Abstract
The epidermis is a very active site of lipid metabolism, and all peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) isoforms are expressed in the epidermis. Activation of PPARalpha, -beta/delta, or -gamma or LXRs stimulates keratinocyte differentiation. Additionally, activation of these receptors also improves permeability barrier homeostasis by a number of mechanisms, including stimulating epidermal lipid synthesis, increasing lamellar body formation and secretion, and increasing the activity of enzymes required for the extracellular processing of lipids in the stratum corneum, leading to the formation of lamellar membranes that mediate permeability barrier function. The stimulation of keratinocyte differentiation and permeability barrier formation also occurs during fetal development, resulting in accelerated epidermal development. PPAR and LXR activation regulates keratinocyte proliferation and apoptosis, and studies have shown that these receptors play a role in cutaneous carcinogenesis. Lastly, PPAR and LXR activation is anti-inflammatory, reducing inflammation in animal models of allergic and irritant contact dermatitis. Because of their broad profile of beneficial effects on skin homeostasis, PPAR and LXR have great potential to serve as drug targets for common skin diseases such as psoriasis, atopic dermatitis, and skin cancer.
Highlights
RELEVANCE OF peroxisome proliferator-activated receptor (PPAR) AND liver X receptor (LXR) TARGETING IN SKIN DISORDERSSeveral of the most common skin diseases, including psoriasis and atopic dermatitis, are characterized by a Manuscript received 7 January 2008 and in revised form 8 January 2008
The epidermis is a very active site of lipid metabolism, and all peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) isoforms are expressed in the epidermis
Cutaneous squamous cell carcinoma and basal cell carcinoma are the two types of nonmelanoma skin cancer that arise from malignant proliferation of keratinocytes and together account for .1 million cases per year in the United States, of which roughly one-quarter is squamous cell carcinoma and three-quarters is basal cell carcinoma; these are the most common cancers in humans [14]
Summary
Several of the most common skin diseases, including psoriasis and atopic dermatitis, are characterized by a Manuscript received 7 January 2008 and in revised form 8 January 2008. A pertinent example that demonstrates the potential importance of abnormalities in keratinocytes is the recent discovery that many cases of atopic dermatitis are caused by mutations in the filaggrin gene, which is thought to allow sustained ingress of antigens through a defective barrier, eliciting a characteristic T helper 2 immune response [5,6,7]. We will discuss their role in epidermal carcinogenesis, which comprises nonmelanoma skin cancer and malignant melanoma. In this review, we will focus on the effects of PPAR and LXR on common inflammatory skin disorders and skin cancer
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