Peroxisome proliferators-activated receptors (PPARs) are nuclear hormone receptors belonging to the superfamily of steroid/thyroid receptors. Three types of nuclear PPARs, PPARa, PPARb/d, and PPARg1/g2, have been identified and cloned, each being encoded by separate genes (1 – 8). Alternative splicing of one gene product yields two transcripts of PPARg: PPARg1 was found to predominate in adipose tissue and large intestines, whereas PPAR g2 seemed to be a minor isoform (9). These receptors have been named according to their capacity to be activated by many compounds, which share in common the property of inducing peroxisome proliferation, especially in rodent liver (10 – 12). They are involved in the control of genes encoding lipid metabolism-associated proteins, particularly those of peroxisomal b-oxidation (13 – 15), and are activated by physiological concentrations of fatty acids (16 – 18), fibrate hypolipidemic drugs (10,19), and certain plasticizers and herbicides (19,20).
The main response to peroxisomal proliferators is an increase in peroxisome proliferation, stimulation of peroxisomal fatty acidb-oxidation, and hepatocarcinogenesis. The oxidative degradation is responsible for the formation of hydrogen peroxide, which might lead to DNA damage and tumor initiation (20 – 22). Besides targeting peroxisomes, PPAR activation has been shown to be important in the regulation of lipid metabolism in fat and liver cells (23,24) and also regulates the expression of target genes involved in many cellular functions, including cell proliferation, differentiation, and immune/inflammatory response (25). The three PPARs (a, b/d, g) show the characteristics of ligand binding, and ligand activation can be related to a number of cellular processes: (i) fatty acid catabolism and modulation of the inflammatory response for PPARa; (ii) embryo implantation, cell proliferation, and apoptosis for PPARb/d; and (iii) adipocytic differentiation, monocytic differentiation, and cell-cycle withdrawal for PPARg (18). It has been shown that 3T3 L1 cells can be induced to differentiate into adipocytes, demonstrating that PPARs not only regulate the expression of lipid metabolism-associated pro- teins but are also directly involved in cell differentiation (26). This suggestion was supported by the finding that PPARg expression is induced early in the differentiation of 3T3 L1 preadipocytes into adipocytes (27,28). Further, examining the effects of the PPARg ligands BRL49653, troglitazone, and
15-deoxy-D12,14-prostaglandin J2 on the differentiation of human preadipocytes derived from subcutaneous and omental fat, it could be shown that these ligands enhanced markedly the differentiation of preadipocytes from subcutaneous sites; in contrast, preadipocytes from omental sites in the same individuals were refractory to the PPARg ligands, although PPARg was expressed at similar levels in both depots (29,30).
Members of the nuclear hormone receptor family have been implicated in epidermal processes such as differentiation, proliferation, and barrier development (31 – 34). Activators of PPARa and PPARg have been shown to regulate differentiation in cultured sebocytes (35 – 39), the hamster flank organ (40), and human sebaceous gland organ cultures (41), modulating sebum formation. Further, PPARs have been shown to be involved in regulating inflammatory responses, in particular PPARa and PPARg activation (42 – 45), and they are able to influence the inflammatory cytokine production and cell recruitment to the inflammatory sites (46).
Acne is a disease of the infundibulum and the sebaceous gland, and is characterized by comedogenesis, inflammation, and increased sebum secretion (47 – 50). Thus, with their involvement in regulating sebum formation and inflammation, PPARs may open up new avenues in the development of novel acne treatments.
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GENES: STRUCTURE AND LOCALIZATION
The genomic organization of the members of the nuclear hormone receptors, belonging to the superfamily of steroid/thyroid receptors, has provided useful information concerning their degree of relatedness. Their most conserved region contains two zinc fingers that constitute the core of the DNA-binding domain, which specifically recognizes hormone receptor elements. This conservation has been exploited to isolate additional members of the superfamily by sequence analysis, cross-hybridization screening of cDNA libraries, and functional studies. The conserved DNA-binding domain (C-domain) is flanked by a variable N-terminal domain (A/B domain) and a C-terminal ligand-binding domain (E/F domain), whereby the EF domain is linked with a hinge domain (D-domain) to the DNA-binding domain (Fig. 1). The A/B domain contains the activation function
1 (AF-1) that is transcriptionally active in the absence of ligands. The C-domain and
FIGURE 1 Typical structure of a peroxisome proliferator activated receptor gene. Abbreviations: AF, activation function; PPAR, peroxisome proliferator activated receptor.
