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Originally published In Press as doi:10.1194/jlr.R800001-JLR200 on January 8, 2008

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Journal of Lipid Research, Vol. 49, 499-509, March 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Thematic Review

Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

Matthias Schmuth1,*,{dagger},§, Yan J. Jiang**,{dagger}{dagger}, Sandrine Dubrac§, Peter M. Elias*,{dagger} and Kenneth R. Feingold*,**,{dagger}{dagger}

* Department of Dermatology, University of California, San Francisco, CA
{dagger} Department of Medicine, University of California, San Francisco, CA
§ Dermatology Section, Department of Veterans Affairs Medical Center, San Francisco, CA
** Metabolism Section, Department of Veterans Affairs Medical Center, San Francisco, CA
{dagger}{dagger} Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria

Published, JLR Papers in Press, January 8, 2008.

1 To whom correspondence should be addressed. e-mail: schmuthm{at}derm.ucsf.edu

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 PPAR{alpha}, -β/{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.

Supplementary key words cancer • cutaneous • differentiation • inflammation • permeability barrier • proliferation • transcription factor • skin • stratum corneum

Abbreviations: IL-1{alpha}, interleukin-1{alpha}; LXR, liver X receptor; NF-{kappa}B, nuclear factor-{kappa}B; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; SULT2B1b, sulfotransferase type 2B isoform 1b; TNF-{alpha}, tumor necrosis factor-{alpha}; TPA, 12-O-tetradecanoyl-phorbol-13-acetate; TUNEL, terminal uridine deoxynucleotidyl transferase






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