Peroxisome Proliferator-Activated Receptors (PPARs) and the Human Skin

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 PPARα and PPARγ is decreased. This observation suggests the possibility that PPARα and PPARγ 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 PPARγ, 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 PPARα immunoreactivity is reduced in human keratinocytes of squamous cell carcinoma (SCC) and actinic keratosis (AK), while PPARδ appears to be upregulated. Additionally, the microvessel density is significantly higher in AK and SCC that express high levels of PPARδ. PPARδ has been demonstrated to have an anti-apoptotic role and to maintain survival and differentiation of epithelial cells, whereas PPARα and PPARγ activators induce differentiation and inhibit proliferation and regulate apoptosis. In melanoma, the growth inhibitory effect of PPARγ 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. PPARα activation causes inhibition of migration of melanoma cells and anchorage-independent growth, whereas primary tumor growth remains unaltered. In clinical trials of gemfibrozil, a PPARα 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.