the E/F-domain determine the specificity of promoters in DNA sequence recog- nition and ligand recognition, respectively. The ligand-binding domain, in addition to determining ligand specificity, contains a ligand-inducible transactivation function and a heptad-repeat motif involved in dimerization of nuclear receptors. This domain contains some regions that are highly conserved between most members of the nuclear receptor superfamily, particularly in the Ti-domain and AF-2 region. The N-terminal domain varies both in length and amino acid composition, and is responsible for the interaction with other transcription factors and transactivation. A distinctive feature of the PPAR subfamily is its great divergence in the ligand-binding domain, allowing researchers to distinguish the different PPAR subtypes pharmacologically (46,51,52).
The chromosomal localization of the human genes encoding PPARa, PPARb/d, and PPARg have been defined. They map on different chromosomes. The PPARg gene is on chromosome 3 at position 3p25 and has six exons (53). The PPARb/d gene is located on chromosome 6 at chromosomal region 6p21.2 and spans approximately 85 kb of DNA consisting of nine exons and eight introns (54). Finally, the PPARa gene has been mapped on chromosome 22 in the general region of 22q12-q13.1 and spans at least 80 kb with eight exons (6).
TRANSCRIPTIONAL ACTIVITY, DIMERIZATION, AND DNA BINDING
The transcriptional activity of the PPARs is regulated by post-translational modifi- cations, such as phosphorylation (55,56) and ubiquitination (57). Phosphorylation of PPARs is controlled by environmental factors, activating different kinase path- ways leading to the modulation of their activities (56). PPAR degradation by the ubiquitin – proteasome system modulates the intensity of the ligand response by controlling the level of PPAR proteins in the cells (46,57). It has been shown, more- over, that the novel orphan nuclear hormone receptor, liver-X-activated receptor (LXR)a, which is distinct from retinoic-X-activated receptor (RXR)a, inhibited PPAR signaling by competing with RXRa for PPARa heterodimerization, whereby the LXRa/PPARa heterodimer was unable to form a DNA-binding complex (58).
Dimerization is essential for the function of PPARs (Fig. 2). It has been demon- strated in vitro that PPARs form heterodimers with RXRs and that activation of PPARs can be increased in vitro by the addition of the RXR ligand, 9-cis-retinoic acid (59 – 63). As for other members of the nuclear hormone receptor family, PPARs regulate gene expression by binding to specific peroxisome proliferator response elements (PPRE) in the promoter regions of target genes (64) (Fig. 2). PPARs recognize a hormone response element that comprises a direct repeat (DR) of the hexameric AGGTCA half-site motif, with a one nucleotide spacer between the half elements (DR-1). The complex formed in vitro on such a response element is a PPAR – RXR heterodimer (59 – 63). The first PPRE characterized was found in the promoter of the acyl-coenzyme A (CoA) oxidase gene and was defined as DR-1 (2). Further, it has been shown that PPARs can achieve gene/ tissue specific activity by being selectively bound as heterodimers to PPRE, whereby specific heterodimers such as PPARg/RXRa or PPARg/RXRg bind more strongly to certain PPREs than other heterodimer combinations (65). Binding of PPAR/RXR to certain PPREs mediates transcriptional activation, but this can be negatively controlled by the presence of other heterodimers such as the thyroid hormone receptor/RXR heterodimer, as they can act as competitive inhibitors for PPRE binding that do not activate transcription (66).
FIGURE 2 Typical peroxisome proliferator activated receptor/retinoic-x-activated receptor heterodimer complex. Abbreviations: PPAR, peroxisome proliferator activated receptor; RXR, retinoic-x-activated receptor.
Transcriptional activity is also influenced by cofactors. Using a yeast two- hybrid system, a number of coactivators have been identified, including the steroid receptor coactivator 1, the PPARg-binding protein, and the PPAR interacting protein (67 – 69).
DIFFERENTIAL EXPRESSION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS
The discovery of several subtypes of PPARs has raised the question of the biological significance of PPAR diversity, which can be addressed by looking at their expression patterns. PPARa is expressed preferentially in the liver and in tissues with high fatty acid catabolism, such as the heart, kidneys, muscles, and brown fat (9,70,71), demonstrating lower expression in adrenal, placenta, and lung (71). PPARg is abundantly expressed in adipose tissue and at much lower levels in colon, spleen, and adrenal tissue (9,72). PPARb/d is the most ubiquitously expressed isoform among the three, but relatively little is known about its functions due to the lack of identification of physiological and specific ligands, as well as its remarkably broad tissue distribution (9,73 – 75).
