Peroxisome proliferator-activated receptors and their ligands: entry into the post-glucocorticoid era of skin treatment?

Glucocorticoids have remained one of the most frequently used classes of drugs for the treatment of skin diseases since their introduction more than 50 years ago. As a result of the discovery of new members of the nuclear hormone receptor (NR) superfamily, alternative therapeutic interventions that target retinoid and vitamin D receptors have been developed. Peroxisome proliferator-activated receptors (PPARs) comprise another important NR subfamily, consisting of three different isotypes: PPARalpha, PPARdelta (PPARbeta) and PPARgamma. These NRs are activated by a variety of natural and synthetic ligands such as fatty acids, eicosanoids, and antidiabetic and antihyperlipidaemic agents. While these receptors are established as regulators of gene expression in lipid and glucose homeostasis, evidence is now accumulating that PPARs also play a crucial role in cutaneous biology. Results from in vitro and in vivo studies have indicated the involvement of PPARs in epidermal maturation, proliferation and differentiation, as well as in immune and inflammatory responses, carcinogenesis, hyperpigmentation and skin wound healing. Furthermore, treatment of psoriatic patients with PPARgamma activators (thiazolidinediones) has been shown to induce beneficial effects. However, the effects of PPAR ligands should be carefully evaluated to determine whether they are in fact mediated via PPAR-dependent mechanisms. Nonetheless, PPARs seem to have significant potential as therapeutic targets in skin inflammatory disorders.