請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29077完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 高照村 | |
| dc.contributor.author | Hsin-Yeh Lee | en |
| dc.contributor.author | 李欣燁 | zh_TW |
| dc.date.accessioned | 2021-06-13T00:38:38Z | - |
| dc.date.available | 2008-08-08 | |
| dc.date.copyright | 2007-08-08 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-07-25 | |
| dc.identifier.citation | 1. Hokanson JE, Austin MA. Plasma triglyceride level is a ridk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996; 213-219.
2. Heller DA, de Faire U, Pedersen NL, Dahlen G, McClearn GE. Genetic and environmental influences on serum lipid levels in twins. N Engl J Med 1993; 328: 1150-1156. 3. Murthy V, Julein P, Gagne C. Molecular pathobiology of the human lipoprotein lipase gene. Pharmacology & Therapeutics 1996; 70: 101-135. 4. Jong MC, Hofker MH, Havekes LM. Role of ApoC1, ApoC2, and ApoC3. Arterioscler Thromb Vasc Biol 1999; 19: 472-484. 5. Hahn PF. Abolishment of Alimentary Lipemia following injection of heparin. Science 1943; 98: 166-167. 6. Korn ED. Clearing factor, a heparin-activated lipoprotein lipase. Isolation and characterization of the enzyme from normal rat heart. J Biol Chem 1954; 215: 1-14. 7. Krauss RM, Hebert PN, Levy RI, Fredrickson DS. Further observations on the activation and inhibition of lipoprotein lipase by apolipoproteins. Circulation Res 1973; 33: 403-411. 8. Havel RJ, Gordon Tr. RS. Idiopathic hyperlipidemia: metabolic studies in an affected family. J Clin Invest 1960; 39: 1777-1790. 9. Krauss RM, Windmuller HG, Levy RI, Fredrickson DS. Selective measurement of two different triglyceride lipase activities in rat postheparin plasma. J Lipid Res 1973; 14: 286-295. 10. Breckenridge WC, Little JA, Steiner G, Grow A, Poast M. Hypertriglyceridemia associated with deficiency of apolipoproteins C-II. New Eng J of Med 1978; 298: 1265-1273. 11. Sparkes RS, Zollman S, Klisak I, Kirchgessner TG, Komaromy MC, Mohandas T, Schotz MC, Lusis AJ. Human genes involved in lipolysis plasma lipoproteins: mapping of loci for lipoprotein lipase to 8q22 and heatic lipase to 15q21. Genomics 1987;1: 138144. 12. Deeb SS, Peng RL. Structure of the human lipoprotein lipase gene. Biochemistry 1989; 28: 4131-4135. 13. Wong H, Davis RC, Thuren T, Goers TW, Nikazy J, Waite M, Schotz MC. Lipoprotein lipase domain function. J Biol Chem 1994; 269: 10319-10323. 14. Braun JE, Severson DL. Regulation of the synthesis, processing and translocation of lipoprotein lipase. Biochem J 1992; 287: 337-347. 15. Camps L, Reina M, Liobera M, Vilaro S, Olivercrona T. Lipoprotein lipase: cellular origin and function distribution. American J Phy 1990; 258: c673-681. 16. Bengtsson G, Oliverona T. Interaction of lipoprotein lipase with heparin-sepharose. Evaluation of condition for affinity binding. Biochem J 1997; 109-119. 17. Eckel RH. Lipoprotein lipase: a multifunctional enzyme relevant to common metabolic diseases. N EnglJ Med 1989; 320: 1060-1067. 18. Oliverona T, Bengtsson OG. Lipoprotein lipase from milk: the model in lipoprotein lipase research. In Lipoprotein Lipase 1987; p.15-58. Boernsatajn J, (ed.) Evener Publisher, Inc., Chicago. 19. Kirchgessner TG, Svenson KL, Lusis AJ, Schotz MC. The sequence of cDNA encoding lipoprotein lipase. J Bio Chem 1987; 262: 8463-8466. 20. Wang C-S, Mcconathy J, Kloer HU, Alauovic P. Modulation of lipoprotein lipase activity by apolipoproteins: effect of apolipoprotein CIII. J Clin Invest 1985; 75: 384-390. 21. Mahley RW, Innerarity, Rall SC Jr, Weisgraber KH. Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res 1984; 25: 1277-1294. 22. Schachter NS. Apolipoprotein C-І and C-Ⅲ as important modulators of lipoprotein metabolism. Curr Opin Lipodol 2001; 12: 297-304. 23. Cox DW, Breckenridge WC, Little JA. Inheritance of apolipoprotein C-II deficiency with hypertriglyceridemia and pancreatitis. N Engl J Med 1978; 298: 1265-1273. 24. Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992; 258: 468-471. 25. Duverger N, Termp G, Caillaud JM, Emmanuel F, Castro G, Fruchart JC, Steinmetz A, Denefle P. Protection against atherogenesis in mice mediated by human apolipoprotein A-IV. Science 1996; 273: 966-968. 26. Pennacchio LA, Oliver M, Hubacek JA, Cohen JC, Cox DR, Fruchart JC, Krauss RM, Rublin EM. An apolipoprotein influencing triglycerides in human and mice revealed by comparative sequencing. Science 2001; 294: 169-173. 27. Pieur X, Coste H, Rodriguez JC. The human apolipoprotein AV gene is regulated by peroxisome proliferators-activated receptor-α and contains a novel farnesoid X-activated response element. J Biol Chem 2003; 278: 25468-25480. 28. van der Vliet HN, Sammels MG, Leegwater AV, Levels JH, Reitsma PH, Boers W, Charmuleau RA. Apolipoprotein A-V: a novel apolipoprotein associated with an early phase of liver regeneration. J Biol Chem 2001; 276: 44512-44520. 29. Vu-Dac N, Gervois P, Jakel H, Nowak M, Baugé E, Dehondt H, Staels B, Pennacchio LA, Rubin EM, Fruchart-Najib J, Fruchart JC. Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome-activated receptor α activators. J Biol Chem 2003; 278: 17982-17985. 30. Prieur X, Huby T, Coste H, Schaap FG, Chapman MJ, Rodríguez JC. Thyroid hormone regulates the hypotriglyceridemic gene APOA5. J Biol Chem 2005; 280: 27533-27543. 31. Genoux A, Dehondt H, Helleboid-Champman A, Duhem C, Hum DW, Martin G, Pennacchio LA, Staels B, Fruchart-Najib J, Fruchart JC. Transcriptional regulation of apolipoprotein A5 gene expression by the nuclear receptor RORα. Arterioscler Thromb Vasc Biol 2005; 25: 1186-1192. 32. Prieur X, Schaap FG, Coste H, Rodriguez JC. Hepatocyte nuclear factor-4alpha regulates the human apolipoprotein AV gene: identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1alpha, AMP-activated protein kinase, and mitogen-activated protein kinase pathway. Mol Endocrinol 2005; 19: 3107-3125. 33. Jakel H, Nowak M, Moitort E, Dehondt H, Hum DW, Pennacchio LA, Fruchart-Najib J, Fruchart JC. The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c. J Biol Chem 2004; 279: 45462-45469. 34. O’brien PJ, Alborn WE, Sloan JH, Ulmer M, Boodhoo A, Knierman MD, Schultze AE, Konrad RJ. The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins. Clin Chem 2005; 51: 351-359. 35. Ishihara M, Kujiraoka T, Iwasaki T, Nagano M, Takano M, Ishii J, Tsuji M, Ide H, Miller IP, Miller NE, Hattori H. A sandwich enzyme-linked immunosorbent assay for human plasma apolipoprotein A-V concentration. J Lipid Res 2005 ; 46 :2015-22. 36. van der Vliet HN, Schaap FG, Levels JH, Ottenhoff R, Looije Norbert, Wesseling JG, Groen AK, Charmuleau RA. Adenoviral overexpression of apolipoprotein A-V reduces serum levels of triglycerides and cholesterol in mice. Biochem Biophys Res Commun 2002; 295: 1156-1159. 37. Schaap FG, Rensen PC, Voshol PJ, Vrins C, van der Vliet HN, Chamuleau RA, Havekes LM, Groen AK, van Dijk KW. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. J Biol Chem 2004; 279: 27941-27947. 38. Huang W, Bi N, Zhang X, Wang Y, Chen B, Liu G. Overexpression of apolipoprotein AV in the liver reduces plasma triglyceride and cholesterol but not HDL in ApoE deficient mice. Biochem Biophys Res Commun. 2006; 346:14-8 39. Pennacchio LA, Olivier M, Hubacek JA, Krauss RM, Rubin EM, Cohen JC. Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. Hum Mol Genet 2002 ; 11: 3031-3038. 40. Ribalta J, Figuera L, Fernandez-Ballart J, Vilella E, Castro Cabezas M, Masana L, Joven J. Newly identified apolipoprotein AV gene predisposes to high plasma triglycerides in familial combined hyperlipidemia. Clin Chem 2002; 48: 1597-1600. 41. Talmud PJ, Hawe E, Martin S, Olivier M, Miller GJ, Rubin EM, Pennacchio LA, Humphries SE. Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Hum Mol Genet 2002; 11: 3039-3046. 42. Endo K, Yanagi H, Araki J, Hirano C, Yamakawa-Kobayashi K, Tomura S. Association found between the promoter region polymorphism in the apolipoprotein A-V gene and the serum triglyceride level in Japanese schoolchildren. Hum Genet 2002; 111: 570-572. 43. Aouizerat BE, Kulkarni M, Heilbron D, Drown D, Raskin S, Pullinger CR, Malloy MJ, Kane JP. Genetic analysis of a polymorphism in the human apoA-V gene: effect on plasma lipids. J Lipid Res. 2003; 44: 1167-1173. 44. Talmud PJ, Palmen J, Putt W, Lins L, Humphries SE. Determination of the functionality of common APOA5 polymorphisms. J Biol Chem 2005; 280: 28215-28220. 45. Kao JT, Wen HC, Chien KL, Hsu HC, Lin SW. A novel genetic variant in the apolipoprotein A5 gene is associated with hypertriglyceridemia. Hum Mol Genet 2003; 12: 2533-2539. 46. Oliva CP, Pisciotta L, Li volti G, Sambataro MP, Calandra A, Bellocchio A, Catapano A, Tarugi P, Bertolini S, Calandra S. Inherited apolipoprotein A-V deficiency in severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol 2005; 25: 411-417. 47. Weinberg RB, Cook VR, Beckstead JA, Martin DD, Gallagher JW, Shelness GS, Ryan RO. Structure and interfacial properties of human apolipoprotein A-V. J Biol Chem 2003; 278: 34438-34444. 48. Schaap FG, Rensen PC, Voshol PJ, Vrins C, van der Vliet HN, Chamuleau RA, Havekes LM, Groen AK, van Dijk KW. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis. J Biol Chem 2004; 279: 27941-27947. 49. Schaap F, Voshol P, Rensen P, Van der Vliet H, Chamuleau R, Maeda N, Havekes L, Groen A, Willems van Dijk K. Apolipoprotein AV expression ameliorates type III hyperlipidemia in mouse model by stimulating lipoprotein lipase-mediated VLDL-triglyceride hydrolysis. Circulation 2003; 108: 257. 50. Fruchart-Najib J, Bauge E, Niculescu LS, Pham T, Thomas B, Rommens C, Majd Z, Brewer B, Pennacchio LA, Fruchart JC. Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5. Biochem Biophys Res Commun 2004; 319: 397-404. 51. Xiao S, Joanne C, Robert OR, Trudy MF. Apolipoprotein A-V association with intracellular lipid droplets. J.Lipid Res 2007；Apr 25. 52. Grosskopf I, Baroukh N, Lee SJ., Kamari Y, Harats D, Rubin EM, Pennacchio LA, Cooper AD. Apolipoprotein A-V deficiency results in marked hypertriglyceridemia attributable to decreased lipolysis of triglyceride-rich lipoproteins and removal of their remnants. Arterioscler Thromb Vasc Biol 2005; 25: 2573-2579. 53. Merkel M, Loeffler B, Kluger M, Fabig N, Geppert G, Pennacchio LA, Laatsch A, Heeren J. Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase. J Biol Chem 2005; 280: 21553-21560. 54. Lookene A, Beckstead JA, Nilsson S, Olivecrona G, Ryan RO. Apolipoprotein A-V-heparin interactions: implications for plasma lipoprotein metabolism. J Biol Chem 2005; 280: 25383-25387. 55. Stefan KN, Aivar L, Jennifer AB, Jorgen G, Robert OR, Gunilla O. Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family. J. Biol Chem 2007; 46: 3896-3904. 56. Richard B. Weinberg, Victoria R. Cook, Jennifer A. Beckstead, Dale D. O. Martin, James W. Gallagher, Gregory S. Shelness, Robert OR. Structure and interfacial properties of human apolipoprotein A-V. J. Biol Chem 2003; 36: 34438-34444. 57. Jennifer AB, Michael NO, Dale DM, Trudy MF, John K. Bielicki TB , Robert L, Cyril MK, Robert OR. Structure-function studies of human apolipoprotein A-V: a regulator of plasma lipid homeostasis . J. Biol Chem 2003; 42: 9416-9423. 58. Alborn WE, Johnson MG, Prince MJ, Konrad RJ. Definitive N-terminal protein sequence and further characterization of the novel apolipoprotein A5 in human serum. Clin Chem 2006; 52:514–517. 59. Sun G, Bi N, Li G. Identification of lipid binding and lipoprotein lipase activation domains of human apoAV. Chem Phys Lipids 2006; 143:22–28. 60. Marcais C, Verges B, Charriere S. Apoa5 Q139X truncation predisposes to late-onset hyperchylomicronemia due to lipoprotein lipase impairment. J Clin Invest 2005; 115:2862–2869. 61. Fruchart J C, Brewer HB Jr,Leitersdorf E. Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Fibrate Consensus Group. Am J Cardiol 1998; 81: 912-917. 62. O’Hara DD, Porte D Jr, Williams RH. The effect of diet and thyroxin on plasma lipids in myxedema. Metabolism 1996; 15: 123–134. 63. Nikkila E A, Kekki M. Plasma triglyceride metabolism in thyroid disease. J Clin Invest. 1972;51:8:2103-2114. 64. Abrams JJ, Grundy SM, Ginsberg, H. Metabolism of plasma triglycerides in hypothyroidism and hyperthyroidism in man. J Lipid Res. 1981; 22:2:307-322. 65. O’Brien T, Dinneen SF, O’Brien P C, Palumbo PJ Hyperlipidemia in patients with primary and secondary hypothyroidism. Mayo Clin. Proc. 1993; 68: 860–866. 66. Pykalisto O, Goldberg AP,Brunzell JD. Reversal of decreased human adipose tissue lipoprotein lipase and hypertriglyceridemia after treatment of hypothyroidism. J. Clin. Endocrinol. Metab. 1976 ; 43: 591–600. 