In the skin, expression of all the three PPAR isoforms has been demonstrated and for recent reviews on PPARs in cutaneous biology, the reader is referred to Kuenzli and Saurat (76) and Wahli (77). PPARb/d is the prevalent PPAR subtype in human epidermis, whereas PPARa and PPARg are expressed at lower levels (34,78,79). In vitro studies have shown that PPARb/d expression remains high during keratinocyte differentiation, whereas expression of PPARa and PPARg increases significantly (34,80,81). In addition, these receptors are also present in rodent keratinocytes where the three isoforms exhibit a specific pattern of expression, suggesting nonredundant functions during development and in the various layers of the epidermis (32,78,79,82,83). PPARa, PPARb/d, and PPARg tran- scripts are already present in the mouse epidermis at foetal day 13.5 (79). PPAR expression decreases after birth to become undetectable in the interfollicular epidermis of the adult mice. In contrast, all three isoforms remain expressed in
Source: From Ref. 41.
FIGURE 3 Peroxisome proliferator activated receptors are expressed in freshly isolated human sebaceous glands. RNA was extracted and reverse transcription polymerase chain reaction (PCR) performed as previously described. Lanes 1 to 3 show PCRs performed on freshly isolated glands derived from three different subjects. Individual lane numbers in each of the PCR refer to cDNA obtained from the same subject. For example the PCR shown in lane 1 in each gel was performed using an aliquot from the same sample of cDNA. Abbreviations: GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PPAR, peroxisome proliferator activated receptors.
murine hair follicles (79). Interestingly, PPARa and PPARb/d expression is reactivated in the adult epidermis after various stimuli (tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing), resulting in keratinocyte prolifer- ation and differentiation (79). Furthermore, expression of all the three isoforms has also been demonstrated in human hair follicles (84).
Further, mRNA expression of the three PPAR subtypes was demonstrated in cultured human sebocytes (39), as well as the protein expression of PPARg. In accordance, mRNA and protein expression of PPARa, PPARb/d, and PPARg was shown in isolated human sebaceous glands (Figs. 3 and 4, respectively) (41). Although no differences in mRNA levels could be observed, the level of protein PPARb/d was much more abundant compared to PPARa and PPARg, which were only weakly expressed (41).
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS ARE ACTIVATED BY A DIVERSE ARRAY OF COMPOUNDS
Nuclear transcription factors can achieve gene- or tissue-specific activity in several ways: (i) restriction of expression to a given tissue and/or at a given time, (ii) binding to specific DNA sequences and thus to specific genes, (iii) activation by tissue-specific ligands or activators, and (iv) modulation of the transactivation properties by physical or functional interactions with tissue specific cofactors. Thus, the predominant expression of PPARg in adipose tissue and the high expression of PPARa in the liver correlate with their specific role in adipose
FIGURE 4 Peroxisome proliferator activated receptor (PPARa), PPARb/d, and PPARg protein is detectable in freshly isolated human sebaceous glands. Sebaceous glands were isolated and processed for immunoblotting as previously described. Approximate protein sizes are indicated. This micrograph is representative of n ¼ 3 subjects. Abbreviations: KC, primary human keratinocytes; PPAR, peroxisome proliferator activated receptor; SG, human sebaceous glands. Source: From Ref. 41.
differentiation and fatty acid catabolism, respectively. Further, fatty acids, leukotriene B4, and hypolipidemic drugs (fibrates and Wy14,643) preferentially activate PPARa, whereas the PPARg subtype binds and is activated by prostaglandin derivatives and insulin-sensitizing thiazolidinediones such as pioglitazone, troglitazone, and BRL 49653 (42,52,65,85).
The identification of fatty acids as endogenous ligands for PPARs has provided a unique approach to study lipid homeostasis at the molecular level. Among the fatty acids, linoleic acid, linolenic acid, and arachidonic acid are potent activators of PPARa (86,87). Other natural ligands include leukotriene B4 and 15-deoxy-D12,14-prostaglandin J2, which are PPARa and PPARg activators, respectively (88,89).
Most studies on PPAR ligand activation have involved transfection experiments. Obviously, in these experiments, the activation of the receptor may result from a cascade of events rather than a direct binding of the tested ligand. Furthermore, the potency of a given compound is dependent on the rate at which it is taken up and metabolized by the cell type used. Finally, due to structural similarity, exogenous applied ligands probably interfere with the metabolic processing of endogenous ligands, possibly fatty acids and/or eicosanoids. Thus,
the measured PPAR response presumably results from the combined actions of direct receptor binding of the exogenous ligand and the indirect effects, owing to the perturbation of endogenous ligand levels (52).
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR TARGET GENES
PPARs regulate gene expression by binding to specific PPRE in the promoter regions of target genes (64). PPREs have a core element called DR-1, in which PPAR – RXR heterodimers preferentially bind to. Since stimulation of peroxisomal fatty acidb-oxidation is one of the key effects of peroxisome proliferators, genes encoding enzymes of this pathway represent prime candidate target genes of PPARs. The first gene described was acyl-CoA oxidase that is the rate-limiting and specificity-defining enzyme of peroxisomal fatty acidb-oxidation (2). PPREs have since been found in regulatory sequences of a number of enzyme of this pathway, including enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenease,
cytochrome P450 4A6 (CYP4A6) gene, fatty acid binding protein gene, acyl-CoA synthetase gene, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene, and the malic enzyme gene (2,14,15,90 – 93). PPAR target genes identified to date belong largely to pathways of lipid transport and metabolism.
The target genes of PPARa, which have mostly been studied in the context of liver parenchymal cells where it is highly expressed, are a relatively homogenous group of genes that participate in aspects of lipid catabolism, such as fatty acid uptake through membranes, fatty acid binding in cells, fatty acid oxidation (in microsomes, peroxisomes, and mitochondria), and lipoprotein assembly and trans- port (94). Recently, novel PPARa regulated genes, including ubiquitin COOH-term- inal hydrolase 37 and cyclin T1, have been described, which could be involved in the regulation of cell cycle and carcinogenesis (95).
Most of the PPARg target genes in adipose tissue are directly implicated in lipogenic pathways, including lipoprotein lipase, adipocyte fatty acid-binding protein, acyl-CoA synthase, and fatty acid transport protein (94). Further, PPARg ligands have been shown to inhibit the growth and induce apoptosis in cells from different cancer lineages, including liposarcoma, breast cancer, melanoma, and colon cancer, demonstrating antitumor effects (96 – 99).
PPARb/d has been shown to regulate the expression of acyl-CoA synthetase 2 in the brain (92) and has also been linked to colon cancer where it is a negative target of the adenomatous polyposis coli gene (100). Further, PPARb/d activation has been implicated in keratinocyte differentiation, regulating the expression of transgluta- minase-1, involucrin, and CD36 (34), and wound healing (79).
PPARs also control the expression of genes implicated in the inflammatory response via negative interference with different inflammatory pathways such as nuclear factor kappa B, activator protein-1, CCAAT/enhancer-binding protein (C/ EBP)b, signal transducer and activator of transcription-1, and nuclear factor of activated T-cell. As such, PPARs influence inflammatory cytokine production and cell recruitment to the inflammatory sites (46).
It is beyond the scope of this review to further discuss the role of PPARs in health and disease, in particular metabolic disorders such as hyperlipidaemia, atherosclerosis, diabetes, obesity, and coronary artery disease, and the reader is referred to a number of excellent reviews on these subjects (24,89,101,102).
PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ACTIVITY IN THE EPIDERMIS AND PILOSEBACEOUS UNIT
Terminal differentiation of the cells of the human pilosebaceous unit is not dissim- ilar from that of the epidermal keratinocytes. Like epidermal keratinocytes, the matrix cells of the hair follicle and the sebocytes of the sebaceous gland terminally differentiate to die, forming the hair fibre or releasing their cell content as sebum, respectively. This program includes a biochemical differentiation, the expression of various structural proteins, and the processing and reorganization of lipids. A wealth of data has been collected to date, suggesting that PPARs have specific roles in these complex processes.
The epidermal expression of the three PPAR isoforms has prompted studies on the effects of PPAR ligands on keratinocyte differentiation. In human primary keratinocytes, PPARa activators, including putative endogenous ligands such as fatty acids, induce differentiation and inhibit proliferation, suggesting a regulatory role for PPARa in epidermal homeostasis (31). In addition, PPARa ligands are able to influence lipid metabolism in an in vitro human skin model (33). In contrast, in a
more recent study, PPARa activators, like PPARg activators, seemed to have little effect on human keratinocyte differentiation (30). However, a selective PPARb/d ligand induced the expression of keratinocyte differentiation markers (30). These apparent discrepancies remain to be elucidated. In the rat, PPARa ligands accelerate epidermal maturation in vitro (31,103,104) and in utero (32), whereas PPARb/d and PPARg activators had no effects. In addition, PPARa ligands induce epidermal differentiation and restore epidermal homeostasis in hyperproliferative mouse epidermis (105).
PPAR mutant mouse models have contributed to our understanding of the role of PPARs in epidermal homeostasis. Using PPARa, PPARb/d, and PPARg mutant mice, it was shown that PPARa and PPARb/d are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARa was mainly involved in the early inflammation phase of the healing, whereas PPARb/d was implicated in the control of keratinocyte prolifer- ation. In addition and very interestingly, PPARb/d mutant primary keratinocytes showed impaired adhesion and migration properties (77,79). However, PPARa, PPARb/d, and PPARg mutations appear to have no obvious effects during normal foetal development of the epidermis (79,106,107).
Unfortunately, epidermal and sebaceous gland functions were not examined in the mouse mutant models. However, in rat preputial sebocytes, PPARg and PPARa activation induced sebocyte lipogenesis in vitro but not in keratinocytes, whereas activators of PPARb/d induced lipid formation in both sebocytes and keratinocytes (36). PPARg ligands promoted the differentiative effects of androgens on sebocytes and PPARg1 was shown to be expressed more strongly in freshly dispersed sebocytes compared to cultured sebocytes, suggesting that androgen influences an early step in sebocyte differentiation, which is related to but distinct from that influenced by PPARg1. Further, PPARb/d was abundantly expressed in sebocytes and keratinocytes (36). RXR agonists augmented the stimulation of sebocyte differentiation by PPAR agonists, as expected from PPAR – RXR hetero- dimerization; however, the evidence for PPAR – RXR cooperativity was limited (37). Moreover, in cultured human sebocytes, PPARb/d activation had a stimulatory effect on lipid production, whereas PPARg and PPARa activation was ineffective (39). In addition, treatment with arachidonic acid resulted in increased lipid for- mation in cultured human sebocytes (38). Furthermore, treatment with arachidonic acid enhanced apoptosis in cultured human sebocytes, as determined by the pre-
sence of fragmented nuclei, indicating that apoptosis is part of the sebocyte differ- entiation process (38). Using a PPARb/d mutant mouse model, proinflammatory cytokines initiated the production of endogenous PPARb/d ligands, which were essential for PPARb/d activation and action, and activated PPARb/d regulated the expression of genes associated with apoptosis (108).
In contrast, in organ maintained human sebaceous glands, PPARg and PPARa selective ligands inhibited total sebaceous lipogenesis (Table 1) and also reduced the production of the sebum-specific lipids, squalene and triacylglycerol (Table 2). Further, arachidonic, linoleic, linolenic, and oleic acid, which are less specific in their PPAR subtype activation, also inhibited sebaceous lipogenesis (41). Similar observations were made using the hamster flank organ where PPARa activation with clofibric acid produced a dose-dependent inhibition of lipo- genesis (40). In addition, it has been demonstrated that the oral administration of eicosatetraynoic acid to human male volunteers significantly reduced sebum secretion (109). These findings indicate that PPAR effects are differentiation
sensitive, that is, one might postulate that structures that are missing in sebocyte monolayers but are present in whole organ cultures may be involved in PPAR agonist activity.
Further, there is an evidence that cutaneous inflammation can be reduced by PPAR agonists, such as linoleic acid, with clinical effects comparable to that of glucocorticoids (110). In addition, the PPARa activators, WY-14,643 and clofibrate, were shown to reverse ultraviolet-B-light-mediated expression of inflammatory cytokines, that is, interleukin (IL)-6 and IL-8 (43). This work suggests the possibility of PPARa activators as novel nonsteroidal anti-inflammatory drugs in the topical treatment of inflammatory skin diseases (43). Further, PPARa activation with clofibrate treatment resulted in the reduction of inflammatory cells and a decrease in tumor necrosis factora and IL-1a in the epidermis of a mouse model of irritant and allergic contact dermatitis (44).
