Peroxisome proliferator-activated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes.
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.
Schmuth
Matthias
M
Department of Medicine, University of California, San Francisco, California, USA.
Haqq
Christopher M
CM
Cairns
William J
WJ
Holder
Julie C
JC
Dorsam
Sheri
S
Chang
Sandra
S
Lau
Peggy
P
Fowler
Ashley J
AJ
Chuang
Gary
G
Moser
Arthur H
AH
Brown
Barbara E
BE
Mao-Qiang
Man
M
Uchida
Yoshikazu
Y
Schoonjans
Kristina
K
Auwerx
Johan
J
Chambon
P
P
Willson
Timothy M
TM
Elias
Peter M
PM
Feingold
Kenneth R
KR
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
D016207:Cytokines; C425931:GW 501516; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors