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