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Review article: Biomedical intelligence

Vol. 140 No. 3738 (2010)

Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels

  • A Yessoufou
  • W Wahli
DOI
https://doi.org/10.4414/smw.2010.13071
Cite this as:
Swiss Med Wkly. 2010;140:w13071
Published
13.09.2010

Abstract

Chronic disorders, such as obesity, diabetes, inflammation, non-alcoholic fatty liver disease and atherosclerosis, are related to alterations in lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPAR)α, PPARβ/δ and PPARγ are involved. These receptors form a subgroup of ligand-activated transcription factors that belong to the nuclear hormone receptor family. This review discusses a selection of novel PPAR functions identified during the last few years. The PPARs regulate processes that are essential for the maintenance of pregnancy and embryonic development. Newly found hepatic functions of PPARα are the mediation of female-specific gene repression and the protection of the liver from oestrogen induced toxicity. PPARα also controls lipid catabolism and is the target of hypolipidaemic drugs, whereas PPARγ controls adipocyte differentiation and regulates lipid storage; it is the target for the insulin sensitising thiazolidinediones used to treat type 2 diabetes. Activation of PPARβ/δ increases lipid catabolism in skeletal muscle, the heart and adipose tissue. In addition, PPARβ/δ ligands prevent weight gain and suppress macrophage derived inflammation. In fact, therapeutic benefits of PPAR ligands have been confirmed in inflammatory and autoimmune diseases, such as encephalomyelitis and inflammatory bowel disease. Furthermore, PPARs promote skin wound repair. PPARα favours skin healing during the inflammatory phase that follows injury, whilst PPARβ/δ enhances keratinocyte survival and migration. Due to their collective functions in skin, PPARs represent a major research target for our understanding of many skin diseases. Taken altogether, these functions suggest that PPARs serve as physiological sensors in different stress situations and remain valuable targets for innovative therapies.

References

  1. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 2004;25(1):4–7. Review.
  2. Desvergne B, Wahli W. Peroxisome proliferator activated receptors: nuclear control of metabolism. Endocr Rev. 1999;20:649–88.
  3. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W. Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors. Cell. 1992;68:879–87.
  4. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–50.
  5. Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999;97:1–3.
  6. Wahli W. Peroxisome proliferator-activated receptors (PPARs): from metabolic control to epidermal wound healing. Swiss Med Wkly. 2002;132(7-8):83–91.
  7. Kota BP, Huang TH, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res. 2005;51:85–94.
  8. Berger JP, Akiyama TE, Meinke PT. PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci. 26(5):244–51.
  9. Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, et al. International Union of Pharmacology. LXI. Peroxisome proliferator-activator receptors. Pharmacol Rev. 2006;58(4):726–41.
  10. Zoete V, Grosdidier A, Michielin O. Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim. Biophys Acta. 2007;1771(8):915–25.
  11. Yu S, Reddy, JK. Transcription coactivators for peroxisome proliferator-activated receptors. Biochim Biophys Acta. 2007;1771(8):936–51.
  12. Guan HP, Ishizuka T, Chui PC, Lehrke M, Lazar MA. Corepressors selectively control the transcriptional activity of PPARγ in adipocytes. Genes Dev. 2005;19(4):453–61.
  13. Leuenberger N, Pradervand S, Wahli W. Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice. J Clin Invest. 2009;119(10):3138–48.
  14. Michalik L, Wahli W. Involvement of PPAR nuclear receptors in tissue injury and wound repair. J Clin Invest. 2006;116(3):598–606.
  15. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–4.
  16. Bosch FX., Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127:S5-16.
  17. Crockett ET, Spielman W, Dowlatshahi S, He J. Sex differences in inflammatory cytokine production in hepatic ischemia-reperfusion. J Inflamm. (Lond.). 2006;3:16.
  18. Mittendorfer B. Sexual dimorphism in human lipid metabolism. J Nutr. 2005;135:681–6.
  19. Anzenbacher P, Anzenbacherova E. Cytochromes P450 and metabolism of xenobiotics. Cell Mol Life Sci. 2001;58:737–47.
  20. Wang H, Zhao Y, Bradbury JA, Graves JP, Foley J, Blaisdell JA, et al. Cloning, expression, and characterization of three new mouse cytochrome p450 enzymes and partial characterization of their fatty acid oxidation activities. Mol Pharmacol. 2004;65(5):1148–58.
  21. Lamba V, Lamba J, Yasuda K, Strom S, Davila J, Hancock ML, et al. Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J Pharmacol Exp Ther. 2003;307(3):906–22.
  22. Stapleton G, Steel M, Richardson M, Mason JO, Rose KA, Morris RG, et al. A novel cytochrome P450 expressed primarily in brain. J Biol Chem. 1995;270(50):29739–45.
  23. Martin C, Bean R, Rose K, Habib F, Seckl J. Cyp7b1 catalyses the 7alpha-hydroxylation of dehydroepiandrosterone and 25-hydroxycholesterol in rat prostate. Biochem J. 2001;355:509–15.
  24. Pettersson H, Holmberg L, Axelson M, Norlin M. CYP7B1-mediated metabolism of dehydroepiandrosterone and 5-alpha-androstane -3beta,17beta-diol--potential role(s) for estrogen signaling. FEBS J. 2008;275:1778–89.
  25. Tang W, Eggertsen G, Chiang JY, Norlin M. Estrogen-mediated regulation of CYP7B1: a possible role for controlling DHEA levels in human tissues. J Steroid Biochem Mol Biol. 2006;100:42–51.
  26. Umetani M, Domoto H, Gormley AK, Yuhanna IS, Cummins CL, Javitt NB, et al. 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat Med. 2007;13(10):1185–92.
  27. Yamamoto Y, Moore R, Hess HA, Guo GL, Gonzalez FJ, Korach KS, et al. Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity. J Biol Chem. 2006;281:16625–31.
  28. Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis. 2007;2:26.
  29. Michalik L, Desvergne B, Wahli W. Peroxisome proliferator-activated receptors and cancers: complex stories. Nature Rev Cancer. 2004;4(1):61–70.
  30. Rotman N, Michalik L, Desvergne B, Wahli W. PPARs in fetal and early postnatal development. Adv Develop Biol. 2006;16:33–64.
  31. Hashimoto T, Cook WS, Qi C, Yeldandi AV, Reddy JK, Rao MS. Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem. 2000;275:28918–28.
  32. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest. 1999;103:1489–98.
  33. Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci. USA 1999;96:7473–8.
  34. Martin G, Schoonjans K, Lefebvre AM, Staels B, Auwerx J. Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARalpha and PPARgamma activators. J Biol Chem. 1997;272:28210–7.
  35. Sato O, Kuriki C, Fukui Y, Motojima K. Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor alpha and gamma ligands. J Biol Chem. 2002;277:15703–11.
  36. Crisafulli C, Bruscoli S, Esposito E, Mazzon E, Di Paola R, Genovese T, et al. PPAR-alpha contributes to the anti-inflammatory activity of 17beta-estradiol. J Pharmacol Exp Ther. 2009;331(3):796–807.
  37. Lemberger T, Saladin R, Vázquez M, Assimacopoulos F, Staels B, Desvergne B, et al. Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J Biol Chem. 1996;271(3):1764–9.
  38. Rotman N, Wahli W. Fatty acid synthesis and PPARalpha hand in hand. Chem Biol. 2009;16(8):801–2.
  39. Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J, et al. Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell. 2009;138(3):476–88.
  40. Yessoufou A, Hichami A, Besnard P, Moutairou K, Khan NA. Peroxisome proliferator-activated receptor alpha deficiency increases the risk of maternal abortion and neonatal mortality in murine pregnancy with or without diabetes mellitus: Modulation of T cell differentiation. Endocrinology. 2006;147(9):4410–8.
  41. Hashimoto F, Oguchi Y, Morita M, Matsuoka K, Takeda S, Kimura M, et al. PPAR-alpha agonists clofibrate and gemfibrozil inhibit cell growth, down-regulate hCG and up-regulate progesterone secretions in immortalized human trophoblast cells. Biochem Pharmacol. 2004;68:313–21.
  42. Michalik L, Desvergne B, Dreyer C, Gavillet M, Laurini RN, Wahli W. PPAR expression and function during vertebrate development. Int J Dev Biol. 2002;46:105–14.
  43. Wang Q, Fujii H, Knipp GT. Expression of PPAR and RXR isoforms in the developing rat and human term placentas. Placenta. 2002;23:661–71.
  44. Tontonoz P, Hu E, Graves R, Budavari A, Spiegelman B. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994;8(10):1224–34.
  45. Forman B, Tontonoz P, Chen J, Brun R, Spiegelman B, Evans R. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell. 1995;83:803–12.
  46. Patsouris D, Reddy JK, Muller M, Kersten S. Peroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression. Endocrinology. 2006;147:1508–16.
  47. Yu S, Matsusue K, Kashireddy P, Cao WQ, Yeldandi V, Yeldandi AV, et al. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression. J Biol Chem. 2003;278:498–505.
  48. Wahli W. PPAR gamma: ally and foe in bone metabolism. Cell Metab. 2008;7(3):188–90.
  49. Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung UI, Kubota N, et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest. 2004;113:846–55.
  50. Cock TA, Back J, Elefteriou F, Karsenty G, Kastner P, Chan S, et al. Enhanced bone formation in lipodystrophic PPARgamma(hyp/hyp) mice relocates haematopoiesis to the spleen. EMBO Rep. 2004;5:1007–12.
  51. Nadra K, Anghel SI, Joye E, Tan NS, Basu-Modak S, Trono D, et al. Differentiation of trophoblast giant cells and their metabolic functions are dependent on peroxisome proliferator-activated receptor β/δ. Mol Cell Biol. 2006;26:3266–81.
  52. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell. 1999;4:585–95.
  53. Barish GD, Narkar VA, Evans RM. PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest. 2006;116:590–7.
  54. Lim H, Dey SK. PPAR delta functions as a prostacyclin receptor in blastocyst implantation. Trends Endocrinol Metab. 2000;11:137–42.
  55. Peters JM, Lee SS, Li W, Ward JM, Gavrilova O, Everett C, et al. Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta (delta). Mol Cell Biol. 2000;20:5119–28.
  56. Mano H, Kimura C, Fujisawa Y, Kameda T, Watanabe-Mano M, Kaneko H, et al. Cloning and function of rabbit peroxisome proliferator-activated receptor delta/beta in mature osteoclasts. J Biol Chem. 2000;275:8126–32.
  57. Hansen JB, Zhang H, Rasmussen TH, Petersen RK, Flindt EN, Kristiansen K. Peroxisome proliferator-activated receptor-δ (PPARδ)-mediated regulation of preadipocyte proliferation and gene expression is dependent on cAMP signaling. J Biol Chem. 2001;276:3175–82.
  58. Schuler M, Ali F, Chambon C, Duteil D, Bornert JM, Tardivel A, et al. PGC1alpha expression is controlled in skeletal muscles by PPARbeta, whose ablation results in fiber-type switching, obesity, and type 2 diabetes. Cell Metab. 2006;4(5):407–14.
  59. Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci. USA 2001;98:5306–11.
  60. Krey G, Braissant O, L’Horset F, Kalkhoven E, Perroud M, Parker MG, et al. Fatty acids, eicosanoids, and hypolipidaemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol. 1997;11:779–91.
  61. Escher P, Braissant O, Basu-Modak S, Michalik L, Wahli W, Desvergne B. Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology. 2001;142:4195–202.
  62. Hoekstra M, Kruijt JK, Van Eck M, Van Berkel TJ. Specific gene expression of ATP-binding cassette transporters and nuclear hormone receptors in rat liver parenchymal, endothelial, and Kupffer cells. J Biol Chem. 2003;278:25448–53.
