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. 1995 Aug;96(2):741–750. doi: 10.1172/JCI118118

Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor.

N Vu-Dac 1, K Schoonjans 1, V Kosykh 1, J Dallongeville 1, J C Fruchart 1, B Staels 1, J Auwerx 1
PMCID: PMC185258  PMID: 7635967

Abstract

In view of the evidence linking plasma high density lipoprotein (HDL)-cholesterol levels to a protective effect against coronary artery disease and the widespread use of fibrates in the treatment of hyperlipidemia, the goal of this study was to analyze the influence of fibrates on the expression of apolipoprotein (apo) A-II, a major protein constituent of HDL. Administration of fenofibrate (300 mg/d) to 16 patients with coronary artery disease resulted in a marked increase in plasma apo A-II concentrations (0.34 +/- 0.11 to 0.45 +/- 0.17 grams/liter; P < 0.01). This increase in plasma apo A-II was due to a direct effect on hepatic apo A-II production, since fenofibric acid induced apo A-II mRNA levels to 450 and 250% of control levels in primary cultures of human hepatocytes and in human hepatoblastoma HepG2 cells respectively. The induction in apo A-II mRNA levels was followed by an increase in apo A-II secretion in both cell culture systems. Transient transfection experiments of a reporter construct driven by the human apo A-II gene promoter indicated that fenofibrate induced apo A-II gene expression at the transcriptional level. Furthermore, several other peroxisome proliferators, such as the fibrate, Wy-14643, and the fatty acid, eicosatetraynoic acid (ETYA), also induced apo A-II gene transcription. Unilateral deletions and site-directed mutagenesis identified a sequence element located in the J-site of the apo A-II promoter mediating the responsiveness to fibrates and fatty acids. This element contains two imperfect half sites spaced by 1 oligonucleotide similar to a peroxisome proliferator responsive element (PPRE). Cotransfection assays showed that the peroxisome proliferator activated receptor (PPAR) transactivates the apo A-II promoter through this AII-PPRE. Gel retardation assays demonstrated that PPAR binds to the AII-PPRE with an affinity comparable to its binding affinity to the acyl coA oxidase (ACO)-PPRE. In conclusion, in humans fibrates increase plasma apo A-II concentrations by inducing hepatic apo A-II production. Apo A-II expression is regulated at the transcriptional level by fibrates and fatty acids via the interaction of PPAR with the AII-PPRE, thereby demonstrating the pivotal role of PPAR in controlling human lipoprotein metabolism.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alvares K., Fan C., Dadras S. S., Yeldandi A. V., Rachubinski R. A., Capone J. P., Subramani S., Iannaccone P. M., Rao M. S., Reddy J. K. An upstream region of the enoyl-coenzyme A hydratase/3-hydroxyacyl-coenzyme A dehydrogenase gene directs luciferase expression in liver in response to peroxisome proliferators in transgenic mice. Cancer Res. 1994 May 1;54(9):2303–2306. [PubMed] [Google Scholar]
  2. Auwerx J. Regulation of gene expression by fatty acids and fibric acid derivatives: an integrative role for peroxisome proliferator activated receptors. The Belgian Endocrine Society Lecture 1992. Horm Res. 1992;38(5-6):269–277. doi: 10.1159/000182557. [DOI] [PubMed] [Google Scholar]
  3. Barbaras R., Puchois P., Fruchart J. C., Ailhaud G. Cholesterol efflux from cultured adipose cells is mediated by LpAI particles but not by LpAI:AII particles. Biochem Biophys Res Commun. 1987 Jan 15;142(1):63–69. doi: 10.1016/0006-291x(87)90451-7. [DOI] [PubMed] [Google Scholar]
  4. Bardot O., Aldridge T. C., Latruffe N., Green S. PPAR-RXR heterodimer activates a peroxisome proliferator response element upstream of the bifunctional enzyme gene. Biochem Biophys Res Commun. 1993 Apr 15;192(1):37–45. doi: 10.1006/bbrc.1993.1378. [DOI] [PubMed] [Google Scholar]
  5. Bossu J. P., Chartier F. L., Vu-Dac N., Fruchart J. C., Laine B. Transcription of the human apolipoprotein A-II is down-regulated by the first intron of its gene. Biochem Biophys Res Commun. 1994 Jul 29;202(2):822–829. doi: 10.1006/bbrc.1994.2004. [DOI] [PubMed] [Google Scholar]
  6. Brewer H. B., Jr, Lux S. E., Ronan R., John K. M. Amino acid sequence of human apoLp-Gln-II (apoA-II), an apolipoprotein isolated from the high-density lipoprotein complex. Proc Natl Acad Sci U S A. 1972 May;69(5):1304–1308. doi: 10.1073/pnas.69.5.1304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cardot P., Chambaz J., Cladaras C., Zannis V. I. Regulation of the human ApoA-II gene by the synergistic action of factors binding to the proximal and distal regulatory elements. J Biol Chem. 1991 Dec 25;266(36):24460–24470. [PubMed] [Google Scholar]
  8. Cardot P., Chambaz J., Kardassis D., Cladaras C., Zannis V. I. Factors participating in the liver-specific expression of the human apolipoprotein A-II gene and their significance for transcription. Biochemistry. 1993 Sep 7;32(35):9080–9093. doi: 10.1021/bi00086a013. [DOI] [PubMed] [Google Scholar]
  9. Cardot P., Pastier D., Lacorte J. M., Mangeney M., Zannis V. I., Chambaz J. Purification and characterization of nuclear factors binding to the negative regulatory element D of human apolipoprotein A-II promoter: a negative regulatory effect is reversed by GABP, an Ets-related protein. Biochemistry. 1994 Oct 11;33(40):12139–12148. doi: 10.1021/bi00206a017. [DOI] [PubMed] [Google Scholar]
  10. Chambaz J., Cardot P., Pastier D., Zannis V. I., Cladaras C. Promoter elements and factors required for hepatic transcription of the human ApoA-II gene. J Biol Chem. 1991 Jun 25;266(18):11676–11685. [PubMed] [Google Scholar]
  11. Chatterjee B., Demyan W. F., Lalwani N. D., Reddy J. K., Roy A. K. Reversible alteration of hepatic messenger RNA species for peroxisomal and non-peroxisomal proteins induced by the hypolipidaemic drug Wy-14,643. Biochem J. 1983 Sep 15;214(3):879–883. doi: 10.1042/bj2140879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chatterjee B., Murty C. V., Olson M. J., Roy A. K. Cloning and expression of the rat liver cDNA for peroxisomal enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase in lambda GT11. Transcriptional regulation of enzyme activity by Wy-14643 in primary cultures of rat hepatocytes. Eur J Biochem. 1987 Jul 15;166(2):273–278. doi: 10.1111/j.1432-1033.1987.tb13511.x. [DOI] [PubMed] [Google Scholar]
  13. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  14. Doolittle M. H., LeBoeuf R. C., Warden C. H., Bee L. M., Lusis A. J. A polymorphism affecting apolipoprotein A-II translational efficiency determines high density lipoprotein size and composition. J Biol Chem. 1990 Sep 25;265(27):16380–16388. [PubMed] [Google Scholar]
  15. Dreyer C., Krey G., Keller H., Givel F., Helftenbein G., Wahli W. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell. 1992 Mar 6;68(5):879–887. doi: 10.1016/0092-8674(92)90031-7. [DOI] [PubMed] [Google Scholar]
  16. Fidge N. H., Nestel P. J. Identification of apolipoproteins involved in the interaction of human high density lipoprotein3 with receptors on cultured cells. J Biol Chem. 1985 Mar 25;260(6):3570–3575. [PubMed] [Google Scholar]
  17. Fried M. G., Crothers D. M. CAP and RNA polymerase interactions with the lac promoter: binding stoichiometry and long range effects. Nucleic Acids Res. 1983 Jan 11;11(1):141–158. doi: 10.1093/nar/11.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gulick T., Cresci S., Caira T., Moore D. D., Kelly D. P. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11012–11016. doi: 10.1073/pnas.91.23.11012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Göttlicher M., Widmark E., Li Q., Gustafsson J. A. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4653–4657. doi: 10.1073/pnas.89.10.4653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hedrick C. C., Castellani L. W., Warden C. H., Puppione D. L., Lusis A. J. Influence of mouse apolipoprotein A-II on plasma lipoproteins in transgenic mice. J Biol Chem. 1993 Sep 25;268(27):20676–20682. [PubMed] [Google Scholar]
  22. Hijikata M., Ishii N., Kagamiyama H., Osumi T., Hashimoto T. Structural analysis of cDNA for rat peroxisomal 3-ketoacyl-CoA thiolase. J Biol Chem. 1987 Jun 15;262(17):8151–8158. [PubMed] [Google Scholar]
  23. Hussain M. M., Zannis V. I. Intracellular modification of human apolipoprotein AII (apoAII) and sites of apoAII mRNA synthesis: comparison of apoAII with apoCII and apoCIII isoproteins. Biochemistry. 1990 Jan 9;29(1):209–217. doi: 10.1021/bi00453a029. [DOI] [PubMed] [Google Scholar]
  24. Issemann I., Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990 Oct 18;347(6294):645–650. doi: 10.1038/347645a0. [DOI] [PubMed] [Google Scholar]
  25. Kardassis D., Zannis V. I., Cladaras C. Purification and characterization of the nuclear factor BA1. A transcriptional activator of the human apoB gene. J Biol Chem. 1990 Dec 15;265(35):21733–21740. [PubMed] [Google Scholar]
  26. Keller H., Dreyer C., Medin J., Mahfoudi A., Ozato K., Wahli W. 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. 1993 Mar 15;90(6):2160–2164. doi: 10.1073/pnas.90.6.2160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kliewer S. A., Forman B. M., Blumberg B., Ong E. S., Borgmeyer U., Mangelsdorf D. J., Umesono K., Evans R. M. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7355–7359. doi: 10.1073/pnas.91.15.7355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Knott T. J., Eddy R. L., Robertson M. E., Priestley L. M., Scott J., Shows T. B. Chromosomal localization of the human apoprotein CI gene and of a polymorphic apoprotein AII gene. Biochem Biophys Res Commun. 1984 Nov 30;125(1):299–306. doi: 10.1016/s0006-291x(84)80368-x. [DOI] [PubMed] [Google Scholar]
  29. Knott T. J., Priestley L. M., Urdea M., Scott J. Isolation and characterisation of a cDNA encoding the precursor for human apolipoprotein AII. Biochem Biophys Res Commun. 1984 May 16;120(3):734–740. doi: 10.1016/s0006-291x(84)80168-0. [DOI] [PubMed] [Google Scholar]
  30. Knott T. J., Wallis S. C., Robertson M. E., Priestley L. M., Urdea M., Rall L. B., Scott J. The human apolipoprotein AII gene: structural organization and sites of expression. Nucleic Acids Res. 1985 Sep 11;13(17):6387–6398. doi: 10.1093/nar/13.17.6387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lackner K. J., Law S. W., Brewer H. B., Jr Human apolipoprotein A-II: complete nucleic acid sequence of preproapo A-II. FEBS Lett. 1984 Sep 17;175(1):159–164. doi: 10.1016/0014-5793(84)80590-6. [DOI] [PubMed] [Google Scholar]
  32. Lackner K. J., Law S. W., Brewer H. B., Jr, Sakaguchi A. Y., Naylor S. L. The human apolipoprotein A-II gene is located on chromosome 1. Biochem Biophys Res Commun. 1984 Aug 16;122(3):877–883. doi: 10.1016/0006-291x(84)91172-0. [DOI] [PubMed] [Google Scholar]
  33. Lackner K. J., Law S. W., Brewer H. B., Jr The human apolipoprotein A-II gene: complete nucleic acid sequence and genomic organization. Nucleic Acids Res. 1985 Jun 25;13(12):4597–4608. doi: 10.1093/nar/13.12.4597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ladias J. A., Hadzopoulou-Cladaras M., Kardassis D., Cardot P., Cheng J., Zannis V., Cladaras C. Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3. J Biol Chem. 1992 Aug 5;267(22):15849–15860. [PubMed] [Google Scholar]
  35. Leid M., Kastner P., Lyons R., Nakshatri H., Saunders M., Zacharewski T., Chen J. Y., Staub A., Garnier J. M., Mader S. Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently. Cell. 1992 Jan 24;68(2):377–395. doi: 10.1016/0092-8674(92)90478-u. [DOI] [PubMed] [Google Scholar]
  36. Leroy A., Vu-dac N., Koffigan M., Clavey V., Fruchart J. C. Characterization of a monoclonal antibody that binds to apolipoprotein E and to lipoprotein of human plasma containing apo E. Applications to ELISA quantification of plasma apo E. J Immunoassay. 1988;9(3-4):309–334. doi: 10.1080/01971528808053219. [DOI] [PubMed] [Google Scholar]
  37. Lock E. A., Mitchell A. M., Elcombe C. R. Biochemical mechanisms of induction of hepatic peroxisome proliferation. Annu Rev Pharmacol Toxicol. 1989;29:145–163. doi: 10.1146/annurev.pa.29.040189.001045. [DOI] [PubMed] [Google Scholar]
  38. Lucero M. A., Sanchez D., Ochoa A. R., Brunel F., Cohen G. N., Baralle F. E., Zakin M. M. Interaction of DNA-binding proteins with the tissue-specific human apolipoprotein-AII enhancer. Nucleic Acids Res. 1989 Mar 25;17(6):2283–2300. doi: 10.1093/nar/17.6.2283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Luckow B., Schütz G. CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Res. 1987 Jul 10;15(13):5490–5490. doi: 10.1093/nar/15.13.5490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Lusis A. J., Taylor B. A., Wangenstein R. W., LeBoeuf R. C. Genetic control of lipid transport in mice. II. Genes controlling structure of high density lipoproteins. J Biol Chem. 1983 Apr 25;258(8):5071–5078. [PubMed] [Google Scholar]
  41. Lussier-Cacan S., Bard J. M., Boulet L., Nestruck A. C., Grothé A. M., Fruchart J. C., Davignon J. Lipoprotein composition changes induced by fenofibrate in dysbetalipoproteinemia type III. Atherosclerosis. 1989 Aug;78(2-3):167–182. doi: 10.1016/0021-9150(89)90221-9. [DOI] [PubMed] [Google Scholar]
  42. MacGregor G. R., Caskey C. T. Construction of plasmids that express E. coli beta-galactosidase in mammalian cells. Nucleic Acids Res. 1989 Mar 25;17(6):2365–2365. doi: 10.1093/nar/17.6.2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Manninen V. Clinical results with gemfibrozil and background to the Helsinki Heart Study. Am J Cardiol. 1983 Aug 22;52(4):35B–38B. doi: 10.1016/0002-9149(83)90656-2. [DOI] [PubMed] [Google Scholar]
  44. Marcus S. L., Miyata K. S., Zhang B., Subramani S., Rachubinski R. A., Capone J. P. Diverse peroxisome proliferator-activated receptors bind to the peroxisome proliferator-responsive elements of the rat hydratase/dehydrogenase and fatty acyl-CoA oxidase genes but differentially induce expression. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5723–5727. doi: 10.1073/pnas.90.12.5723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Marsh J. L., Erfle M., Wykes E. J. The pIC plasmid and phage vectors with versatile cloning sites for recombinant selection by insertional inactivation. Gene. 1984 Dec;32(3):481–485. doi: 10.1016/0378-1119(84)90022-2. [DOI] [PubMed] [Google Scholar]
  46. McQuaid S., Russell S. E., Withe S. A., Pearson C. M., Elcombe C. R., Humphries P. Analysis of transcripts homologous to acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase induced in rat liver by methylclofenapate. Cancer Lett. 1987 Oct;37(1):115–121. doi: 10.1016/0304-3835(87)90152-2. [DOI] [PubMed] [Google Scholar]
  47. Mehrabian M., Qiao J. H., Hyman R., Ruddle D., Laughton C., Lusis A. J. Influence of the apoA-II gene locus on HDL levels and fatty streak development in mice. Arterioscler Thromb. 1993 Jan;13(1):1–10. doi: 10.1161/01.atv.13.1.1. [DOI] [PubMed] [Google Scholar]
  48. Moore M. N., Kao F. T., Tsao Y. K., Chan L. Human apolipoprotein A-II: nucleotide sequence of a cloned cDNA, and localization of its structural gene on human chromosome 1. Biochem Biophys Res Commun. 1984 Aug 30;123(1):1–7. doi: 10.1016/0006-291x(84)90371-1. [DOI] [PubMed] [Google Scholar]
  49. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  50. Muerhoff A. S., Griffin K. J., Johnson E. F. The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid omega-hydroxylase, by clofibric acid. J Biol Chem. 1992 Sep 25;267(27):19051–19053. [PubMed] [Google Scholar]
  51. Nakamaye K. L., Eckstein F. Inhibition of restriction endonuclease Nci I cleavage by phosphorothioate groups and its application to oligonucleotide-directed mutagenesis. Nucleic Acids Res. 1986 Dec 22;14(24):9679–9698. doi: 10.1093/nar/14.24.9679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Osumi T., Ozasa H., Hashimoto T. Molecular cloning of cDNA for rat acyl-CoA oxidase. J Biol Chem. 1984 Feb 25;259(4):2031–2034. [PubMed] [Google Scholar]
  53. Osumi T., Wen J. K., Hashimoto T. Two cis-acting regulatory sequences in the peroxisome proliferator-responsive enhancer region of rat acyl-CoA oxidase gene. Biochem Biophys Res Commun. 1991 Mar 29;175(3):866–871. doi: 10.1016/0006-291x(91)91645-s. [DOI] [PubMed] [Google Scholar]
  54. Palmer C. N., Hsu M. H., Muerhoff A. S., Griffin K. J., Johnson E. F. Interaction of the peroxisome proliferator-activated receptor alpha with the retinoid X receptor alpha unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-1-binding site in the CYP4A6 promoter. J Biol Chem. 1994 Jul 8;269(27):18083–18089. [PubMed] [Google Scholar]
  55. Puchois P., Kandoussi A., Fievet P., Fourrier J. L., Bertrand M., Koren E., Fruchart J. C. Apolipoprotein A-I containing lipoproteins in coronary artery disease. Atherosclerosis. 1987 Nov;68(1-2):35–40. doi: 10.1016/0021-9150(87)90091-8. [DOI] [PubMed] [Google Scholar]
  56. Reddy J. K., Azarnoff D. L., Hignite C. E. Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature. 1980 Jan 24;283(5745):397–398. doi: 10.1038/283397a0. [DOI] [PubMed] [Google Scholar]
  57. Reddy J. K., Goel S. K., Nemali M. R., Carrino J. J., Laffler T. G., Reddy M. K., Sperbeck S. J., Osumi T., Hashimoto T., Lalwani N. D. Transcription 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. 1986 Mar;83(6):1747–1751. doi: 10.1073/pnas.83.6.1747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Reddy J. K., Warren J. R., Reddy M. K., Lalwani N. D. Hepatic and renal effects of peroxisome proliferators: biological implications. Ann N Y Acad Sci. 1982;386:81–110. doi: 10.1111/j.1749-6632.1982.tb21409.x. [DOI] [PubMed] [Google Scholar]
  59. Rodríguez J. C., Gil-Gómez G., Hegardt F. G., Haro D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem. 1994 Jul 22;269(29):18767–18772. [PubMed] [Google Scholar]
  60. Schmidt A., Endo N., Rutledge S. J., Vogel R., Shinar D., Rodan G. A. Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol. 1992 Oct;6(10):1634–1641. doi: 10.1210/mend.6.10.1333051. [DOI] [PubMed] [Google Scholar]
  61. Schonfeld G., Patsch W., Rudel L. L., Nelson C., Epstein M., Olson R. E. Effects of dietary cholesterol and fatty acids on plasma lipoproteins. J Clin Invest. 1982 May;69(5):1072–1080. doi: 10.1172/JCI110542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Schultz J. R., Verstuyft J. G., Gong E. L., Nichols A. V., Rubin E. M. Protein composition determines the anti-atherogenic properties of HDL in transgenic mice. Nature. 1993 Oct 21;365(6448):762–764. doi: 10.1038/365762a0. [DOI] [PubMed] [Google Scholar]
  63. Sharpe C. R., Sidoli A., Shelley C. S., Lucero M. A., Shoulders C. C., Baralle F. E. Human apolipoproteins AI, AII, CII and CIII. cDNA sequences and mRNA abundance. Nucleic Acids Res. 1984 May 11;12(9):3917–3932. doi: 10.1093/nar/12.9.3917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Shelley C. S., Baralle F. E. Dual tissue-specific expression of apo-AII is directed by an upstream enhancer. Nucleic Acids Res. 1987 May 11;15(9):3801–3821. doi: 10.1093/nar/15.9.3801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Shelley C. S., Sharpe C. R., Baralle F. E., Shoulders C. C. Comparison of the human apolipoprotein genes. Apo AII presents a unique functional intron-exon junction. J Mol Biol. 1985 Nov 5;186(1):43–51. doi: 10.1016/0022-2836(85)90255-4. [DOI] [PubMed] [Google Scholar]
  66. Sher T., Yi H. F., McBride O. W., Gonzalez F. J. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry. 1993 Jun 1;32(21):5598–5604. doi: 10.1021/bi00072a015. [DOI] [PubMed] [Google Scholar]
  67. Simpson H. S., Williamson C. M., Olivecrona T., Pringle S., Maclean J., Lorimer A. R., Bonnefous F., Bogaievsky Y., Packard C. J., Shepherd J. Postprandial lipemia, fenofibrate and coronary artery disease. Atherosclerosis. 1990 Dec;85(2-3):193–202. doi: 10.1016/0021-9150(90)90111-u. [DOI] [PubMed] [Google Scholar]
  68. Sirtori C. R., Franceschini G. Effects of fibrates on serum lipids and atherosclerosis. Pharmacol Ther. 1988;37(2):167–191. doi: 10.1016/0163-7258(88)90024-1. [DOI] [PubMed] [Google Scholar]
  69. Staels B., Vu-Dac N., Kosykh V. A., Saladin R., Fruchart J. C., Dallongeville J., Auwerx J. Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates. J Clin Invest. 1995 Feb;95(2):705–712. doi: 10.1172/JCI117717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Staels B., van Tol A., Andreu T., Auwerx J. Fibrates influence the expression of genes involved in lipoprotein metabolism in a tissue-selective manner in the rat. Arterioscler Thromb. 1992 Mar;12(3):286–294. doi: 10.1161/01.atv.12.3.286. [DOI] [PubMed] [Google Scholar]
  71. Svoboda D. J., Azarnoff D. L. Response of hepatic microbodies to a hypolipidemic agent, ethyl chlorophenoxyisobutyrate (CPIB). J Cell Biol. 1966 Aug;30(2):442–450. doi: 10.1083/jcb.30.2.442. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Tokunaga K., Nakamura Y., Sakata K., Fujimori K., Ohkubo M., Sawada K., Sakiyama S. Enhanced expression of a glyceraldehyde-3-phosphate dehydrogenase gene in human lung cancers. Cancer Res. 1987 Nov 1;47(21):5616–5619. [PubMed] [Google Scholar]
  73. Tolbert N. E. Metabolic pathways in peroxisomes and glyoxysomes. Annu Rev Biochem. 1981;50:133–157. doi: 10.1146/annurev.bi.50.070181.001025. [DOI] [PubMed] [Google Scholar]
  74. Tontonoz P., Hu E., Graves R. A., Budavari A. I., Spiegelman B. M. mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994 May 15;8(10):1224–1234. doi: 10.1101/gad.8.10.1224. [DOI] [PubMed] [Google Scholar]
  75. Tora L., White J., Brou C., Tasset D., Webster N., Scheer E., Chambon P. The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell. 1989 Nov 3;59(3):477–487. doi: 10.1016/0092-8674(89)90031-7. [DOI] [PubMed] [Google Scholar]
  76. Tsao Y. K., Wei C. F., Robberson D. L., Gotto A. M., Jr, Chan L. Isolation and characterization of the human apolipoprotein A-II gene. Electron microscopic analysis of RNA:DNA hybrids, nucleotide sequence, identification of a polymorphic MspI site, and general structural organization of apolipoprotein genes. J Biol Chem. 1985 Dec 5;260(28):15222–15231. [PubMed] [Google Scholar]
  77. Tugwood J. D., Issemann I., Anderson R. G., Bundell K. R., McPheat W. L., Green S. The mouse peroxisome proliferator activated receptor recognizes a response element in the 5' flanking sequence of the rat acyl CoA oxidase gene. EMBO J. 1992 Feb;11(2):433–439. doi: 10.1002/j.1460-2075.1992.tb05072.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Vanloo B., Taveirne J., Baert J., Lorent G., Lins L., Ruyschaert J. M., Rosseneu M. LCAT activation properties of apo A-I CNBr fragments and conversion of discoidal complexes into spherical particles. Biochim Biophys Acta. 1992 Oct 30;1128(2-3):258–266. doi: 10.1016/0005-2760(92)90316-n. [DOI] [PubMed] [Google Scholar]
  79. Vu-Dac N., Schoonjans K., Laine B., Fruchart J. C., Auwerx J., Staels B. Negative regulation of the human apolipoprotein A-I promoter by fibrates can be attenuated by the interaction of the peroxisome proliferator-activated receptor with its response element. J Biol Chem. 1994 Dec 9;269(49):31012–31018. [PubMed] [Google Scholar]
  80. Warden C. H., Hedrick C. C., Qiao J. H., Castellani L. W., Lusis A. J. Atherosclerosis in transgenic mice overexpressing apolipoprotein A-II. Science. 1993 Jul 23;261(5120):469–472. doi: 10.1126/science.8332912. [DOI] [PubMed] [Google Scholar]
  81. Zhang B., Marcus S. L., Sajjadi F. G., Alvares K., Reddy J. K., Subramani S., Rachubinski R. A., Capone J. P. Identification of a peroxisome proliferator-responsive element upstream of the gene encoding rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7541–7545. doi: 10.1073/pnas.89.16.7541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Zhu Y., Alvares K., Huang Q., Rao M. S., Reddy J. K. Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J Biol Chem. 1993 Dec 25;268(36):26817–26820. [PubMed] [Google Scholar]
  83. van den Bosch H., Schutgens R. B., Wanders R. J., Tager J. M. Biochemistry of peroxisomes. Annu Rev Biochem. 1992;61:157–197. doi: 10.1146/annurev.bi.61.070192.001105. [DOI] [PubMed] [Google Scholar]

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