67. Porte DJr, O’Hara D D, Williams RH. The relation between postheparin lipolytic activity and plasma triglyceride in myxedemaMetabolism 1966; 15, 107–113. 68. Tan K C, Shiu SW, Kung AW. Effect of thyroid dysfunction on high-density lipoprotein subfraction metabolism: roles of hepatic lipase and cholesteryl ester transfer protein. J. Clin. Endocrinol. Metab.1998; 83: 2921–2924. 69. Ito M, Takamatsu J, Matsuo T, Kameoka K, Kubota S, Fukata S,Tamai H, Miyauchi A, Kuma K, Hanafusa T. Serum concentrations of remnant-like particles in hypothyroid patients before and after thyroxine replacement. Clin. Endocrinol. 2003; 58: 621–626. 70. Annelise G, Philippe G, Corinne R, Helene D, Michel F, Maud D, Edward MR, Len AP,Jamila FN, Jean CF. Apolipoprotein A5 is an inflammatory responsive gene down-regulated by tumor necrosis factor alpha and interleukin-1. Atherosclerosis. 2003; 4:241. 71. Khovidhunkit W, Duchateau PN, Medzihradszky KF, Moser AH, Naya-Vigne J, Shigenaga JK, Kane JP, Grunfeld C, Feingold KR. Apolipoproteins A-IV and A-V are acute-phase proteins in mouse HDL. Atherosclerosis. 2004; 176:37–44 72. Babu PS, Srinivasan K. Hypolipidemic action of curcumin, the active principle of turmeric (Curcuma longa) in streptozotocin induced diabetic rats. Mol Cell Biochem. 1997; 166:169-175. 73. Wei S, Yan J. Regulation effect of curcumin on blood lipids and antioxidation in hyperlipidemia rats. 2000; 29:4 : 240-242. 74. Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B,de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet. 1996; 347: 849-853. 75. Turay J, Grniakova V, Valka J. Changes in paraoxonase and apolipoprotein A-I, B, C-III and E in subjects with combined familiar hyperlipoproteinemia treated with ciprofibrate. Drugs Exp Clin Res. 2000; 26: 83-88. 76. Willson T M, Brown P J, Sternbach DD, Henke B R. The PPARs: from orphan receptors to drug discovery. J Med Chem.2000; 43: 527-550. 77. Raslova K, Dobiasova M, Nagyova A, Fabry R, Rauchova H, Dusinska, M. Ciprofibrate treatment in patients with atherogenic lipoprotein phenotype: effects on HDL quality, LDL susceptibility to oxidation and DNA damage. Eur J Clin Pharmacol. 1998; 54: 697-699. 78. Guay DR. Micronized fenofibrate: a new fibric acid hypolipidemic agent. Ann Pharmacother.1999; 33: 1083-1103. 79. Despres J P. Increasing high-density lipoprotein cholesterol: an update on fenofibrate. Am J Cardiol.2001; 88: 30N-36N. 80. Schoonjans K, Peinado-Onsurbe J, Lefebvre A M, Heyman R A, Briggs M, Deeb S, Staels B, Auwerx J. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. Embo J. 1996; 15: 5336-5348. 81. Antunes L M, Darin J D, Bianchi NL. Effects of the antioxidants curcumin or selenium on cisplatin-induced nephrotoxicity and lipid peroxidation in rats. Pharmacol Res, 2001; 43: 145-150. 82. Moragoda L, Jaszewski R, Majumdar, A P. Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res. 2001; 21: 873-878. 83. Chang WS, Lin CC, Chuang SC, Chiang HC. Superoxide anion scavenging effect of coumarins. Am J Chin Med.1996; 24: 11-17. 84. Lin W L, Wang C J, Tsai YY, Liu C L, Hwang J M, Tseng TH. Inhibitory effect of esculetin on oxidative damage induced by t-butyl hydroperoxide in rat liver. Arch Toxicol. 2000; 74: 467-472. 85. Chu C Y, Tsai YY, Wang C J, Lin W L, Tseng T H. Induction of apoptosis by esculetin in human leukemia cells. Eur J Pharmacol. 2001; 416: 25-32. 86. Tang Y, Sun P, Guo D, Ferro A, Ji Y, Chen Q, Fan L. A genetic variant c.553G > T in the apolipoprotein A5 gene is associated with an increased risk of coronary artery disease and altered triglyceride levels in a Chinese population. Atherosclerosis 2006;185: 433–437 87. Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York,1989; 8:64. 88. Feliciello I, Chinali G. A modified alkaline lysis method for the preparation of highly purified DNA from Escherichia Coli. Anal Biochem 1993; 212: 394-401. 89. Joly E. Preparation of plasmid DNA using alkaline lysis. Methods Mol Cell Biol 1996; 58: 257-263. 90. Yang TT, Sinai P, Kain SR An acid phosphatase assay for quantifying the growth of adherent and nonadherent cells. Anal Biochem. 1996 ; 241:1:103-8. 91. Chirgwin JM, Przybylz AE, MacDonald RJ, Rutter WJ. Isolation of biological active ribonucleic acid from source enriched in ribonuclease. Biochemistry 1979; 18: 5294-5299. 92. Tietz textbook of clinical chemistry. Third edition 1999; 850-851. 93. Schaap FG, Nierman MC, Berbee JF. Evidence for a complex relationship between apoA-V and apoC-III in patients with severe hypertriglyceridemia. J Lipid Res 2006; 47:2333–2339. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29077 | - |
| dc.description.abstract | 高三酸甘油酯血症(HTG)在人類族群中的盛行率高，且以列為致死疾病中心血管疾病的危險因子，所以發展對其有效治療的方式日益受到關注與重視。血液中脂質由脂蛋白所運輸攜帶，然而脂質的代謝主要受到脂蛋白表面各式各樣且功能各異的脂蛋白元所調控。脂蛋白元AV為近年新發現的脂蛋白元，據先前基因轉殖小鼠實驗中顯示出其含量與三酸甘油脂(TG)的濃度呈負相關。同時APOA5的許多基因多型性(SNPs)與HTG具有統計學上的相關性。其降TG功能於近期的發表研究中指出可能藉由間接提升脂蛋白解脂酶(LPL)的活性、降低體內VLDL-TG的形成與加速其透過LPL水解的代謝途徑，除此之外並可作為一個ligand透過LDL受體結合的方式使富含TG的脂蛋白被細胞內吞後而加以代謝清除。APOA5可被影響TG代謝的轉錄因子(e.g. PPAR-α、PPAR-γ,TR-β )所調控，顯示於TG代謝與TG恆定中扮演著不可或缺的角色。近期研究更指出APOA5也會影響著膽固醇的恒定，可能也在與糖尿病和發炎相關的HTG中參予要角。
本實驗室所發現華人特有的c.553G>T多型性與HTG具有統計學上的相關性，會造成脂蛋白元AV的第185個胺基酸由甘胺酸（glycine）變為半胱胺酸（cysteine），並且後續的研究指出其亦是罹患心血管疾病的危險因子之ㄧ。 故本論文為針對華人中帶有特有之APOA5 c.553G>T而好發HTG的治療法中探討此多型性是否可作為新的藥物標的，及有效的治療策略，以提供臨床上作為用藥的參考。 首先我們觀察到APOA5的驅動子在有PPAR-α的激活物Fibrates、TR-β的激活物T3、T4與調節發炎反應的Curcumin、Esculetin等等藥物的作用下，其轉錄活性皆有所提升，其提升百分比從118.4 %至453.9 %不等。又於藥物作用後，所轉譯出的野生型及變異型脂蛋白元AV的蛋白表現量，分別有62.5 %~208.9 %與39 % ~273.1 %不等的提升。然而初步實驗結果顯示藥物激活後的野生型與變異型apoAV強化LPL的水解能力與對照組相比並無差異，雖然此結果需待更佳的實驗設計後才能確認，但是否暗示不同的調控機制亦值得討論。 | zh_TW |
| dc.description.abstract | Hypertriglyceridemia (HTG) is an independent risk factor for the development of cardiovascular disease and is often associated with diabetes, inflammation and the metabolic syndrome. Recently, apolipoprotein A5 (APOA5) was identified as a novel member of the APOAI/CIII/AIV gene cluster. Data from mice over-expressing or lacking apoAV provide direct evidence that this apolipoprotein plays a crucial role in triglyceride metabolism. Moreover, plasma triglyceride levels were found to be strongly associated with APOA5 polymorphisms. We previously identified genetic variant in Chinese people, c.553G > T in the APOA5 gene which causes a substitution of a cysteine for a glycine residue at amino acid residue 185 is associated with increased TG levels, also a risk factor for coronary artery disease.
The human APOA5 gene is regulated by transcription factors known to affect triglyceride metabolism such as PPARα, RORα, LXR ,SREBP-1c and thyroid receptorβ and this supports its function. To date, the triglyceride lowering action of apoA5 is attributed to the activation of lipoprotein lipase (LPL) and an acceleration of very low density lipoprotein catabolism. Recent findings indicate that APOA5 could also influence cholesterol homeostasis and probably play a role in hypertriglyceridemia associated with diabetes and inflammation. Considering clinical application, we want to examine whether APO A5 is the new drug target for HTG. For that, we examined drugs and chemicals effects on APOA A5 promoter activity. Further, whether these new strategies for curing HTG are practicable therapies. All drugs and chemicals increased the expression of APOA5 promoter from 118.4 % to 453.9 % . While drugs or chemicals increased the wild type and variant apoAV concentractions from 62.5 % to 208.9 % and 39 % to 273.1 % respectively, the LPL-activating abilities of drugs-treated apoAV remained the same among wild type, variant and control. Maybe proper methodology of LPL activity assay is needed for further studies. Further studie is needed to explore the mechanism. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T00:38:38Z (GMT). No. of bitstreams: 1 ntu-96-R94424023-1.pdf: 1384618 bytes, checksum: 14d0f994ef96e2ded8e2423d926cc1dc (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | 總目次.……………………………………………………………………………I
圖目次……………………………………………………………………………III 表目次……………………………………………………………………………IV 附錄目次…………………………………………………………………………IV 簡稱或縮寫對照表………………………………………………………………V 摘要……………………………………………………………………………VIII Abstract……………………………………………………………………………IX 第一章 導論 第一節 前言……………………………………………………………….…1 第二節 高三酸甘油酯血症……………………………………………….…1 第三節 脂蛋白解脂酶…………………………………………………….…1 第四節 脂蛋白元………………………………………………………….…3 第五節 脂蛋白元AV……………………………………………… …….…3 第六節 高脂血症的治療…………………………………………………....7 第七節 藥物選用……………………………………………………………8 第八節 藥物特性……………………………………………………………9 第九節 研究動機…………………………………………………………12 第二章 實驗材料與方法 第一節 儀器設備……………………………………………………...........13 第二節 試藥、試劑組與耗材……………………………….......……..….14 第三節 實驗方法…………………………………………………...………18 第三章 實驗結果 第一節 脂蛋白元A5啟動子(pBlue-TOPO-A5p)的選殖…………………24 第二節 溶液對細胞毒性的測試…………………………………………..24 第三節 藥物對細胞毒性的測試………………………….………….........26 第四節 藥物作用脂蛋白元A5啟動子後報導基因表現量之分析...........28 第五節 全長脂蛋白元A5（pTOPO-A5WT）之選殖………………..........29 第六節 全長變異型脂蛋白元A5（pTOPO-A5c.553G>T）的選殖................30 第七節 藥物作用野生型與變異型脂蛋白元A5後蛋白表現量之分析...31 第八節 極低密度脂蛋白的分離………………………………...…...........32 第九節 藥物作用野生型與變異型脂蛋白元A5後蛋白強化LPL活性之分析…...…......................................................................................…32 第四章 討論…………………………………………........…………….…….…...33 附圖…………………………………………………………….……........……..…37 附表……………………………………………………………….……….........….57 附錄...................…………………………………………………….……...........…62 參考文獻…………………………………………………………….…….….........85 圖目次 圖 1 :人類脂蛋白元A5啟動子之PCR電泳圖…………………...…….…….....….37 圖 2 : pBlue-TOPO-A5p的XmnI 切割確認圖譜…………………………...….......38 圖 3 : pBlue-TOPO-A5p直接定序..............................................................................39 圖 4 :溶液對細胞存活度的影響………………………….……...……….............…40 圖 5 :藥物對細胞存活度的影響……………………………………...……..............41 圖 6: Fibrates類藥物作用後報導基因之表現量分析………………..........43 圖 7 : Esculetin與Curcumin作用後報導基因之表現量分析……...….......44 圖 8: T3與T4作用後報導基因之表現量分析……………………..…...........45 圖 9 : 藥物作用後hAPOA5啟動子誘發驅動值增量百分比…………………...…46 圖10: XbaI、EcoRI 雙酵素切割圖譜………………………………..…..............….47 圖11 : pTOPO-A5WT的ApaLI 切割確認圖譜…………………………....….......…48 圖12 :MspI 切割確認………………………………………………………....…......49 圖13 : pTOPO-A5c.553G>T直接定序…………………………..……………...............50 圖14 :Fibrates類藥物作用後細胞培養液中apoAV表現量分析…...........................51 圖15 : Curcumin與Esculetin作用後細胞培養液中apoAV表現量分析…..........….52 圖16 : T3與T4作用後細胞培養液中apoAV表現量分析…....................……........53 圖17 :藥物作用後細胞培養液中標準化apoAV濃度值增量百分………..……..…54 圖18、Esculetin作用後細胞培養液中野生型與變異型apoAV強化能力分析.…55 圖1 9:野生型與變異型apoAV強化LPL作用分析...…..........................……........56 表目次 表一 : 調節人類脂蛋白元A5基因之轉錄因子................................................57 表二 : 調節人類脂蛋白元A5基因之脂質恆定相關核受體...........................58 表三 : 實驗過程中所需之寡核酸引子序列......................................................58 表四 : 人類全長脂蛋白元AV的基本特性分析..............................................59 表五 : 人類成熟脂蛋白元AV的基本特性分析..............................................60 表六 : 世界衛生組織對高脂蛋白血症的分類…..............................................61 附錄目次 附錄一 : 人類脂蛋白元A5啟動子序列之示意圖............................................62 附錄二 : pBlue-TOPO 之示意圖........................................................................63 附錄三 : pTOPO-A5WT 之示意圖.................................................................... 64 附錄四 : 定位點突變..........................................................................................65 附錄五： 實驗流程...............................................................................................66 | |
| dc.language.iso | zh-TW | |
| dc.subject | 三酸甘油脂 | zh_TW |
| dc.subject | 脂蛋白元A5 | zh_TW |
| dc.subject | 脂蛋白元A5c.553G>T | zh_TW |
| dc.subject | 脂蛋白解脂酶 | zh_TW |
| dc.subject | 高三酸甘油酯血症 | zh_TW |
| dc.subject | lipoprotein lipase | en |
| dc.subject | Hypertriglyceridemia | en |
| dc.subject | triglyceride | en |
| dc.subject | apolipoprotein A5 | en |
| dc.subject | apolipoprotein A5 c.553G >T | en |
| dc.title | 藥物對變異型脂蛋白元A5 c.553G>T之影響 | zh_TW |
| dc.title | Drugs Effects on Apolipoprotein A5 c.553 G>T Variant | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林淑華,林淑萍,江福田 | |
| dc.subject.keyword | 高三酸甘油酯血症,三酸甘油脂,脂蛋白元A5,脂蛋白元A5c.553G>T,脂蛋白解脂酶, | zh_TW |
| dc.subject.keyword | Hypertriglyceridemia,triglyceride,apolipoprotein A5,apolipoprotein A5 c.553G >T,lipoprotein lipase, | en |
| dc.relation.page | 95 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-07-25 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-96-1.pdf 未授權公開取用 | 1.35 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。