Peroxisome proliferator-activated receptor (PPAR)-β/δ 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-α activation stimulates keratinocyte differentiation in vitro and in vivo, is anti-inflammatory, and improves barrier homeostasis. Recent studies have shown that PPAR-β/δ activation induces keratinocyte differentiation in vitro. This study demonstrated that topical treatment of mice with a selective PPAR-β/δ agonist (GW501516) in vivo had pro-differentiating effects, was anti- inflammatory, improved barrier homeostasis, and stimulated differentiation in a disease model of epidermal hyperproliferation. In contrast to PPAR-α activation, PPAR-β/δ in vivo did not display anti-proliferative or proapoptotic effects. The pro-differentiating effects persisted in mice lacking PPAR-α, but were decreased in mice deficient in retinoid X receptor-α, the major heterodimerization partner of PPAR. Furthermore, in vitro PPAR-β/δ 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-β/δ and PPAR-α activation revealed distinct profiles. Together, these studies indicate that PPAR-β/δ activation stimulates keratinocyte differentiation, is anti-inflammatory, improves barrier homeostasis, and stimulates TG accumulation in keratinocytes.