title: Peroxisome proliferator-activated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes.
abstract: Peroxisome proliferator-activated receptor (PPAR) are nuclear hormone receptors that are activated by endogenous lipid metabolites. Previous studies have demonstrated that PPAR-alpha activation stimulates keratinocyte differentiation in vitro and in vivo, is anti-inflammatory, and improves barrier homeostasis. Recent studies have shown that PPAR-beta/delta activation induces keratinocyte differentiation in vitro. This study demonstrated that topical treatment of mice with a selective PPAR-beta/delta agonist (GW1514) in vivo had pro-differentiating effects, was anti-inflammatory, improved barrier homeostasis, and stimulated differentiation in a disease model of epidermal hyperproliferation [corrected]. In contrast to PPAR-alpha activation, PPAR-beta/deltain vivo did not display anti-proliferative or pro-apoptotic effects. The pro-differentiating effects persisted in mice lacking PPAR-alpha, but were decreased in mice deficient in retinoid X receptor-alpha, the major heterodimerization partner of PPAR. Furthermore, in vitro PPAR-beta/delta activation, aside from stimulating differentiation-related genes, additionally induced adipose differentiation-related protein (ADRP) and fasting induced adipose factor (FIAF) mRNA in cultures keratinocytes, which was paralleled by increased oil red O staining indicative of lipid accumulation, the bulk of which were triglycerides (TG). Comparison of differentially expressed genes between PPAR-beta/delta and PPAR-alpha activation revealed distinct profiles. Together, these studies indicate that PPAR-beta/delta activation stimulates keratinocyte differentiation, is anti-inflammatory, improves barrier homeostasis, and stimulates TG accumulation in keratinocytes.
authors.affiliation: Department of Medicine, University of California, San Francisco, California, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmuth
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Haqq
authors.forename: William J
authors.initials: WJ
authors.lastname: Cairns
authors.forename: Julie C
authors.initials: JC
authors.lastname: Holder
authors.forename: Sheri
authors.initials: S
authors.lastname: Dorsam
authors.forename: Sandra
authors.initials: S
authors.lastname: Chang
authors.forename: Peggy
authors.initials: P
authors.lastname: Lau
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Fowler
authors.forename: Gary
authors.initials: G
authors.lastname: Chuang
authors.forename: Arthur H
authors.initials: AH
authors.lastname: Moser
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Brown
authors.forename: Man
authors.initials: M
authors.lastname: Mao-Qiang
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uchida
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: P
authors.initials: P
authors.lastname: Chambon
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Willson
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Feingold
mesh_terms: D000287:Administration, Topical; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000494:pharmacology; D003872:Dermatitis / Q000517:prevention & control; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D010539:Permeability; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: D016207:Cytokines; C425931:GW 501516; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors