PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GENES: STRUCTURE AND LOCALIZATION | Kickoff

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GENES: STRUCTURE AND LOCALIZATION

13 May

INTRODUCTION
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

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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

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.

CONCLUSIONS

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

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