Peroxisome proliferator-activated receptors (PPARs) and the human skin - Importance of PPARs in skin physiology and dermatologic diseases

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate lipid, glucose, and amino acid metabolism. More recently, PPARs and corresponding ligands have been shown in skin and other organs to regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. These new functions identify PPARs and corresponding ligands as potential targets for the treatment of various skin diseases and other disorders. It has been shown that in inflammatory skin disorders, including hyperproliferative psoriatic epidermis and the skin of patients with atopic dermatitis, the expression of both PPAR alpha and PPAR gamma is decreased. This observation suggests the possibility that PPAR alpha and PPAR gamma activators, or compounds that positively regulate PPAR gene expression, may represent novel NSAIDs for the topical or systemic treatment of common inflammatory skin diseases such as atopic dermatitis, psoriasis, and allergic contact dermatitis. Moreover, recent findings indicate that PPAR-signaling pathways may act as a promising therapeutic target for the treatment of hyperproliferative skin diseases including skin malignancies. Studies in non-diabetic patients suggest that oral thiazolidinediones, which are synthetic ligands of PPAR gamma, not only exert an antidiabetic effect but also may be beneficial for moderate chronic plaque psoriasis by suppressing proliferation and inducing differentiation of keratinocytes; furthermore, they may even induce cell growth arrest, apoptosis, and terminal differentiation in various human malignant tumors. It has been reported that PPAR alpha immunoreactivity is reduced in human keratinocytes of squamous cell carcinoma (SCC) and actinic keratosis (AK), while PPAR delta appears to be upregulated. Additionally, the microvessel density is significantly higher in AK and SCC that express high levels of PPAR delta. PPAR delta has been demonstrated to have an anti-apoptotic role and to maintain survival and differentiation of epithelial cells, whereas PPAR alpha and PPAR gamma activators induce differentiation and inhibit proliferation and regulate apoptosis. In melanoma, the growth inhibitory effect of PPAR gamma activation is independent of apoptosis and seems to occur primarily through induction of cell cycle arrest in the G1 phase of the cell cycle or induction of re-differentiation. PPAR alpha activation causes inhibition of migration of melanoma cells and anchorage-independent growth, whereas primary tumor growth remains unaltered. In clinical trials of gemfibrozil, a PPAR alpha ligand, significantly fewer patients treated with this lipid-lowering drug were diagnosed with melanoma as compared to those in the control group. In conclusion, an increasing body of evidence indicates that PPAR signaling pathways may represent interesting therapeutic targets for a broad variety of skin disorders, including inflammatory skin diseases such as psoriasis and atopic dermatitis, and skin malignancies.