  63. Shan W, Nicol CJ, Ito S, Bility MT, Kennett MJ, Ward JM, et al. Peroxisome proliferator-activated receptor-beta/delta protects against chemically induced liver toxicity in mice. Hepatology. 2008;47:225–35.
  64. Sanderson LM, Boekschoten MV, Desvergne B, Müller M, Kersten S. Transcriptional profiling reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver. Physiol Genomics. 2010;41(1):42–52.
  65. Ravnskjaer K, Frigerio F, Boergesen M, Nielsen T, Maechler P, Mandrup S. PPARδ is a fatty acid sensor, which enhances mitochondrial oxidation in insulin-secreting cells and protects against fatty acid induced dysfunction. J Lipid Res. 2009 Nov 30. [Epub ahead of print] PMID: 19965574.
  66. Coll T, Rodrïguez-Calvo R, Barroso E, Serrano L, Eyre E, Palomer X, et al. Peroxisome proliferator-activated receptor (PPAR) beta/delta: a new potential therapeutic target for the treatment of metabolic syndrome. Curr Mol Pharmacol. 2009;2(1):46–55.
  67. Kielian T, Drew PD. Effects of perixosome proliferator activated receptor-g agonists on central nervous system inflammation. J Neurosci Res. 2003;71:315–25.
  68. Lovett-Racke AE, Hussain RZ, Northrop S, Choy J, Rocchini A, Matthes L, et al. Peroxisome proliferator-activated receptor alpha agonists as therapy for autoimmune disease. J Immunol. 2004;172:5790–8.
  69. Dubuquoy L, Rousseaux C, Thuru X, Peyrin-Biroulet L, Romano O, Chavatte P, et al. PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut. 2006;55:1341–9.
  70. Polak PE, Kalinin S, Dello Russo C, Gavrilyuk V, Sharp A, Peters JM, et al. Protective effects of a peroxisome proliferator activated receptor-b/d agonist in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2005;168:65–75.
  71. Attakpa E, Hichami A, Simonin AM, Sansón EG, Dramane KL, Khan NA. Docosahexaenoic acid modulates the expression of T-bet and GATA-3 transcription factors, independently of PPARalpha, through suppression of MAP kinase activation. Biochimie. 2009;91(11-12):1359–65.
  72. Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, et al. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-κB and AP-1. J Biol Chem. 1999;274:32048–54.
  73. Takano H, Hasegawa H, Nagai T, Komuro I. The role of PPARγ dependent pathway in the development of cardiac hypertrophy. Drugs Today. (Barc) 2003;39:347–57.
  74. Shah YM, Morimura K, Gonzalez FJ. Expression of peroxisome proliferator activated receptor-g in macrophage suppresses experimentally induced colitis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G657–66.
  75. Adachi M, Kurotani R, Morimura K, Shah Y, Sanford M, Madison BB, et al. Peroxisome proliferator activated receptor gamma in colonic epithelial cells protects against experimental inflammatory bowel disease. Gut. 2006;55:1104–11.
  76. Straus DS, Glass CK. Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol. 2007;28:551–8.
  77. Okamoto H, Iwamoto T, Kotake S, Momohara S, Yamanaka H, Kamatani N. Inhibition of NF-κB signaling by fenofibrate, a peroxisome proliferator-activated receptor-α ligand, presents a therapeutic strategy for rheumatoid arthritis. Clin Exp Rheumatol. 2005;23:323-30.
  78. Madej A, Okopien B, Kowalski J, Zielinski M, Wysocki J, Szygula B, et al. Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyper-lipoproteinemia IIb. Int J Clin Pharmacol Ther. 1998;36:345–9.
  79. Michalik L, Wahli W. PPARs mediate lipid signaling in inflammation and cancer. PPAR Res. 2008;2008:1–15.
  80. Michalik L, B. Desvergne B, Tan NS, Basu-Modak S, Escher P, Rieusset J, et al. Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)α and PPARβ mutant mice. J Cell Biol. 2001;154:799–814.
  81. Tan NS, Michalik L, Noy N, Yasmin R, Pacot C, Heim M, et al. Critical roles of PPAR beta/delta in keratinocyte response to inflammation. Genes Dev. 2001;15:3263–77.
  82. Michalik L, Feige JN, Gelman L, Pedrazzini T, Keller H, Desvergne B, et al. Selective expression of a dominant-negative form of peroxisome proliferator-activated receptor in keratinocytes leads to impaired epidermal healing. Mol Endocrinol. 2005;19:2335–48.
  83. Chong HC, Tan MJ, Philippe V, Tan SH, Tan CK, Ku CW, et al. Regulation of epithelial-mesenchymal IL-1 signaling by PPARbeta/delta is essential for skin homeostasis and wound healing. J Cell Biol. 2009;184(6):817–31.
  84. Hanley K, Jiang Y, Crumrine D, Bass NM, Appel R, Elias PM, et al. Activators of the nuclear hormone receptors PPARalpha and FXR accelerate the development of the fetal epidermal permeability barrier, J Clin Invest. 1997;100:705–12.
  85. Mao-Qiang M, Fowler AJ, Schmuth M, Lau P, Chang S, Brown BE, et al. Peroxisome-proliferator-activated receptor (PPAR)-gamma activation stimulates keratinocyte differentiation. J Invest Dermatol. 2004;123:305–12.