PPARs are nuclear hormone receptors. PPAR subtypes (α, γ, δ, the latter a xPPARβ homologue) were initially investigated in skin because of their known role in regulating lipid metabolism. Studies adding specific PPAR ligand activators to cultured skin or skin cells are compatible with the concepts that PPARα activation mediates early lipogenic steps common to the function of both skin epidermal cells (keratinocytes) and sebaceous cells (sebocytes), PPARγ activation plays a unique role in stimulating sebocyte lipogenesis, and PPARδ activation may contribute to lipid biosynthesis in both sebocytes and keratinocytes under certain circumstances. Epidermal keratinocytes appear to express small amounts of PPARα and PPARδ mRNA and a trace of PPARγ mRNA which is up-regulated with differentiation. Sebocytes express all subtypes; PPARγ gene expression excedes that in epidermis. The emerging data on PPAR protein expression suggests that epidermis normally expresses predominantly PPARα, while sebocytes express more PPARγ than PPARα. These expression patterns may change during hyperplasia, differentiation and inflammation. Gene disruption studies in mice are compatible with a contribution of PPARα to skin barrier function, suggest that PPARγ is necessary for sebocyte differentiation, and indicate that PPARδ can ameliorate inflammatory responses in skin. PPARs appear to play a role in keratinocyte synthesis of the lipids that they export to the intercellular space to form the skin permeability barrier. They also appear to be important for sebocyte formation of the intracellular fused lipid droplets that constitute the holocrine secretion of the sebaceous gland. In addition, they may play roles in keratinocyte growth and differentiation and the inhibition of skin inflammation by diverse mechanisms not necessarily related to fat metabolism.

1.
Mangelsdorf D, Evans R: The RXR heterodimers and orphan receptors. Cell 1995;83:841–850.
2.
Kliewer S, Forman B, Blumberg B, Ong E, Borgmeyer U, Mangelsdorf D, Umesono K, Evans R: Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci 1994;91:7355–7359.
3.
Xing G, Zhang L, Zhang L, Heynen T, Yoshikawa T, Smith M, Weiss S, Detera-Wadleigh S: Rat PPARd contains a CGG triplet repeat and is prominently expressed in the thalamic nuclei. Biochem Biophys Res Commun 1995;217:1015–1025.
4.
Takada I, Yu RT, Xu HE, Lambert MH, Montana VG, Kliewer SA, Evans RM, Umesono K: Alteration of a single amino acid in peroxisome proliferator-activated receptor-alpha (PPAR alpha) generates a PPAR delta phenotype. Mol Endocrinol 2000;14:733–740.
5.
Brun R, Tontonoz P, Forman B, Ellis R, Chen J, Evans R, Spiegelman B: Differential activation of adipogenesis by multiple PPAR isoforms. Genes Develop 1996;10:974–984.
6.
Dussault I, Forman BM: Prostaglandins and fatty acids regulate transcriptional signaling via the peroxisome proliferator activate receptor nuclear receptors. Prostaglandins Other Lipid Mediators 2000;62:1–13.
7.
Kliewer S, Lenhard J, Wilson T, Patel I, Morris D, Lehmann J: A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995;83:813–819.
8.
Berger J, Bailey P, Biswas C, Cullinan CA, Doebber TW, Hayes NS, Saperstein R, Smith RG, Leibowitz MD: Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: Binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology 1996;137:4189–4195.
9.
Forman B, Chen J, Evans R: Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proc Natl Acad Sci USA 1997;94:4312–4317.
10.
Lehmann J, Moore L, Smith-Oliver T, Wilkinson W, Willson T, Kliewer S: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma. J Biol Chem 1995;270:12953–12956.
11.
Schoonjans K, Staels B, Auwerx J: The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim Biophys Acta 1996;1302:93–109.
12.
Green S: PPAR: A mediator of peroxisome proliferator action. Mutat Res 1995;333:101–109.
13.
Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr Rev 1999;20:649–688.
14.
Tontonoz P, Hu E, Spiegelman BM: Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid- activated transcription factor [published erratum appears in Cell 1995;80: following 957]. Cell 1994;79:1147–1156.
15.
Hanley K, Jiang Y, Crumrine D, Bass N, Appel R, Elias P, Williams M, Feingold K: Activators of the nuclear hormone receptors PPARα and FXR accelerate the development of the fetal epidermal permeability barrier. J Clin Invest 1997;100:705–712.
16.
Rivier M, Castiel I, Safonova I, Ailhaud G, Michel S: Peroxisome proliferator-activated receptor-alpha enhances lipid metabolism in a skin equivalent model. J Invest Dermatol 2000;114:681–687.
17.
Rosenfield RL, Kentsis A, Deplewski D, Ciletti N: Rat preputial sebocyte differentiation involves peroxisome proliferator-activated receptors. J Invest Dermatol 1999;112:226–232.
18.
Rosenfield RL, Deplewski D, Kentsis A, Ciletti N: Mechanisms of androgen induction of sebocyte differentiation. Dermatology 1998;196:43–46.
19.
