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Contributions of Peroxisome Proliferator-Activated Receptor Β /Δ to Skin Health and Disease

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Contributions of Peroxisome Proliferator-Activated Receptor Β /Δ to Skin Health and Disease DOI 10.1515/bmc-2012-0035 BioMol Concepts 2013; 4(1): 53–64 Alexandra Montagner and Walter Wahli * Contributions of peroxisome proliferator-activated receptor β / δ to skin health and disease Abstract: Among the three peroxisome proliferator- skin compose the epidermis, which together with the activated receptor (PPAR) transcription factors, PPAR β / δ is dermis forms the cutis. In the latest stages of fetal devel- the isotype with the broadest expression pattern. In fact, the opment, the epidermis develops into a fully stratified expression of PPAR β / δ is ubiquitous, albeit at levels that are and differentiated epithelium that undergoes continu- tightly regulated. Herein, we reviewed its multiple functions ous renewal after birth. In fact, the basal layer of this in skin health and disease. PPAR β / δ has pro-differentiating stratified tissue contains undifferentiated proliferating effects in keratinocytes, regulates sebocyte differentiation, keratinocytes that undergo a differentiation program as and promotes hair follicle growth in healthy skin. Further- they migrate from the basal to the uppermost layer of more, we reviewed novel insights into the roles of PPAR β / δ the epidermis. The basal layer is the source of skin cells in skin wound healing, especially in inhibiting apoptosis throughout life, which are generated through asymmetri- and in modulating keratinocyte proliferation and migra- cal division (1, 2) . This cell layer is maintained through tion. Therefore, PPAR β / δ represents a research target for the several autocrine and paracrine acting factors, which are understanding and treatment of inflammatory skin diseases, important for epidermal homeostasis (3 – 5) . The vectorial such as psoriasis and acne vulgaris. In addition, PPAR β / δ differentiation program of keratinocytes comprises the is a tumor growth modifier. Epidemiological studies have processing of lipids [sphingolipids, free fatty acids (FAs), established that tumor progression may be exacerbated by and cholesterol] and the sequential expression of struc- chronic low-grade inflammation, a condition promoting the tural proteins (keratins, involucrin, loricrin, and filag- production of the lipids that act as modulators of PPAR β / δ grin), which are each essential to the protective function activity. The action of PPAR β / δ in skin cancer is ambivalent, of the epidermis. In fact, the outermost layer of the epi- which might be explained by this receptor ’ s putative highly dermis, the stratum corneum, consists of a layer of cross- context-specific behavior, which depends on a combination linked proteins and lipids and dead keratinocytes (cor- of factors ranging from receptor expression levels to co-reg- neocytes), which form an efficient barrier against water ulator distribution, diversity and activity of the ligands pro- loss, microorganism invasion, mechanical damage, and duced, and other tissue-specific conditions. Given its diverse chemical poisoning. The stratum corneum is also where and crucial roles in many tissues and organs, PPARβ / δ will desquamation, the natural process by which dead outer remain a major focus of future research. skin cells are sloughed away and replaced, occurs (6) . Epi- dermal homeostasis and the integrity of the barrier func- Keywords: keratinocytes; non-melanoma skin cancer; tion depend on a well-tuned coordination of keratinocyte nuclear receptors; psoriasis; wound healing. proliferation, differentiation, positioning in the tissue, and apoptosis. *Corresponding author: Walter Wahli, Center for Integrative As in other organs, lipid signaling contributes to Genomics , National Research Center Frontiers in Genetics, skin health and disease. The nuclear receptors called University of Lausanne, CH-1015 Lausanne , Switzerland , peroxisome proliferator-activated receptors (PPARs) e-mail: [email protected] are key mediators of lipid signaling. They sense diverse Alexandra Montagner: Center for Integrative Genomics , National Research Center Frontiers in Genetics, University of Lausanne, lipophilic molecules that act as ligands and thereby link CH-1015 Lausanne , Switzerland ; and Toxicology and Integrative fluctuations in the levels and distribution of FAs, eicos- Metabolism, INRA ToxAlim, 180 Chemin de Tournefeville, 31027 anoids, and some phospholipids to differential gene Toulouse Cedex 3, France expression (7, 8) . There are three related PPAR isotypes that compose a small subfamily of nuclear receptors: PPAR α (NR1C1), PPARβ / δ (NR1C2), and PPAR γ (NR1C3) Introduction (9) . The transcriptional activity of all three of them is mediated by PPAR:retinoid X receptor heterodimers that The