請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/42902完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 翁昭旼 | |
| dc.contributor.author | Yu-Ting Chang | en |
| dc.contributor.author | 張毓廷 | zh_TW |
| dc.date.accessioned | 2021-06-15T01:28:11Z | - |
| dc.date.available | 2012-09-15 | |
| dc.date.copyright | 2009-09-15 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-07-22 | |
| dc.identifier.citation | Aguilera, C. M., M. Gil-Campos, et al. (2008). 'Alterations in plasma and tissue lipids associated with obesity and metabolic syndrome.' Clin Sci (Lond) 114(3): 183-93.
Arduino, C., M. Gallo, et al. (1999). 'Polyvariant mutant CFTR genes in patients with chronic pancreatitis.' Clin Genet 56(5): 400-4. Athyros, V. G., O. I. Giouleme, et al. (2002). 'Long-term follow-up of patients with acute hypertriglyceridemia-induced pancreatitis.' J Clin Gastroenterol 34(4): 472-5. Balog, A., Z. Gyulai, et al. (2005). 'Polymorphism of the TNF-alpha, HSP70-2, and CD14 genes increases susceptibility to severe acute pancreatitis.' Pancreas 30(2): e46-50. Banks, P. A. and M. L. Freeman (2006). 'Practice guidelines in acute pancreatitis.' Am J Gastroenterol 101(10): 2379-400. Buch, A., J. Buch, et al. (1980). 'Hyperlipidemia and pancreatitis.' World J Surg 4(3): 307-14. Buratti, E. and F. E. Baralle (2001). 'Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9.' J Biol Chem 276(39): 36337-43. Cameron, J. L., G. D. Zuidema, et al. (1975). 'A pathogenesis for alcoholic pancreatitis.' Surgery 77(6): 754-63. Cavallini, G., L. Frulloni, et al. (2004). 'Prospective multicentre survey on acute pancreatitis in Italy (ProInf-AISP): results on 1005 patients.' Dig Liver Dis 36(3): 205-11. Chandak, G. R., M. M. Idris, et al. (2004). 'Absence of PRSS1 mutations and association of SPINK1 trypsin inhibitor mutations in hereditary and non-hereditary chronic pancreatitis.' Gut 53(5): 723-8. Chang, M. C., Y. T. Chang, et al. (2006). 'Association of tumour necrosis factor alpha promoter haplotype with chronic pancreatitis.' Gut 55(11): 1674-6. Chang, M. C., Y. T. Chang, et al. (2007). 'Spectrum of mutations and variants/haplotypes of CFTR and genotype-phenotype correlation in idiopathic chronic pancreatitis and controls in Chinese by complete analysis.' Clin Genet 71(6): 530-9. Chang, M. C., C. H. Su, et al. (2003). 'Etiology of acute pancreatitis--a multi-center study in Taiwan.' Hepatogastroenterology 50(53): 1655-7. Chang, Y. T., S. C. Wei, et al. (2009). 'Association and differential role of PRSS1 and SPINK1 mutation in early-onset and late-onset idiopathic chronic pancreatitis in Chinese subjects.' Gut 58(6): 885. Chen, P., Y. S. Jou, et al. (2005). 'Lipoprotein lipase gene is linked and associated with hypertension in Taiwan young-onset hypertension genetic study.' J Biomed Sci 12(4): 651-8. Cohn, J. A., K. J. Friedman, et al. (1998). 'Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis.' N Engl J Med 339(10): 653-8. Cuppens, H., W. Lin, et al. (1998). 'Polyvariant mutant cystic fibrosis transmembrane conductance regulator genes. The polymorphic (Tg)m locus explains the partial penetrance of the T5 polymorphism as a disease mutation.' J Clin Invest 101(2): 487-96. Das, H. K., C. L. Jackson, et al. (1987). 'The human apolipoprotein C-II gene sequence contains a novel chromosome 19-specific minisatellite in its third intron.' J Biol Chem 262(10): 4787-93. Dimagno, M. J., S. H. Lee, et al. (2005). 'A proinflammatory, antiapoptotic phenotype underlies the susceptibility to acute pancreatitis in cystic fibrosis transmembrane regulator (-/-) mice.' Gastroenterology 129(2): 665-81. Dominguez-Munoz, J. E., P. Malfertheiner, et al. (1991). 'Hyperlipidemia in acute pancreatitis. Relationship with etiology, onset, and severity of the disease.' Int J Pancreatol 10(3-4): 261-7. Dreiling, D. A. and M. Koller (1985). 'The natural history of alcoholic pancreatitis: update 1985.' Mt Sinai J Med 52(5): 340-2. Durno, C., M. Corey, et al. (2002). 'Genotype and phenotype correlations in patients with cystic fibrosis and pancreatitis.' Gastroenterology 123(6): 1857-64. El-Omar, E. M., C. S. Rabkin, et al. (2003). 'Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms.' Gastroenterology 124(5): 1193-201. Etemad, B. and D. C. Whitcomb (2001). 'Chronic pancreatitis: diagnosis, classification, and new genetic developments.' Gastroenterology 120(3): 682-707. Fallat, R. W., J. W. Vester, et al. (1973). 'Suppression of amylase activity by hypertriglyceridemia.' Jama 225(11): 1331-4. Farmer, R. G., E. I. Winkelman, et al. (1973). 'Hyperlipoproteinemia and pancreatitis.' Am J Med 54(2): 161-5. Fojo, S. S., S. W. Law, et al. (1987). 'The human preproapolipoprotein C-II gene. Complete nucleic acid sequence and genomic organization.' FEBS Lett 213(1): 221-6. Fortson, M. R., S. N. Freedman, et al. (1995). 'Clinical assessment of hyperlipidemic pancreatitis.' Am J Gastroenterol 90(12): 2134-9. Fredrickson, D. S., R. I. Levy, et al. (1967). 'Fat transport in lipoproteins--an integrated approach to mechanisms and disorders.' N Engl J Med 276(1): 34-42 contd. Frossard, J. L. and A. Hadengue (2001). '[Acute pancreatitis: new physiopathological concepts].' Gastroenterol Clin Biol 25(2): 164-76. Frossard, J. L., M. L. Steer, et al. (2008). 'Acute pancreatitis.' Lancet 371(9607): 143-52. Fujiki, K., H. Ishiguro, et al. (2004). 'Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis.' J Med Genet 41(5): e55. Gerasimenko, J. V., M. Sherwood, et al. (2006). 'NAADP, cADPR and IP3 all release Ca2+ from the endoplasmic reticulum and an acidic store in the secretory granule area.' J Cell Sci 119(Pt 2): 226-38. Ghanem, N., B. Costes, et al. (1994). 'Identification of eight mutations and three sequence variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.' Genomics 21(2): 434-6. Gloor, B., K. E. Todd, et al. (1998). 'Mechanism of increased lung injury after acute pancreatitis in IL-10 knockout mice.' J Surg Res 80(1): 110-4. Gotoda, T., N. Yamada, et al. (1991). 'Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency.' J Clin Invest 88(6): 1856-64. Greenberg, B. H., W. C. Blackwelder, et al. (1977). 'Primary type V hyperlipoproteinemia. A descriptive study in 32 families.' Ann Intern Med 87(5): 526-34. Guzman, S., F. Nervi, et al. (1985). 'Impaired lipid clearance in patients with previous acute pancreatitis.' Gut 26(9): 888-91. Haber, P. S., J. S. Wilson, et al. (1994). 'Lipid intolerance does not account for susceptibility to alcoholic and gallstone pancreatitis.' Gastroenterology 106(3): 742-8. Hacken, J. B. and R. M. Moccia (1979). 'Calcific pancreatitis in a patient with type 5 hyperlipoproteinemia.' Gastrointest Radiol 4(2): 143-6. Havel, R. J. (1969). 'Pathogenesis, differentiation and management of hypertriglyceridemia.' Adv Intern Med 15: 117-54. Hofbauer, B., H. Friess, et al. (1996). 'Hyperlipaemia intensifies the course of acute oedematous and acute necrotising pancreatitis in the rat.' Gut 38(5): 753-8. Imrie, C. W. (1997). 'Acute pancreatitis: overview.' Eur J Gastroenterol Hepatol 9(2): 103-5. Jaakkola, M. and I. Nordback (1993). 'Pancreatitis in Finland between 1970 and 1989.' Gut 34(9): 1255-60. Jap, T. S., S. F. Jenq, et al. (2003). 'Mutations in the lipoprotein lipase gene as a cause of hypertriglyceridemia and pancreatitis in Taiwan.' Pancreas 27(2): 122-6. Kerem, B., J. M. Rommens, et al. (1989). 'Identification of the cystic fibrosis gene: genetic analysis.' Science 245(4922): 1073-80. Kimura, T., J. K. Toung, et al. (1980). 'Respiratory failure in acute pancreatitis: the role of free fatty acids.' Surgery 87(5): 509-13. Krauss, R. M. and A. G. Levy (1977). 'Subclinical chronic pancreatitis in type I hyperlipoproteinemia.' Am J Med 62(1): 144-9. Kruger, B., E. Albrecht, et al. (2000). 'The role of intracellular calcium signaling in premature protease activation and the onset of pancreatitis.' Am J Pathol 157(1): 43-50. Lee, J. H., J. H. Choi, et al. (2003). 'A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.' Hum Mol Genet 12(18): 2321-32. Lerch, M. M., A. K. Saluja, et al. (1993). 'Pancreatic duct obstruction triggers acute necrotizing pancreatitis in the opossum.' Gastroenterology 104(3): 853-61. Lesser, P. B. and A. L. Warshaw (1975). 'Diagnosis of pancreatitis masked by hyperlipemia.' Ann Intern Med 82(6): 795-8. Lindgren, F. T., L. C. Jensen, et al. (1972). The isolation and quantitative analysis of serum lipoproteins. New York, John Wiley & Sons. Lund, H., H. Tonnesen, et al. (2006). 'Long-term recurrence and death rates after acute pancreatitis.' Scand J Gastroenterol 41(2): 234-8. Miller, A., R. S. Lees, et al. (1979). 'The natural history and surgical significance of hyperlipemic abdominal crisis.' Ann Surg 190(3): 401-8. Morton, C., A. L. Klatsky, et al. (2004). 'Smoking, coffee, and pancreatitis.' Am J Gastroenterol 99(4): 731-8. Murphy, J. A., D. N. Criddle, et al. (2008). 'Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells.' Gastroenterology 135(2): 632-41. Nam, M. H., M. Hijikata, et al. (2005). 'Variations of the CFTR gene in the Hanoi-Vietnamese.' Am J Med Genet A 136(3): 249-53. Nauck, M. S., H. Nissen, et al. (1998). 'Detection of mutations in the apolipoprotein CII gene by denaturing gradient gel electrophoresis. Identification of the splice site variant apolipoprotein CII-Hamburg in a patient with severe hypertriglyceridemia.' Clin Chem 44(7): 1388-96. Ngiam, N. S., S. S. Chong, et al. (2006). 'Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study.' J Cyst Fibros 5(3): 159-64. Norman, J. G., G. W. Fink, et al. (1996). 'Timing of tumor necrosis factor antagonism is critical in determining outcome in murine lethal acute pancreatitis.' Surgery 120(3): 515-21. Oppenheimer, E. H. and J. R. Esterly (1975). 'Pathology of cystic fibrosis review of the literature and comparison with 146 autopsied cases.' Perspect Pediatr Pathol 2: 241-78. Pandol, S. J., A. K. Saluja, et al. (2007). 'Acute pancreatitis: bench to the bedside.' Gastroenterology 132(3): 1127-51. Parekh, A. B. and J. W. Putney, Jr. (2005). 'Store-operated calcium channels.' Physiol Rev 85(2): 757-810. Petersen, O. H. and R. Sutton (2006). 'Ca2+ signalling and pancreatitis: effects of alcohol, bile and coffee.' Trends Pharmacol Sci 27(2): 113-20. Raraty, M., J. Ward, et al. (2000). 'Calcium-dependent enzyme activation and vacuole formation in the apical granular region of pancreatic acinar cells.' Proc Natl Acad Sci U S A 97(24): 13126-31. Riordan, J. R., J. M. Rommens, et al. (1989). 'Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.' Science 245(4922): 1066-73. Rommens, J. M., M. C. Iannuzzi, et al. (1989). 'Identification of the cystic fibrosis gene: chromosome walking and jumping.' Science 245(4922): 1059-65. Rowntree, R. and A. Harris (2002). 'DNA polymorphisms in potential regulatory elements of the CFTR gene alter transcription factor binding.' Hum Genet 111(1): 66-74. Rowntree, R. K. and A. Harris (2003). 'The phenotypic consequences of CFTR mutations.' Ann Hum Genet 67(Pt 5): 471-85. Saharia, P., S. Margolis, et al. (1977). 'Acute pancreatitis with hyperlipemia: studies with an isolated perfused canine pancreas.' Surgery 82(1): 60-7. Sandler, R. S., J. E. Everhart, et al. (2002). 'The burden of selected digestive diseases in the United States.' Gastroenterology 122(5): 1500-11. Schmitt-Grohe, S., F. Stuber, et al. (2006). 'TNF-alpha promoter polymorphism in relation to TNF-alpha production and clinical status in cystic fibrosis.' Lung 184(2): 99-104. Sharer, N., M. Schwarz, et al. (1998). 'Mutations of the cystic fibrosis gene in patients with chronic pancreatitis.' N Engl J Med 339(10): 645-52. Sparkes, R. S., S. Zollman, et al. (1987). 'Human genes involved in lipolysis of plasma lipoproteins: mapping of loci for lipoprotein lipase to 8p22 and hepatic lipase to 15q21.' Genomics 1(2): 138-44. Speck, L. (1865). 'Fall von lipamia.' Arch Verin Wissenschaftl Heilkunde 1: 232. Steinberg, W. and S. Tenner (1994). 'Acute pancreatitis.' N Engl J Med 330(17): 1198-210. Steiner, B., K. Truninger, et al. (2004). 'The role of common single-nucleotide polymorphisms on exon 9 and exon 12 skipping in nonmutated CFTR alleles.' Hum Mutat 24(2): 120-9. Sztefko, K. and J. Panek (2001). 'Serum free fatty acid concentration in patients with acute pancreatitis.' Pancreatology 1(3): 230-6. Trapnell, J. E. and E. H. Duncan (1975). 'Patterns of incidence in acute pancreatitis.' Br Med J 2(5964): 179-83. Truninger, K., P. A. Schmid, et al. (2006). 'Recurrent acute and chronic pancreatitis in two brothers with familial chylomicronemia syndrome.' Pancreas 32(2): 215-9. Tsuang, W., U. Navaneethan, et al. (2009). 'Hypertriglyceridemic pancreatitis: presentation and management.' Am J Gastroenterol 104(4): 984-91. Tukiainen, E., M. L. Kylanpaa, et al. (2005). 'Pancreatic secretory trypsin inhibitor (SPINK1) gene mutations in patients with acute pancreatitis.' Pancreas 30(3): 239-42. Wang, C. S., J. Hartsuck, et al. (1992). 'Structure and functional properties of lipoprotein lipase.' Biochim Biophys Acta 1123(1): 1-17. Wang, Y., L. Sternfeld, et al. (2008). 'Enhanced susceptibility to pancreatitis in severe hypertriglyceridemic lipoprotein lipase deficient mice and agonist-like function of pancreatic lipase in pancreatic cells.' Gut. Warshaw, A. L., C. A. Bellini, et al. (1975). 'Inhibition of serum and urine amylase activity in pancreatitis with hyperlipemia.' Ann Surg 182(1): 72-5. Wei, C. F., Y. K. Tsao, et al. (1985). 'The structure of the human apolipoprotein C-II gene. Electron microscopic analysis of RNA:DNA hybrids, complete nucleotide sequence, and identification of 5' homologous sequences among apolipoprotein genes.' J Biol Chem 260(28): 15211-21. Weiss, F. U., W. Halangk, et al. (2008). 'New advances in pancreatic cell physiology and pathophysiology.' Best Pract Res Clin Gastroenterol 22(1): 3-15. Werner, J., S. Feuerbach, et al. (2005). 'Management of acute pancreatitis: from surgery to interventional intensive care.' Gut 54(3): 426-36. Whitcomb, D. C. (2004). 'Value of genetic testing in the management of pancreatitis.' Gut 53(11): 1710-7. Whitcomb, D. C. (2005). 'Genetic polymorphisms in alcoholic pancreatitis.' Dig Dis 23(3-4): 247-54. Whitcomb, D. C., M. C. Gorry, et al. (1996). 'Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.' Nat Genet 14(2): 141-5. Whitcomb, D. C., R. A. Preston, et al. (1996). 'A gene for hereditary pancreatitis maps to chromosome 7q35.' Gastroenterology 110(6): 1975-80. Williams, M. and H. H. Simms (1999). 'Prognostic usefulness of scoring systems in critically ill patients with severe acute pancreatitis.' Crit Care Med 27(5): 901-7. Wilson, A. G., J. A. Symons, et al. (1997). 'Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.' Proc Natl Acad Sci U S A 94(7): 3195-9. Wion, K. L., T. G. Kirchgessner, et al. (1987). 'Human lipoprotein lipase complementary DNA sequence.' Science 235(4796): 1638-41. Witt, H., M. V. Apte, et al. (2007). 'Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy.' Gastroenterology 132(4): 1557-73. Witt, H., W. Luck, et al. (2000). 'Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis.' Nat Genet 25(2): 213-6. Yadav, D., G. I. Papachristou, et al. (2007). 'Alcohol-associated pancreatitis.' Gastroenterol Clin North Am 36(2): 219-38, vii. Yadav, D. and C. S. Pitchumoni (2003). 'Issues in hyperlipidemic pancreatitis.' J Clin Gastroenterol 36(1): 54-62. Yu, X. H., T. Q. Zhao, et al. (2006). 'A novel substitution at the translation initiator codon (ATG-->ATC) of the lipoprotein lipase gene is mainly responsible for lipoprotein lipase deficiency in a patient with severe hypertriglyceridemia and recurrent pancreatitis.' Biochem Biophys Res Commun 341(1): 82-7. Zielenski, J. and L. C. Tsui (1995). 'Cystic fibrosis: genotypic and phenotypic variations.' Annu Rev Genet 29: 777-807. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/42902 | - |
| dc.description.abstract | 高三酸甘油酯血症是導致急性胰臟炎的原因之一，約有3∼38%的急性胰臟炎是由高三酸甘油酯血症所引起。在台灣，高三酸甘油酯血症是造成急性胰臟炎第三常見的原因。至於高三酸甘油酯血症如何引發急性胰臟炎，目前致病機轉並不清楚。過去對lipoprotein lipase (LPL)及apolipoprotein基因的研究，發現這類基因的突變與高三酸甘油酯血症有關，但並不能解釋為何有些高三酸甘油酯血症病人會發生急性胰臟炎，而有些病人卻從不發生急性胰臟炎。而與胰臟發炎有關的基因如：cystic fibrosis transmembrane conductance regulator (CFTR)、cationic trypsinogen gene (PRSS1)、serine protease inhibitor Kazal type 1 (SPINK1)及致發炎基因像是腫瘤壞死因子(Tumor necrosis factor, TNF)-α等，這些基因在高三酸甘油酯血症合併急性胰臟炎的病人，從未被研究過。之前動物實驗研究顯示，當cftr 基因被完全毁壞的老鼠，因其易發炎的特徵而容易導致嚴重的急性胰臟炎。過去高三酸甘油酯血症急性胰臟炎的宿主易發病傾向並未被深入研究。本研究的第一部分是高三酸甘油酯胰臟炎的相關基因研究，假說之一是高三酸甘油酯血症的病人其CFTR、SPINK1、PRSS1及發炎基因像是TNF-α的突變或變異，使宿主易發生急性胰臟炎。為了研究此假說及高三酸甘油酯血症的致病機轉，本研究分析高三酸甘油酯血症病人合併急性胰臟炎，與高三酸甘油酯血症無急性胰臟炎病人，其CFTR、SPINK1、PRSS1及TNF-α之基因變化。我們對126位高三酸甘油酯血症的病患進行基因分析，其中包含46位曾有過高三酸甘油酯血症急性胰臟炎和另外80位從未發生過急性胰臟炎高三酸甘油酯血症病患。這126位高三酸甘油酯血症病患的PRSS1、SPINK 1及CFTR三個基因的突變與變異以及腫瘤壞死因子驅動子的多型性，全部都以變性高效能液相色層分析（Denaturing High Performance Liquid Chromatography, DHPLC）或以直接核苷酸定序來確定基因的變異。吾人發現在126位高三酸甘油酯血症的病患中，13位(10.3%)有CFTR基因的突變，而全部的病患都沒有PRSS1或 SPINK1的基因突變發生。CFTR基因突變的比例在高三酸甘油酯血症合併急性胰臟炎病患及高三酸甘油酯血症無合併急性胰臟炎病患各為46%(12/26)及1.3%(1/80)，兩者在統計學上有顯著的差異(p<0.0001) 。而CFTR基因的突變都是Ile 556 Val。多變項分析發現血中三酸甘油酯的濃度, CFTR470val及腫瘤壞死因子α驅動子-863A基因多型性各為高三酸甘油酯血症產生急性胰臟炎的獨立危險因子。而高三酸甘油酯胰臟炎的基因研究中我們也分析與脂質代謝有關的基因包括脂蛋白脂肪酶(lipoprotein lipase; LPL)及Apolipoprotein CⅡ (APO CII) 的基因突變是否與高三酸甘油酯血症產生急性胰臟炎的發作或導致慢性胰臟炎有相關。我們共分析了134位高三酸甘油酯血症的病患，其中53位曾發生過急性胰臟炎，而另外81位則從未曾發生急性胰臟炎。這134位高三酸甘油酯血症病患的LPL及APO CII的基因變異，都用變性高效能液相色層分析或高解析熔點分析(High Resolution Melting ; HRM)來篩檢，而篩檢出來的變異均用核苷酸定序來確認。我們發現在134位高三酸甘油酯血症病患中有9.7%(134位中有13位)有LPL基因的突變。LPL在高三酸甘油酯血症發生急性胰臟炎的病患有基因突變的機率是17%(53位中有9位)，遠比在高三酸甘油酯血症沒有急性胰臟炎病患的4.7%(81位中有4位)來的高，兩者在統計學上有顯著的差異(p<0.0001) 。最常見的LPL基因突變位置是L252V及S447X，而在高三酸甘油酯血症合併急性胰臟炎且有LPL基因突變的病患中77.8%(9位中有7位)是S447X的變異。多變項分析發現LPL基因的突變與急性胰臟炎發作的次數是產生胰臟鈣化及脂便等慢性胰臟炎特徵的獨立危險因子。本研究第二部分我們提出假說認為三酸甘油酯的成份也就是飽和脂肪酸及不飽和脂肪酸的比例會影響高三酸甘油酯血症的病患是否會發生急性胰臟炎有關。