الفهرس 
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Abstract
Peroxisome proliferator-activated receptors (PPARs) have been shown to play an important role in the regulation of energy homeostasis by modulating glucose and lipid metabolism and transport. Moreover recent studies have demonstrated that PPARs regulate important cellular functions in the skin and other organs, including inflammation, immune responses, cell proliferation, cell differentiation and apoptosis. Knowing that several of the most common skin diseases (i.e., psoriasis and atopic dermatitis) are characterized by a spectrum of abnormalities, including abnormal keratinocyte differentiation, epidermal hyperplasia, inflammation and defects in permeabilitiy barrier function, PPARs and their corresponding ligands are potential targets in treating various skin diseases.
Wound healing has traditionally been divided into three distinct phases: the initial inflammatory stage of repair is followed by the proliferation and migration of keratinocytes, and a process called remodeling. After injury the expression of PPAR is upregulated in keratinocytes at the wound edge of damaged skin. While the expression of PPARα is transiently upregulated during the early inflammatory phase of healing, that of PPARβ/δ remains expressed until completion of the healing process. The release of pro-inflammatory cytokines triggers the production of PPARβ/δ ligands, leading to an increase in keratinocyte PPARβ/δ transcriptional activity in wounded epithelium. So, PPARα and PPARβ/δ appear to be key mediators of epidermal effects in wound healing by converting the extracellular inflammatory signal
into an organized pattern of gene expression, leading to survival, migration and differentiation of keratinocytes.
Knowing that psoriasis is an inflammatory skin disorder characterized by epidermal hyperproliferation and abnormal differentiation of keratinocytes, PPARs may be interesting targets for treatment. In psoriatic skin expression of both PPARα and PPARγ is decreased, whereas PPARβ/δ expression is increased. This increase of the PPARβ/δ expression is probably due to pro-inflammatory signals, a condition reminiscent of that following skin injury. Overmore the activation of PPARβ/δ in the epidermis was shown to be sufficient to trigger inflammatory changes, immune activation and gene dysregulation characteristic of psoriasis.
It was long thought that atopic dermatitis (AD) is solely attributable to immunological defects. Evidence is accumulating that primary keratinocyte abnormalities may underlie the pathogenesis of this skin disorder in many patients. Among others PPARs reduce certain inflammatory mediators in the skin and regulate epidermal barrier homeostasis, alterations of which contribute to the inflammation associated with AD.
It has been shown that PPAR ligands inhibit T helper cell (TH) responses in terms of inhibition of IL-2 production by T cell clones, while not inhibiting proliferation of such clones. Especially PPARγ play a critical role in the regulation of genes that are involved in cellular proliferation, specific components of the TH2 inflammatory pathway and maintenance of the skin barrier. This suggestion was supported by the observation that the PPARγ ligand ciglitazone inhibits allergic immune response by inhibiting
TH2-driven IgE production and also production of (pro)inflammatory cytokines of the TH response in vitro and in vivo. Recent analysis of AD skin lesions show increased PPARγ expression not only in keratinocytes, but also in infiltrating T cells and monocytes.
Because of the many similarities that exist between adipogenesis and sebaceous lipogenesis PPARs may be important in the regulation of human sebum production and the development of acne. Studies in sebocytes and human sebaceous glands indicate that PPAR agonists alter sebaceous lipid production. In addition to this, PPAR regulation can modulate the tissue inflammation in acne lesions by inhibiting the expression of proinflammatory genes. Recent evidence indicates a role for lipoxygenase products, such as leukotrienes B4 (LTB4), in the development of inflammatory acne lesions. Interestingly, LTB4 is also a natural ligand for peroxisome proliferator-activated receptor PPARα.
In addition to Non-Melanoma Skin Cancer (NMSC), evidence is accumulating that PPAR ligands also had mild antiproliferative effects in melanocytes and human melanoma cells. Whether this inhibition of cell proliferation is induced by apoptosis or through specific PPAR-dependent pathways is not clear. Correlating to the antiproliferative effects, the vitamin D receptor (VDR) expression was increased in the melanoma cell line by some PPAR ligands at the same time-point. This gave an indication of an interconnection of the PPAR and VDR signaling pathways at the level of cross-regulation of their respective transcription factor mRNA levels. The complete mechanisms and the physiological and pathophysiological relevance of this cross-talk are not yet known, but may open new
Summary & Conclusion
perspectives for treatment and/or prevention of melanoma. So, clinical studies using PPAR ligands as a supplementary agent in melanoma treatment show promising results.