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DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 于明暉(Ming-Whei Yu) | |
dc.contributor.author | Chi-Jen Hsu | en |
dc.contributor.author | 許智仁 | zh_TW |
dc.date.accessioned | 2021-06-16T06:35:04Z | - |
dc.date.available | 2019-10-20 | |
dc.date.copyright | 2014-10-20 | |
dc.date.issued | 2014 | |
dc.date.submitted | 2014-08-02 | |
dc.identifier.citation | [1] Schwenzer, N. F., F. Springer, C. Schraml, N. Stefan, J. Machann and F. Schick. Non-invasive assessment and quantification of liver steatosis by ultrasound, com-puted tomography and magnetic resonance. J Hepatol 2009;51(3): 433-445.
[2] Starley, B. Q., C. J. Calcagno and S. A. Harrison. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010;51(5): 1820-1832. [3] Dyson, J., B. Jaques, D. Chattopadyhay, R. Lochan, J. Graham, D. Das, T. Aslam, I. Patanwala, S. Gaggar, M. Cole, K. Sumpter, S. Stewart, J. Rose, M. Hudson, D. Manas and H. L. Reeves. Hepatocellular cancer: the impact of obesity, type 2 dia-betes and a multidisciplinary team. J Hepatol 2014;60(1): 110-117. [4] Torres, DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology 2008;134:1682-1698. [5] El-Serag, H. B. and K. L. Rudolph. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132(7): 2557-2576. [6] Farrell, G. C.. Non-alcoholic steatohepatitis: what is it, and why is it important in the Asia-Pacific region? J Gastroenterol Hepatol 2003;18(2): 124-138. [7] Schaffner F, Thaler H. Nonalcoholic fatty liver disease. Prog Liver Dis 1986;8:283-298. [8] Shen L, Fan JG, Shao Y, Zeng MD, Wang JR, Luo GH, et al. Prevalence of non-alcoholic fatty liver among administrative officers in Shanghai: an epidemiological survey. World J Gastroenterol 2003;9: 1106-1110. [9] Adams LA, Feldstein AE. Nonalcoholic steatohepatitis: risk factors and diagnosis. Expert Rev Gastroenterol Hepatol. 2010;4:623-635. [10] de Ledinghen V, Ratziu V, Causse X et al. Diagnostic and predictive factors of significant liver fibrosis and minimal lesions in patients with persistent unex-plained elevated transaminases. A prospective multicenter study. J. Hepatol. 2006;45: 592–599. [11] Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124-131. [12] Chen CH, Huang MH, Yang JC, Nien CK, Yang CC, Yeh YH, et al. Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of Tai-wan: metabolic significance of nonalcoholic fatty liver disease in nonobese adults. J Clin Gastroenterol 2006;40. [13] Lin TJ, Lin CL, Wang CS, Liu SO, Liao LY. Prevalence of HFE mutations and relation to serum iron status in patients with chronic hepatitis C and patients with nonalcoholic fatty liver disease in Taiwan. World J Gastroenterol 2005;11:3905e8. [14] Fu CC, Chen MC, Li YM, Liu TT, Wang LY. The risk factors for ultra-sound-diagnosed non-alcoholic fatty liver disease among adolescents. Ann Acad Med Singap 2009;38. [15] Ong, JP, Younossi, ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis 2007;11:1-16, vii. [16] Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221-1231. [17] Fusamoto H, Suzuki K, Hayashi N, Sasaki Y, Kono M, Kasahara A, et al. Obesity and liver disease: evaluation of fatty infiltration of the liver using ultrasonic atten-uation. J Nutr Sci Vitaminol (Tokyo) 1991;37. [18] K.L. Kopec, D. Burns. Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutr Clin Pract 2011;26 :565–576. [19] Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position state-ment on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010;53. [20] Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006;43. [21] Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41 [22] Li H, Wang L, Yan X, Liu Q, Yu C, Wei H, et al. A proton nuclear magnetic reso-nance metabonomics approach for biomarker discovery in non-alcoholic fatty liver disease. J Proteome Res 2011;10:2797–2806. [23] Yamaguchi, S.; Koda, N.; Eto, Y.; Aoki, K. J. Pediatr. 1985;106: 620–622. [24] Nicholson, J. K., M. P. O'Flynn, P. J. Sadler, A. F. Macleod, S. M. Juul and P. H. Sonksen Proton-nuclear-magnetic-resonance studies of serum, plasma and urine from fasting normal and diabetic subjects. Biochem J 1984;217(2): 365-375. [25] Dunn, W. B.; Ellis, D. I. Trends Anal. Chem. 2005;24: 285–294. [26] Pauling, L.; Robinson, A. B.; Teranishi, R.; Cary, P. Proc. Natl. Acad. Sci. U.S.A. 1971;68: 2374–2376. [27] Gadian, D. G. Nuclear Magnetic Resonance and Its Applications to Living Sys-tems, 1st ed.; Oxford University Press: Oxford, 1982. [28] Iles, R. A.; Hind, A. J.; Chalmers, R. A. Clin. Chem. 1985;31: 1975–1801. [29] Robinson, A. B.; Cary, P.; Dore, B.; Keaveny, I.; Brenneman, L.; Turner, M.; Pau-ling, L. J. Int. Res. Commun. 1973;1: 47. [30] Toye AA, Dumas ME, Blancher C, Rothwell AR, Fearnside JF, Wilder SP, et al. Subtle metabolic and liver gene transcriptional changes underlie dietinduced fatty liver susceptibility in insulin-resistant mice. Diabetologia 2007;50:1867–1879. [31] Tanaka N, Matsubara T, Krausz KW, Patterson AD, Gonzalez FJ. Disruption of phospholipid and bile acid homeostasis in mice with non-alcoholic steatohepatitis. Hepatology 2012;56:118–129. [32] Puri P, Wiest MM, Cheung O, Mirshahi F, Sargeant C, Min HK, et al. The plasma lipidomic signature of non-alcoholic steatohepatitis. Hepatology 2009;50:1827–1838. [33] Garcia-Canaveras JC, Donato MT, Castell JV, Lahoz A. A comprehensive untar-geted metabonomic analysis of human steatotic liver tissue by RP and HILIC chromatography coupled to mass spectrometry reveals important metabolic altera-tions. J Proteome Res 2011;10:4825–4834. [34] Kalhan SC, Guo L, Edmison J, Dasarathy S, McCullough AJ, Hanson RW, et al. Plasma metabolomic profile in non-alcoholic fatty liver disease. Metabolism 2011;60:404–413. [35] Yu MW, Shih WL, Lin CL et al. Body-mass index and progression of hepatitis B: a population-based cohort study in men. J. Clin. Oncol. 2008; 26: 5576–82. [36] Viant, M. R. Improved methods for the acquisition and interpretation of NMR metabolomic data. Biochemical and Biophysical Research Communications 2003;310(3): 943-948. [37] K.L. Kopec, D. