Peroxisome proliferator-activated receptor (PPAR)-beta/delta stimulates differentiation and lipid accumulation in keratinocytes

J Invest Dermatol. 2004 Apr;122(4):971-83. doi: 10.1111/j.0022-202X.2004.22412.x.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Topical
  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cytokines / pharmacology
  • Dermatitis / prevention & control
  • Epidermal Cells
  • Epidermis / metabolism
  • Gene Expression Regulation
  • Humans
  • Keratinocytes / cytology*
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism*
  • Keratinocytes / radiation effects
  • Lipid Metabolism*
  • Male
  • Mice
  • Mice, Hairless
  • Permeability
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Thiazoles / administration & dosage
  • Thiazoles / pharmacology
  • Transcription Factors / agonists
  • Transcription Factors / physiology*
  • Ultraviolet Rays


  • Cytokines
  • GW 501516
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Transcription Factors