為了檢驗這個假說我們建立老鼠胰臟腺細胞的胰臟炎研究模式，探討各種不同濃度，不同飽合及不飽和脂肪酸對胰臟腺細胞細胞質中鈣離子濃度的影響。我們發現高濃度的不飽和脂肪酸如亞麻油酸(linoleic acid)、油酸(oleic acid)及棕梠油酸(palmitoleic acid)等會引發胰臟腺細胞細胞質中鈣離子濃度的上升，而低濃度的不飽和脂肪酸如亞麻油酸、油酸及棕梠油酸等，以及高濃度與低濃度的飽和脂肪酸如棕梠酸(palmitic acid) 及硬脂酸(stearic acid)均不能引發胰臟腺細胞細胞質中鈣離子濃度的上升。而高濃度的三酸甘油酯也無法立即引發腺細胞細胞質中鈣離子濃度的上升，顯示高濃度的三酸甘油酯本身並不能引發急性胰臟炎的發作，而必須在三酸甘油酯水解成脂肪酸之後且不飽和脂肪酸/飽和脂肪酸的比例偏高時，胰臟腺細胞才會受損而引發急性胰臟炎。這結果提供臨床上為什麼只有部份高三酸甘油酯血症病患會產生急性胰臟炎的一個可能解釋。綜合本研究結果顯示CFTR基因的不同變異與各種不同成因的胰臟炎的表現型有相關。而高三酸甘油酯血症的病患如果同時有CFTR基因的變異產生急性胰臟炎的風險比較高，而若同時再有腫瘤壞死因子α驅動子基因多型性-863A的特徵，胰臟炎的發生機率會更高。另外LPL基因變異與高三酸甘油酯急性胰臟炎的發作也與高三酸甘油酯血症形成慢性胰臟炎有關。高三酸甘油酯血症產生急性胰臟炎或高三酸甘油酯血症產生慢性胰臟炎是多因子，多基因共同作用的結果並與高三酸甘油酯的組成成份有關。 | zh_TW |
| dc.description.abstract | Hypertriglyceridemia (HTG) is a well known association of acute pancreatitis and found in 3-38% of patients with acute pancreatitis. HTG is the third frequent etiology of acute pancreatitis in Taiwan, account for about 10-15% of our patients suffering acute pancreatitis. The mechanism that how hypertriglyceridemia leads to pancreatitis attack and whether HTG could cause chronic pancreatitis are not clear. Genetic factors such as lipoprotein lipase and apolipoprotein mutations are reported to be associated with occurrence of HTG but could not explain why some patients experienced acute pancreatitis and why some patients with HTG seldom develop pancreatitis, even with marked elevation of triglyceride level. Whether the genes involved in pancreatic ductal or acinar cell injury including cationic trypsinogen gene (PRSS1), pancreatic secretory trypsin inhibitor gene (SPINK1), cystic fibrosis transmembrance conductance regulator (CFTR) and inflammation genes (tumor necrosis factor, TNF-alpha) are associated with hyperlipidemic pancreatitis (HLP) in patients with hypertriglyceridemia (HTG) has never been studied. In an animal study with cftr(-/-) mice, a baseline proinflammatory state and an antiapoptotic phenotype were observed and the cftr(-/-) mice was susceptible to severe acute pancreatitis. We hypothesized those genetic variations, including CFTR, PRSSI, SPINK1 genes, and proinflammatory cytokine gene: such as TNF-α, etc., make patients with HTG susceptible to developing acute pancreatitis. To investigate the hypothesis, we analyzed the genetic variations of CFTR and TNF-α in patients with HTG and acute pancreatitis, and in patients with HTG but without acute pancreatitis. we performed genetic analysis of 126 HTG patients in Taiwan (46 with HLP and 80 without HLP). The entire coding and intronic regions of the PRSS1, SPINK1, and CFTR genes were identified by heteroduplex analysis techniques and were confirmed by sequencing analysis. The presence of 125G/C, 1001 + 11C>T, 1540A>G (Met470Val), 2694T>G, and 4521G>A in CFTR, the presence of 272C>T in SPINK1, and TNF promoter polymorphisms (nucleotide positions -1031, -863, -857, -308, and -238) were measured by direct sequencing. Of the 126 HTG patients, 13 (10.3%) carried a CFTR mutation. No PRSS1 or SPINK1 mutations were detected in our patients or in HTG controls. The CFTR gene mutation rates in HTG with and without HLP were 26.1% (12 of 46) and 1.3% (1 of 80), respectively (P <0.0001). The CFTR gene mutations were all Ile556Val. A multivariate analysis of HTG patients indicated that triglycerides, CFTR 470Val, and TNF promoter -863A were independent risk markers for HLP. In addition, we sought to determine whether the genes involved lipid metabolism including lipoprotein lipase (LPL) and apolipoprotein CII (APO CII) are associated with HLP and chronic pancreatitis in patients with HTG. We performed genetic analysis of 134 patients in Taiwan with HTG (53 with HLP and 81 without HLP). The entire coding and intronic regions of the LPL and APO CII genes were identified with heteroduplex analytical techniques or high resolution melting analysis. All mutations were confirmed by sequencing analysis. Correlation of phenotype and genotype also analyzed. The frequency of LPL gene mutation rates in HLP patients17.0 %( 9 of 53) is significantly higher than that without HLP attack 4.9% (4 of 81) (P<0.0001). A total of 9.7% (13 of 134) of our HTG patients carried LPL mutation. The most two common LPL gene mutations were L252V and S447X. Our results also firstly demonstrate a high prevalence (77.8%) of HLP attack in HTG patients carrying S447X mutation. Multivariate analysis in HLP patients indicated that the presence of LPL mutation and episode of acute attack were independent risk markers for pancreatic calcification occurrence and steatorrhea. This genetic study is the first one to address the association of HLP with the CFTR mutation/variant/haplotype and TNF promoter polymorphism in a Chinese HTG population. This is also the first complete genetic study to address the association of HLP with the LPL mutation in a Chinese HTG population. LPL gene mutation is associated with pancreatic calcification in HLP patient. The results enhance that the occurrence of HLP is multifactorial and polygenic. In the second part of the studies, we hypothesized that the components of triglyceride, that is: saturated and unsaturated fatty acids, may influence the susceptibility to develop acute pancreatitis in HTG patients. To investigate the hypothesis, we set up primary pancreatic acinar cell culture to measure the cytosolic Ca2+ signal change in acinar cells after treated with different saturated and unsaturated fatty acids. We found that the unsaturated fatty acids, including Oleic acid, Linoleic acid, and Palmitoleic acid, in high concentration induced the persistent rise of cytosolic Ca2+ concentration in acinar cell similar to the condition with supra-maximal concentrations of CCK-induced elevation of baseline Ca2+ in isolated pancreatic acinar cells. However, unsaturated fatty acids, including Oleic acid, Linoleic acid, and Palmitoleic acid, in low concentration and saturated fatty acids, including Palmitic acid and Stearic acid, in low and high concentrations could not induce the rise of Ca2+ concentration in acinar cell. Triglyceride in high concentration itself initially did not cause the rise of cytosolic Ca2+ concentration in acinar cell. The results indicted that the HTG itself could not induce the attack of acute pancreatitis. Only under circumstance of the hydrolysis of triglyceride by lipase into free fatty acids, and the ratio of unsaturated/saturated fatty acid high enough, the acinar cells become injured then pancreatitis developed. The results provide a potential explanation that why clinically only a portion of HTG patients develop HLP. The unsaturated fatty acids may play a crucial role in the pathogenesis of HLP. In conclusion, CFTR mutations are associated with a broad spectrum of pancreatic phenotypes. Identification of the association of CFTR and other genes with HLP has provided evidence that HTG patients with CFTR mutations/variants are more susceptible to developing HLP. This susceptibility increased after CFTR mutation/variant interaction with proinflammatory cytokines such as TNF. In addition, LPL gene mutations are associated with attack of HLP in HTG populations. Identification of distinct genes associated with HTG has provided evidence that HTG patients with LPL mutations are more susceptible to HLP attack and development of chronic pancreatitis. The development of HLP in HTG patients and chronic pancreatitis related to HTG appear to be a multifactorial and polygenic event and related to the components of triglyceride. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T01:28:11Z (GMT). No. of bitstreams: 1 ntu-98-D91421003-1.pdf: 2366953 bytes, checksum: c6a033fcbe289a2af12b2c76e0261923 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 一、 中文摘要---5
二、 英文摘要---8 三、 緒論------12 3.1 急性胰臟炎的臨床表現及病態生理學-------12 3.2 急性胰臟炎的成因--13 3.3 高三酸甘油酯血症與高三酸甘油酯急性胰臟炎---------14 3.4 高三酸甘油酯急性胰臟炎的特殊臨床表現---15 3.5 高三酸甘油酯急性胰臟炎的致病機轉-------16 3.6 高三酸甘油酯急性胰臟炎的治療及預防-----17 3.7 高三酸甘油酯急性胰臟炎的基因研究-------18 3.8 鈣離子訊息傳遞在急性胰臟炎的角色-------24 3.9 高三酸甘油酯急性胰臟炎尚未解決的問題---28 3.10 研究方向假說及目標---------28 四、 方法 4.1 高三酸甘油酯急性胰臟炎的基因研究-------30 4.2三酸甘油酯及各種脂肪酸對胰臟腺細胞鈣離子濃度的影響--36 五 結果 5.1 CFTR基因的變異(突變、基因多型性與配子型基因分析)與TNF-α promoter多型性和高三酸甘油酯急性胰臟炎臨床表現之相關-40 5.2 LPL 與APO CII 基因的變異和高三酸甘油酯急性胰臟炎臨床表現之相關---43 5.3 三酸甘油酯及各種脂肪酸對胰臟腺細胞鈣離子濃度的影響---45 六 討論-------48 七 展望-------57 八 論文英文簡述----------60 九 參考文獻---82 十 圖表-------89 十一 附錄----126 | |
| dc.language.iso | zh-TW | |
| dc.subject | 飽和脂肪酸 | zh_TW |
| dc.subject | 高三酸甘油酯血症 | zh_TW |
| dc.subject | 高三酸甘油酯急性胰臟炎 | zh_TW |
| dc.subject | cystic fibrosis transmembrane conductance regulator (CFTR) | zh_TW |
| dc.subject | 腫瘤壞死因子TNF-α | zh_TW |
| dc.subject | lipoprotein lipase | zh_TW |
| dc.subject | Apolipoprotein CⅡ | zh_TW |
| dc.subject | 高效能液相色層分析（Denaturing High Performance Liquid Chromatography | zh_TW |
| dc.subject | DHPLC） | zh_TW |
| dc.subject | 高解析熔點分析(High Resolution Melting | zh_TW |
| dc.subject | HRM) | zh_TW |
| dc.subject | 鈣離子 | zh_TW |
| dc.subject | 不飽和脂肪酸 | zh_TW |
| dc.subject | Ca2+ | en |
| dc.subject | Denaturing High Performance Liquid Chromatography(DHPLC) | en |
| dc.subject | High Resolution Melting(HRM) | en |
| dc.subject | saturated fatty acid | en |
| dc.subject | unsaturated fatty acid | en |
| dc.subject | hyperlipidemic pancreatitis(HLP) | en |
| dc.subject | hypertriglyceridemia (HTG) | en |
| dc.subject | cystic fibrosis transmembrane conductance regulator (CFTR) | en |
| dc.subject | Tumor necrosis factor-alpha(TNF-α) | en |
| dc.subject | lipoprotein lipase(LPL) | en |
| dc.subject | Apolipoprotein CII(APO CII) | en |
| dc.title | 高三酸甘油酯胰臟炎之基因易感性及致病機轉研究 | zh_TW |
| dc.title | Hypertriglyceridemic Pancreatitis: Studies of Genetic Susceptibility and Pathogenesis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.coadvisor | 高嘉宏 | |
| dc.contributor.oralexamcommittee | 張美惠,陳繼明,沈柏青 | |
| dc.subject.keyword | 高三酸甘油酯血症,高三酸甘油酯急性胰臟炎,cystic fibrosis transmembrane conductance regulator (CFTR),腫瘤壞死因子TNF-α,lipoprotein lipase,Apolipoprotein CⅡ,高效能液相色層分析（Denaturing High Performance Liquid Chromatography, DHPLC）,高解析熔點分析(High Resolution Melting , HRM),鈣離子,不飽和脂肪酸,飽和脂肪酸, | zh_TW |
| dc.subject.keyword | hyperlipidemic pancreatitis(HLP),hypertriglyceridemia (HTG),cystic fibrosis transmembrane conductance regulator (CFTR),Tumor necrosis factor-alpha(TNF-α),lipoprotein lipase(LPL),Apolipoprotein CII(APO CII),Denaturing High Performance Liquid Chromatography(DHPLC),High Resolution Melting(HRM),Ca2+,saturated fatty acid,unsaturated fatty acid, | en |
| dc.relation.page | 129 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2009-07-22 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床醫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-98-1.pdf 未授權公開取用 | 2.31 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。