topically applied PPARalpha ligands regulate keratinocyte differentiation in murine epidermis. Topical treatment with PPARalpha 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 PPARalpha activators. Furthermore, topically applied PPARalpha activators also increased apoptosis, decreased cell proliferation, and accelerated recovery of barrier function following acute barrier abrogation. Experiments with PPARalpha-/- knockout mice showed that these effects are specifically mediated via PPARalpha. Compared with the epidermis of PPARalpha+/+ mice, involucrin, profilaggrin-filaggrin, and loricrin expression were slightly decreased in PPARalpha-/- mice. Moreover, topical clofibrate treatment did not increase epidermal differentiation in PPARalpha-/- mice. Furthermore, in cultured human keratinocytes we have demonstrated that PPARalpha 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 PPARalpha stimulates keratinocyte/epidermal differentiation and inhibits proliferation.
authors.affiliation: Departments of Dermatology, Medicine, and Pediatrics, University of California, San Francisco School of Medicine, San Francisco, California, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Kömüves
authors.forename: K
authors.initials: K
authors.lastname: Hanley
authors.forename: A M
authors.initials: AM
authors.lastname: Lefebvre
authors.forename: M Q
authors.initials: MQ
authors.lastname: Man
authors.forename: D C
authors.initials: DC
authors.lastname: Ng
authors.forename: D D
authors.initials: DD
authors.lastname: Bikle
authors.forename: M L
authors.initials: ML
authors.lastname: Williams
authors.forename: P M
authors.initials: PM
authors.lastname: Elias
authors.forename: J
authors.initials: J
authors.lastname: Auwerx
authors.forename: K R
authors.initials: KR
authors.lastname: Feingold
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002994:Clofibrate / Q000494:pharmacology; D000091344:Filaggrin Proteins; D015603:Keratinocytes / Q000166:cytology*; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D010539:Permeability / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011498:Protein Precursors / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D012867:Skin / Q000166:cytology / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000235:genetics; D014157:Transcription Factors / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D011498:Protein Precursors; D018160:Receptors, Cytoplasmic and Nuclear; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C032253:involucrin; D002994:Clofibrate