Acne is a disease unique to humans. It affects up to 80 % of young adults, in whom it can induce stress, depression, and anxiety, as determined by psychometric scoring (47,111,112). Acne is a disease of the infundibulum or “pore” of the human sebaceous pilosebaceous unit and of the gland itself. This unit develops at puberty, appears only at the site of acne lesions (the chest, back, and face), and seems to have no other function than to sometimes produce acne lesions. The earlier forms of acne are characterized by microcomedones, which represent an intrainfundibular scaling-like phenomenon. As the disease progresses in sever- ity, comedogenesis develops, as does inflammation. Duct rupture is a late event in the development of most inflammatory lesions (47 – 50).
Acne is generally accepted by clinicians to be a multifactorial disease and it is believed that acne is associated with seborrhea, the excess production of sebum by the sebaceous gland (49,113). Further, Propionibacterium acnes is a major bacterium implicated in the pathogenesis of acne (114). Acne is characterized by the presence of noninflammatory lesions, termed comedones (47,50). The earliest pathological change in acne is altered follicular epithelial differentiation, resulting in a follicular retention hyperkeratosis—the microcomedo (50). In addition to the non- inflammatory lesions, inflammatory lesions can develop when such microcomedos are colonized by P. acnes. For inflammatory lesions such as papules, pustules, and nodulocystic lesions to occur, a variety of pathogenic factors are involved, including besides P. acnes, inflammatory mediators, and host immunity (115). In vitro exper- iments on organ maintained human infudibula have identified a number of cyto- kines that can model the morphological and inflammatory aspects of acne (116). These cytokines not only induce the infundibular changes in acne, namely (i) hyper- cornification (scaling) of the infundibulum, (ii) expression of intercellular adhesion molecule-1 and human leukocyte antigen-D related, and (iii) disruption of infun- dibular morphology, but will also inhibit the secretion of lipid from the sebaceous gland (117). Since acne seems to be provoked by P. acnes in sebum and since P. acnes depends on sebum for nutrition, the inhibition of sebum secretion would be expected to promote the remission of the disease by inhibiting P. acnes colonization (117).
A number of acne therapies are currently in use, including retinoids (e.g., iso- tretinoin, adapalene), antiandrogens (e.g., cyproterone acetate), contraceptives, antibacterials (e.g., clindamycin, erythromycin), benzoyl peroxide, and salicylic acid (118,119). In milder cases, topical therapy is sufficient, but in more severe
cases where papulopustular or nodulocystic acne is present, there is a need of sys- temic treatment. However, there is a continued need for effective drugs for the therapy of acne, although judicious combined use of existing topical and systemic therapies offers great relief to many patients and a recent review of these therapies indicated that approximately 68% of treatment is effective (120). Nonetheless, PPARs may offer a solution for the development of novel effective drugs for acne therapy.
The study of PPAR expression profiles and the identification of target genes and ligands in the skin and its appendages as well as the utilization of PPAR mouse mutant models have unveiled distinct physiological functions of the PPARs (Table 3). In particular, activation of PPARs regulates differentiation and prolifer- ation, lipid metabolism, inflammation, and apoptosis. However, the molecular mechanisms by which PPARs coordinate the regulation of these processes remain largely unknown, and thus PPARs represent a major research target for the under- standing and treatment of many skin diseases including acne.
The research reviewed here focused on PPAR activity in human epidermis and its appendages. The data demonstrates that PPARs regulate many of the phys- iological processes that are involved in acne. However, it is also apparent that there is some discrepancies with regard to the physiological effects of PPAR ligands on sebaceous lipogenesis, which may be attributed to the different study models used, but this requires further elucidation. It would be of particular interest to evaluate the efficacy of PPAR ligands on acne and other skin disorders in the clinic.
Since the completion of this manuscript, more research has been done into examining the effects of PPAR ligands on sebaceous lipogenesis. The PPAR ligands GW7647, GW0742, GW2433, rosiglitazone, and GW4148 significantly increased lipogenesis in SEB-1 sebocytes (121), confirming earlier reports refer- enced in this chapter. Interestingly, patient data collected in the same paper showed increased sebum secretion in patients receiving fibrates for hyperlipidemia or thialzolidienediones for diabetes. However, this is in contrast to observation in healthy volunteers, and one might argue that these patients are treated for meta- bolic diseases of the liver and pancreas, which may also effect sebaceous gland metabolism, and therefore these data should be treated with caution. In addition, PPAR involvement in the prostaglandin pathway has been shown in a recent paper where PPARg activation has been implicated in oxidative stress-mediated prostaglandin E(2) production in SX95 human sebaceous cells (122).
Antimicrobial Peptides and Acne