Journal of Molecular Medicine

, Volume 83, Issue 10, pp 774–785 | Cite as

Peroxisome proliferator-activated receptor-α and liver cancer: where do we stand?

  • Jeffrey M. Peters
  • Connie Cheung
  • Frank J. Gonzalez
Review

Abstract

The peroxisome proliferator-activated receptor-α (PPARα), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPARα is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPARα occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPARα agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPARα also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPARα. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPARα target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPARα in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPARα agonist-induced hepatocarcinogenesis.

Keywords

Peroxisome proliferator-activated receptor-α (PPARα) Hepatocarcinogenesis Fibrates Human cancer 

References

  1. 1.
    Hess R, Staubli W, Reiss W (1965) Nature of the hepatomegalic effect produced by ethyl-chlorphenoxyisobutyrate in the rat. Nature 208:856–858Google Scholar
  2. 2.
    Reddy JK, Krishnakantha TP (1975) Hepatic peroxisome proliferation: induction by two novel compounds structurally unrelated to clofibrate. Science 190:787–789PubMedGoogle Scholar
  3. 3.
    Reddy JK, Azarnoff DL, Hignite CE (1980) Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature 283:397–398Google Scholar
  4. 4.
    Reddy JK, Lalwai ND (1983) Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit Rev Toxicol 12:1–58PubMedGoogle Scholar
  5. 5.
    Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347:645–650Google Scholar
  6. 6.
    Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W (1992) Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68:879–887CrossRefPubMedGoogle Scholar
  7. 7.
    Kliewer SA, Forman BM, Blumberg B et al (1994) Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A 91:7355–7359PubMedGoogle Scholar
  8. 8.
    Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649–688CrossRefPubMedGoogle Scholar
  9. 9.
    Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A 94:4312–4317CrossRefPubMedGoogle Scholar
  10. 10.
    Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W (1993) Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor–retinoid X receptor heterodimers. Proc Natl Acad Sci U S A 90:2160–2164PubMedGoogle Scholar
  11. 11.
    Kliewer SA, Sundseth SS, Jones SA et al (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U S A 94:4318–4323CrossRefPubMedGoogle Scholar
  12. 12.
    Krey G, Braissant O, L’Horset F et al (1997) Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 11:779–791CrossRefPubMedGoogle Scholar
  13. 13.
    Fan CY, Pan J, Usuda N, Yeldandi AV, Rao MS, Reddy JK (1998) Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism. J Biol Chem 273:15639–15645Google Scholar
  14. 14.
    Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53:409–435CrossRefPubMedGoogle Scholar
  15. 15.
    Shearer BG, Hoekstra WJ (2003) Recent advances in peroxisome proliferator-activated receptor science. Curr Med Chem 10:267–280PubMedGoogle Scholar
  16. 16.
    Sumanasekera WK, Tien ES, Davis JW II, Turpey R, Perdew GH, Vanden Heuvel JP (2003) Heat shock protein-90 (Hsp90) acts as a repressor of peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARbeta activity. Biochemistry 42:10726–10735CrossRefPubMedGoogle Scholar
  17. 17.
    Sumanasekera WK, Tien ES, Turpey R, Vanden Heuvel JP, Perdew GH (2003) Evidence that peroxisome proliferator-activated receptor alpha is complexed with the 90-kDa heat shock protein and the hepatitis virus B X-associated protein 2. J Biol Chem 278:4467–4473Google Scholar
  18. 18.
    Glass CK, Rosenfeld MG (2000) The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14:121–141PubMedGoogle Scholar
  19. 19.
    Puigserver P, Spiegelman BM (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev 24:78–90CrossRefPubMedGoogle Scholar
  20. 20.
    Puigserver P, Adelmant G, Wu Z et al (1999) Activation of PPARgamma coactivator-1 through transcription factor docking. Science 286:1368–1371CrossRefPubMedGoogle Scholar
  21. 21.
    Jia Y, Qi C, Kashireddi P et al (2004) Transcription coactivator PBP, the peroxisome proliferator-activated receptor (PPAR)-binding protein, is required for PPARalpha-regulated gene expression in liver. J Biol Chem 279:24427–24434Google Scholar
  22. 22.
    Mandard S, Muller M, Kersten S (2004) Peroxisome proliferator-activated receptor alpha target genes. Cell Mol Life Sci 61:393–416CrossRefPubMedGoogle Scholar
  23. 23.
    Cherkaoui-Malki M, Meyer K, Cao WQ et al (2001) Identification of novel peroxisome proliferator-activated receptor alpha (PPARalpha) target genes in mouse liver using cDNA microarray analysis. Gene Expr 9:291–304Google Scholar
  24. 24.
    Chu R, Lim H, Brumfield L et al (2004) Protein profiling of mouse livers with peroxisome proliferator-activated receptor alpha activation. Mol Cell Biol 24:6288–6297CrossRefPubMedGoogle Scholar
  25. 25.
    Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137:354–366CrossRefPubMedGoogle Scholar
  26. 26.
    Escher P, Braissant O, Basu-Modak S, Michalik L, Wahli W, Desvergne B (2001) Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology 142:4195–4202CrossRefPubMedGoogle Scholar
  27. 27.
    Yeldandi AV, Rao MS, Reddy JK (2000) Hydrogen peroxide generation in peroxisome proliferator-induced oncogenesis. Mutat Res 448:159–177PubMedGoogle Scholar
  28. 28.
    Peters JM, Cattley RC, Gonzalez FJ (1997) Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis 18:2029–2033CrossRefPubMedGoogle Scholar
  29. 29.
    Hays T, Rusyn I, Burns AM et al (2005) Role of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) in bezafibrate-induced hepatocarcinogenesis and cholestasis. Carcinogenesis 26:219–227CrossRefPubMedGoogle Scholar
  30. 30.
    Klaunig JE, Babich MA, Baetcke KP et al (2003) PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol 33:655–780PubMedGoogle Scholar
  31. 31.
    Moya-Camarena SY, Vanden Heuvel JP, Blanchard SG, Leesnitzer LA, Belury MA (1999) Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARalpha. J Lipid Res 40:1426–1433PubMedGoogle Scholar
  32. 32.
    Mukherjee R, Sun S, Santomenna L et al (2002) Ligand and coactivator recruitment preferences of peroxisome proliferator activated receptor alpha. J Steroid Biochem Mol Biol 81:217–225CrossRefPubMedGoogle Scholar
  33. 33.
    Gould SJ, Keller GA, Subramani S (1988) Identification of peroxisomal targeting signals located at the carboxy terminus of four peroxisomal proteins. J Cell Biol 107:897–905CrossRefPubMedGoogle Scholar
  34. 34.
    Gould SJ, Keller GA, Hosken N, Wilkinson J, Subramani S (1989) A conserved tripeptide sorts proteins to peroxisomes. J Cell Biol 108:1657–1664CrossRefPubMedGoogle Scholar
  35. 35.
    Marsman DS, Cattley RC, Conway JG, Popp JA (1988) Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats. Cancer Res 48:6739–6744PubMedGoogle Scholar
  36. 36.
    Nemali MR, Reddy MK, Usuda N et al (1989) Differential induction and regulation of peroxisomal enzymes: predictive value of peroxisome proliferation in identifying certain nonmutagenic carcinogens. Toxicol Appl Pharmacol 97:72–87CrossRefPubMedGoogle Scholar
  37. 37.
    Reddy JK, Lalwani ND, Reddy MK, Qureshi SA (1982) Excessive accumulation of autofluorescent lipofuscin in the liver during hepatocarcinogenesis by methyl clofenapate and other hypolipidemic peroxisome proliferators. Cancer Res 42:259–266PubMedGoogle Scholar
  38. 38.
    Marsman DS, Goldsworthy TL, Popp JA (1992) Contrasting hepatocytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid. Carcinogenesis 13:1011–1017PubMedGoogle Scholar
  39. 39.
    Ikeda H, Tauchi H, Shimasaki H, Ueta N, Sato T (1985) Age and organ difference in amount and distribution of autofluorescent granules in rats. Mech Ageing Dev 31:139–146PubMedGoogle Scholar
  40. 40.
    Glauert HP, Beaty MM, Clark TD, Greenwell WS, Chow CK (1990) Effect of dietary selenium on the induction of altered hepatic foci and hepatic tumors by the peroxisome proliferator ciprofibrate. Nutr Cancer 14:261–271PubMedGoogle Scholar
  41. 41.
    Rao MS, Lalwani ND, Watanabe TK, Reddy JK (1984) Inhibitory effect of antioxidants ethoxyquin and 2(3)-tert-butyl-4-hydroxyanisole on hepatic tumorigenesis in rats fed ciprofibrate, a peroxisome proliferator. Cancer Res 44:1072–1076PubMedGoogle Scholar
  42. 42.
    Glauert HP, Srinivasan S, Tatum VL et al (1992) Effects of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on hepatic cellular antioxidants and lipid peroxidation in rats. Biochem Pharmacol 43:1353–1359CrossRefPubMedGoogle Scholar
  43. 43.
    O’Brien ML, Twaroski TP, Cunningham ML, Glauert HP, Spear BT (2001) Effects of peroxisome proliferators on antioxidant enzymes and antioxidant vitamins in rats and hamsters. Toxicol Sci 60:271–278CrossRefPubMedGoogle Scholar
  44. 44.
    Cattley RC, DeLuca J, Elcombe C et al (1998) Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? Regul Toxicol Pharmacol 27:47–60CrossRefGoogle Scholar
  45. 45.
    Rusyn I, Asakura S, Pachkowski B et al (2004) Expression of base excision DNA repair genes is a sensitive biomarker for in vivo detection of chemical-induced chronic oxidative stress: identification of the molecular source of radicals responsible for DNA damage by peroxisome proliferators. Cancer Res 64:1050–1057PubMedGoogle Scholar
  46. 46.
    Fan CY, Pan J, Chu R et al (1996) Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene. J Biol Chem 271:24698–24710Google Scholar
  47. 47.
    O’Brien ML, Spear BT, Glauert HP (2005) Role of oxidative stress in peroxisome proliferator-mediated carcinogenesis. Crit Rev Toxicol 35:61–88CrossRefGoogle Scholar
  48. 48.
    Rose ML, Rusyn I, Bojes HK, Belyea J, Cattley RC, Thurman RG (2000) Role of Kupffer cells and oxidants in signaling peroxisome proliferator-induced hepatocyte proliferation. Mutat Res 448:179–192PubMedGoogle Scholar
  49. 49.
    Peters JM, Aoyama T, Cattley RC, Nobumitsu U, Hashimoto T, Gonzalez FJ (1998) Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver. Carcinogenesis 19:1989–1994CrossRefPubMedGoogle Scholar
  50. 50.
    Anderson SP, Dunn CS, Cattley RC, Corton JC (2001) Hepatocellular proliferation in response to a peroxisome proliferator does not require TNFalpha signaling. Carcinogenesis 22:1843–1851CrossRefPubMedGoogle Scholar
  51. 51.
    Lawrence JW, Wollenberg GK, DeLuca JG (2001) Tumor necrosis factor alpha is not required for WY14,643-induced cell proliferation. Carcinogenesis 22:381–386CrossRefPubMedGoogle Scholar
  52. 52.
    Roberts RA, James NH, Hasmall SC et al (2000) Apoptosis and proliferation in nongenotoxic carcinogenesis: species differences and role of PPARalpha. Toxicol Lett 112–113:49–57Google Scholar
  53. 53.
    Fruchart JC, Brewer HB Jr, Leitersdorf E (1998) Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Fibrate Consensus Group. Am J Cardiol 81:912–917. ReviewCrossRefPubMedGoogle Scholar
  54. 54.
    Bility M, Thompson JT, McKee RH et al (2004) Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters. Toxicol Sci 82:170–182Google Scholar
  55. 55.
    Hasmall SC, James NH, Macdonald N, Soames AR, Roberts RA (2000) Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression. Arch Toxicol 74:85–91CrossRefPubMedGoogle Scholar
  56. 56.
    Lawrence JW, Li Y, Chen S et al (2001) Differential gene regulation in human versus rodent hepatocytes by peroxisome proliferator-activated receptor (PPAR) alpha. PPARalpha fails to induce peroxisome proliferation-associated genes in human cells independently of the level of receptor expression. J Biol Chem 276:31521–31527Google Scholar
  57. 57.
    Maloney EK, Waxman DJ (1999) Trans-activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals. Toxicol Appl Pharmacol 161:209–218CrossRefPubMedGoogle Scholar
  58. 58.
    Sher T, Yi HF, McBride OW, Gonzalez FJ (1993) cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry 32:5598–5604Google Scholar
  59. 59.
    Anthony LE, Schmucker DL, Mooney JS, Jones AL (1978) A quantitative analysis of fine structure and drug metabolism in livers of clofibrate-treated young adult and retired breeder rats. J Lipid Res 19:154–165PubMedGoogle Scholar
  60. 60.
    Hanefeld M, Kemmer C, Kadner E (1983) Relationship between morphological changes and lipid-lowering action of p-chlorphenoxyisobutyric acid (CPIB) on hepatic mitochondria and peroxisomes in man. Atherosclerosis 46:239–246PubMedGoogle Scholar
  61. 61.
    Hanefeld M, Kemmer C, Leonhardt W, Kunze KD, Jaross W, Haller H (1980) Effects of p-chlorophenoxyisobutyric acid (CPIB) on the human liver. Atherosclerosis 36:159–172PubMedGoogle Scholar
  62. 62.
    De La Iglesia FA, Lewis JE, Buchanan RA, Marcus EL, McMahon G (1982) Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment. Atherosclerosis 43:19–37PubMedGoogle Scholar
  63. 63.
    Blumcke S, Schwartzkopff W, Lobeck H, Edmondson NA, Prentice DE, Blane GF (1983) Influence of fenofibrate on cellular and subcellular liver structure in hyperlipidemic patients. Atherosclerosis 46:105–116PubMedGoogle Scholar
  64. 64.
    Gariot P, Barrat E, Drouin P et al (1987) Morphometric study of human hepatic cell modifications induced by fenofibrate. Metabolism 36:203–210CrossRefPubMedGoogle Scholar
  65. 65.
    Doull J, Cattley R, Elcombe C et al (1999) A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA Risk Assessment Guidelines. Regul Toxicol Pharmacol 29:327–357CrossRefPubMedGoogle Scholar
  66. 66.
    Watanabe T, Horie S, Yamada J et al (1989) Species differences in the effects of bezafibrate, a hypolipidemic agent, on hepatic peroxisome-associated enzymes. Biochem Pharmacol 38:367–371CrossRefPubMedGoogle Scholar
  67. 67.
    Makowska JM, Gibson GG, Bonner FW (1992) Species differences in ciprofibrate induction of hepatic cytochrome P450 4A1 and peroxisome proliferation. J Biochem Toxicol 7:183–191Google Scholar
  68. 68.
    Lake BG, Evans JG, Gray TJ, Korosi SA, North CJ (1989) Comparative studies on nafenopin-induced hepatic peroxisome proliferation in the rat, Syrian hamster, guinea pig, and marmoset. Toxicol Appl Pharmacol 99:148–160Google Scholar
  69. 69.
    Graham MJ, Wilson SA, Winham MA et al (1994) Lack of peroxisome proliferation in marmoset liver following treatment with ciprofibrate for 3 years. Fundam Appl Toxicol 22:58–64CrossRefPubMedGoogle Scholar
  70. 70.
    Lalwani ND, Reddy MK, Ghosh S, Barnard SD, Molello JA, Reddy JK (1985) Induction of fatty acid beta-oxidation and peroxisome proliferation in the liver of rhesus monkeys by DL-040, a new hypolipidemic agent. Biochem Pharmacol 34:3473–3482CrossRefPubMedGoogle Scholar
  71. 71.
    Reddy JK, Lalwani ND, Qureshi SA, Reddy MK, Moehle CM (1984) Induction of hepatic peroxisome proliferation in nonrodent species, including primates. Am J Pathol 114:171–183PubMedGoogle Scholar
  72. 72.
    Hoivik DJ, Qualls CW Jr, Mirabile RC et al (2004) Fibrates induce hepatic peroxisome and mitochondrial proliferation without overt evidence of cellular proliferation and oxidative stress in cynomolgus monkeys. Carcinogenesis 25:1757–1769CrossRefPubMedGoogle Scholar
  73. 73.
    Reddy JK, Goel SK, Nemali MR et al (1986) Transcriptional regulation of peroxisomal fatty acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase in rat liver by peroxisome proliferators. Proc Natl Acad Sci U S A 83:1747–1751PubMedGoogle Scholar
  74. 74.
    Roglans N, Bellido A, Rodriguez C et al (2002) Fibrate treatment does not modify the expression of acyl coenzyme A oxidase in human liver. Clin Pharmacol Ther 72:692–701Google Scholar
  75. 75.
    Reddy JK, Rao MS, Azarnoff DL, Sell S (1979) Mitogenic and carcinogenic effects of a hypolipidemic peroxisome proliferator, [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14, 643), in rat and mouse liver. Cancer Res 39:152–161PubMedGoogle Scholar
  76. 76.
    Moody DE, Rao MS, Reddy JK (1977) Mitogenic effect in mouse liver induced by a hypolipidemic drug, nafenopin. Virchows Arch B Cell Pathol 23:291–296PubMedGoogle Scholar
  77. 77.
    Parzefall W, Berger W, Kainzbauer E, Teufelhofer O, Schulte-Hermann R, Thurman RG (2001) Peroxisome proliferators do not increase DNA synthesis in purified rat hepatocytes. Carcinogenesis 22:519–523CrossRefPubMedGoogle Scholar
  78. 78.
    Karam WG, Ghanayem BI (1997) Induction of replicative DNA synthesis and PPAR alpha-dependent gene transcription by Wy-14 643 in primary rat hepatocyte and non-parenchymal cell co-cultures. Carcinogenesis 18:2077–2083CrossRefPubMedGoogle Scholar
  79. 79.
    Hall M, Matthews A, Webley L, Harling R (1999) Effects of di-isononyl phthalate (DINP) on peroxisomal markers in the marmoset-DINP is not a peroxisome proliferator. J Toxicol Sci 24:237–244Google Scholar
  80. 80.
    Huttunen JK, Heinonen OP, Manninen V et al (1994) The Helsinki Heart Study: an 8.5-year safety and mortality follow-up. J Intern Med 235:31–39PubMedGoogle Scholar
  81. 81.
    Frick MH, Elo O, Haapa K et al (1987) Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 317:1237–1245PubMedGoogle Scholar
  82. 82.
    Investigators CoP (1978) A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J 40:1069–1118Google Scholar
  83. 83.
    Investigators CoP (1980) W.H.O. cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Lancet 2:379–385Google Scholar
  84. 84.
    Investigators CoP (1984) WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet 2:600–604Google Scholar
  85. 85.
    Sapone A, Peters JM, Sakai S et al (2000) The human peroxisome proliferator-activated receptor alpha gene: identification and functional characterization of two natural allelic variants. Pharmacogenetics 10:321–333CrossRefPubMedGoogle Scholar
  86. 86.
    Flavell DM, Pineda Torra I, Jamshidi Y et al (2000) Variation in the PPARalpha gene is associated with altered function in vitro and plasma lipid concentrations in type II diabetic subjects. Diabetologia 43:673–680CrossRefPubMedGoogle Scholar
  87. 87.
    Vohl MC, Lepage P, Gaudet D et al (2000) Molecular scanning of the human PPARa gene. Association of the L162V mutation with hyperapobetalipoproteinemia. J Lipid Res 41:945–952PubMedGoogle Scholar
  88. 88.
    Brisson D, Ledoux K, Bosse Y et al (2002) Effect of apolipoprotein E, peroxisome proliferator-activated receptor alpha and lipoprotein lipase gene mutations on the ability of fenofibrate to improve lipid profiles and reach clinical guideline targets among hypertriglyceridemic patients. Pharmacogenetics 12:313–320CrossRefPubMedGoogle Scholar
  89. 89.
    Bosse Y, Pascot A, Dumont M et al (2002) Influences of the PPAR alpha-L162V polymorphism on plasma HDL(2)-cholesterol response of abdominally obese men treated with gemfibrozil. Genet Med 4:311–315PubMedGoogle Scholar
  90. 90.
    Flavell DM, Jamshidi Y, Hawe E et al (2002) Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease. Circulation 105:1440–1445CrossRefPubMedGoogle Scholar
  91. 91.
    Robitaille J, Brouillette C, Houde A et al (2004) Association between the PPARalpha-L162V polymorphism and components of the metabolic syndrome. J Hum Genet 49:482–489CrossRefPubMedGoogle Scholar
  92. 92.
    Puckey LH, Knight BL (2001) Variation at position 162 of peroxisome proliferator-activated receptor alpha does not influence the effect of fibrates on cholesterol or triacylglycerol concentrations in hyperlipidaemic subjects. Pharmacogenetics 11:619–624CrossRefPubMedGoogle Scholar
  93. 93.
    Yamakawa-Kobayashi K, Ishiguro H, Arinami T, Miyazaki R, Hamaguchi H (2002) A Val227Ala polymorphism in the peroxisome proliferator activated receptor alpha (PPARalpha) gene is associated with variations in serum lipid levels. J Med Genet 39:189–191CrossRefPubMedGoogle Scholar
  94. 94.
    Gervois P, Torra IP, Chinetti G et al (1999) A truncated human peroxisome proliferator-activated receptor alpha splice variant with dominant negative activity. Mol Endocrinol 13:1535–1549CrossRefPubMedGoogle Scholar
  95. 95.
    Leung KC (2004) Regulation of cytokine receptor signaling by nuclear hormone receptors: a new paradigm for receptor interaction. DNA Cell Biol 23:463–474CrossRefPubMedGoogle Scholar
  96. 96.
    Waxman DJ (1999) P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch Biochem Biophys 369:11–23CrossRefPubMedGoogle Scholar
  97. 97.
    Palmer CN, Hsu MH, Griffin KJ, Raucy JL, Johnson EF (1998) Peroxisome proliferator activated receptor-alpha expression in human liver. Mol Pharmacol 53:14–22PubMedGoogle Scholar
  98. 98.
    Tugwood JD, Aldridge TC, Lambe KG, Macdonald N, Woodyatt NJ (1996) Peroxisome proliferator-activated receptors: structures and function. Ann N Y Acad Sci 804:252–265Google Scholar
  99. 99.
    Walgren JE, Kurtz DT, McMillan JM (2000) Expression of PPAR(alpha) in human hepatocytes and activation by trichloroacetate and dichloroacetate. Res Commun Mol Pathol Pharmacol 108:116–132PubMedGoogle Scholar
  100. 100.
    Cheung C, Akiyama TE, Ward JM et al (2004) Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor-α. Cancer Res 64:3849–3854PubMedGoogle Scholar
  101. 101.
    Smith CL, O’Malley BW (2004) Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 25:45–71CrossRefPubMedGoogle Scholar
  102. 102.
    Varanasi U, Chu R, Huang Q, Castellon R, Yeldandi AV, Reddy JK (1998) Identification of a peroxisome proliferator-responsive element upstream of the human peroxisomal fatty acyl coenzyme A oxidase gene. J Biol Chem 273:30842Google Scholar
  103. 103.
    Varanasi U, Chu R, Huang Q, Castellon R, Yeldandi AV, Reddy JK (1996) Identification of a peroxisome proliferator-responsive element upstream of the human peroxisomal fatty acyl coenzyme A oxidase gene. J Biol Chem 271:2147–2155Google Scholar
  104. 104.
    Woodyatt NJ, Lambe KG, Myers KA, Tugwood JD, Roberts RA (1999) The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population: significance for species differences in response to PPs. Carcinogenesis 20:369–372CrossRefPubMedGoogle Scholar
  105. 105.
    Lambe KG, Woodyatt NJ, Macdonald N, Chevalier S, Roberts RA (1999) Species differences in sequence and activity of the peroxisome proliferator response element (PPRE) within the acyl CoA oxidase gene promoter. Toxicol Lett 110:119–127Google Scholar
  106. 106.
    Peters JM, Rusyn I, Rose ML, Gonzalez FJ, Thurman RG (2000) Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis. Carcinogenesis 21:823–826CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Jeffrey M. Peters
    • 1
  • Connie Cheung
    • 2
  • Frank J. Gonzalez
    • 2
  1. 1.Department of Veterinary Science and Center for Molecular Toxicology and CarcinogenesisThe Pennsylvania State UniversityUniversity ParkUSA
  2. 2.The Laboratory of MetabolismNational Cancer InstituteBethesdaUSA

Personalised recommendations