Mangelsdorf D, Thummel C, Beato M, Herrlich P, Schütz G, Kastner P, Mark M, Chambon P, Evans R: The nuclear receptor superfamily: the second decade. Cell 1995;83:835–839.
20.
Heyman R, Mangelsdorf D, Dyck J, Stein R, Eichele G, Evans R, Thaller C: 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 1992;68:397.
21.
Levin AA, Sturzenbecker LJ, Kazmer S, Bosakowski T, Huselton C, Allenby G, Speck J, Kratzeisen C, Rosenberger M, Lovey A: 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXR alpha. Nature 1992;355:359–361.
22.
Petkovich M, Brand NJ, Krust A, Chambon P: A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature 1987;330:444–450.
23.
Zhang XK, Lehmann J, Hoffmann B, Dawson MI, Cameron J, Graupner G, Hermann T, Tran P, Pfahl M: Homodimer formation of retinoid X receptor induced by 9-cis retinoic acid. Nature 1992;358:587–591.
24.
Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM: Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 1992;358:771–774.
25.
Gearing K, Gottlicher M, Teboul M, Widmark E, Gustafsson J-A: Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor. Proc Natl Acad Sci 1993;90:1440–1444.
26.
Mukherjee R, Jow L, Croston GE, Paterniti JR Jr: Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem 1997;272:8071–8076.
27.
Tontonoz P, Singer S, Forman BM, Sarraf P, Fletcher JA, Fletcher CD, Brun RP, Mueller E, Altiok S, Oppenheim H: Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci USA 1997;94:237–241.
28.
Kim MJ, Ciletti N, Michel S, Reichert U, Rosenfield RL: The role of specific retinoid receptors in sebocyte growth and differentiation in culture. J Invest Dermatol 2000;114:349–353.
29.
Kim MJ, Ciletti N, Michel S, Reichert U, Rosenfield RL: Limited cooperation between peroxisome proliferator-activated receptors and retinoid X receptors in induction of sebocyte differentiation and proliferation. Pediatric Research 2000;47:72A (abstr 424).
30.
Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W: Differential expression of peroxisome proliferator-activated receptors (PPARs): Tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinol 1996;137:354–366.
31.
Braissant O, Wahli W: Differential expression of peroxisome proliferator-activated receptor- alpha, -beta, and -gamma during rat embryonic development. Endocrinology 1998;139:2748–2754.
32.
Rivier M, Safonova I, Lebrun P, Griffiths CE, Ailhaud G, Michel S: Differential expression of peroxisome proliferator-activated receptor subtypes during the differentiation of human keratinocytes. J Invest Dermatol 1998;111:1116–1121.
33.
Ellis CN, Varani J, Fisher GJ, Zeigler ME, Pershadsingh HA, Benson SC, Chi Y, Kurtz TW: Troglitazone improves psoriasis and normalizes models of proliferative skin disease: Ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation. Arch Dermatol 2000;136:609–616.
34.
Thiboutot DM, Gilliland KL, Sivarajah S, Cong Z: Peroxisome proliferator-activated receptor (PPAR) expression in human sebaceous glands. J Invest Dermatol 2000;114:810 (abstr 354).
35.
Street T, Holland A, Meyers N, Cunliffe W, Randall V: Is there a role for PPARs (peroxisome proliferator activated receptors) in the human sebaceous gland? J Invest Dermatol 2000;114:796 (abstr 270).
36.
Greene ME, Pitts J, McCarville MA, Wang XS, Newport JA, Edelstein C, Lee F, Ghosh S, Chu S: PPARγ: Observations in the hematopoietic system. Prostaglandins Other Lipid Mediat 2000;62:45–73.
37.
Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ: Targeted disruption of the alpha isoform of the peroxisome proliferator- activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 1995;15:3012–3022.
38.
Gonzalez F, Fernandez-Salguero P, Lee S, Pineau T, Ward J: Xenobiotic receptor knockout mice. Toxicol Let 1995;82/83:117–121.
39.
Imakado S, Bickenbach J, Bundman D, Rothnagel J, Attar P, Wang X-J, Walczak V, Wisniewski S, Pote J, Gordon J: Targeting expression of a dominant-negative retinoic acid receptor mutant in the epidermis of transgenic mice results in loss of barrier function. Genes Develop 1994;9:317–329.
40.
Peters JM, Lee SS, Li W, Ward JM, Gavrilova O, Everett C, Reitman ML, Hudson LD, Gonzalez FJ: Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta (delta). Mol Cell Biol 2000;20:5119–5128.
41.
Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman BM, Mortensen RM: PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611–617.
42.
Hanley K, Jiang Y, He SS, Friedman M, Elias PM, Bikle DD, Williams ML, Feingold KR: Keratinocyte differentiation is stimulated by activators of the nuclear hormone receptor PPARalpha. J Invest Dermatol 1998;110:368–375.
43.
He TC, Chan TA, Vogelstein B, Kinzler KW: PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell 1999;99:335–345.
44.
Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W: The PPARalpha-leukotriene B4 pathway to inflammation control [see comments]. Nature 1996;384:39–43.
45.
Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK: The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 1998;391:79–82.
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