skin is the largest organ of the body with respect to bind to specific DNA sequence elements termed peroxi- weight and surface area. The outer layers of cells in the some proliferator response elements. By doing so, they 54 A. Montagner and W. Wahli: PPAR β / δ functions in skin regulate the expression of genes implicated in several such as hyperproliferative and inflammatory diseases, important processes, such as lipid and carbohydrate and cancer. metabolism, tissue repair, vascular biology, and sexual dimorphism, as well as in more general basic cellular processes, such as proliferation, differentiation, and Skin development: cell differentia- migration (10, 11) . The expression patterns of PPAR α , PPAR β / δ , and tion, epidermis, and appendages PPAR γ are well described (10, 12, 13) . Although present- ing some specificity, they are also overlapping, with The three PPAR isotypes are expressed in rodent and distinct expression levels. PPAR α , which has been human skin. Cell culture and in vivo approaches have well described in FA catabolism, is highly expressed in demonstrated that PPAR β / δ has pro-differentiating effects brown adipose tissue, heart, liver, kidney, and intes- in keratinocytes in normal and inflammatory conditions, tines, whereas PPAR β / δ is relatively abundant in the regulates hair follicle growth, and promotes sebocyte brain, skeletal muscle, gut, placenta, and skin. The third differentiation. isotype, PPAR γ , is expressed as two isoforms, γ 1 and γ 2. In keratinocytes from adult human epidermis, PPARβ / δ PPAR γ 1 is 28 and 30 amino acids shorter at its N-termi- is constitutively expressed and is present throughout all epi- nus than PPAR γ 2 in rodents and humans, respectively. dermal layers (16 – 18) . In contrast, in the interfollicular epi- PPAR γ 1 also has a broader expression pattern, which dermis of rodents, PPAR β / δ is expressed at relatively high includes immune cells, brain, gut, and endothelial cells, levels during development and much less in the adult epi- whereas PPAR γ 2 is found mainly in adipose tissues. This dermis (19) . In mouse keratinocytes, PPARβ / δ expression list is not exhaustive; a more detailed description of can be down-regulated by C/EBPα and C/EBP β through PPAR expression can be found in previous articles (10, a mechanism that requires both the binding of C/EBP to 12 – 14) . the promoter of the PPAR β / δ gene and histone deacetyla- In recent years, PPARs (and especially PPARβ / δ ) have tion. We propose that such interplay between PPARβ / δ and emerged as having multifaceted key roles in skin health C/EBP transcription factors is crucial to the molecular and disease (Figure 1 ). Characterized natural PPAR β / δ control of the balance between differentiation and prolif- ligands are unsaturated FAs, saturated FAs (weak), pros- eration (20) . Furthermore, keratinocyte fatty acid binding tacyclin, 4-hydroxy-2-nonenal, 4-hydroxydodeca-(2E ,6 Z )- protein (K-FABP) is essential to the ability of PPARβ / δ to dienal, and very low-density lipoprotein components (15) . properly induce keratinocyte differentiation. Hence, the tis- The present review summarizes our current knowledge of sue-specific expression of particular FABPs may support the PPAR β / δ functions in rodent and human skin, including tissue-specific functions of PPARs, which raises the intrigu- embryonic development, the maintenance of adult skin ing possibility that the same K-FABP – PPAR β / δ pair plays and skin appendages, and normal skin repair. We also a similar role in mediating the differentiation of other cell discuss the implication of PPAR β / δ in skin pathologies, types in which both factors are expressed concomitantly PPARβ/δ PPARα PPARγ Interfollicular Keratinocyte proliferation Epidermal development (fetus) epidermis Keratinocyte differentiation Keratinocyte differentiation Epidermis Barrier repair Barrier development Barrier repair Lipid synthesis Lipid synthesis Lipid synthesis Sebocyte Differentiation Differentiation Dermis Hair follicle Morphogenesis Survival in vitro Hypodermis Figure 1 Functions of PPARs in the epidermis and epidermal appendages. This schematic outlines the skin structures and functions of PPARs in the interfollicular epidermis, sebocytes, and hair follicles. Observa- tions obtained after activation of PPARs by their specific ligands in three skin structures are summarized (see text for references). A. Montagner and W. Wahli: PPAR β / δ functions in skin 55 (21) . The pro-differentiating action of ligand-activated enriched with extracellular neutral lipids surrounding the PPAR β / δ is keratinocyte-autonomous and mediated by an corneocytes (29, 30) . These extracellular lipids differ from indirect mechanism that involves the transcriptional regu- the lipids that constitute most biological membranes. lation of adipocytokine angiopoietin-like 4 (ANGPTL4) and Their total
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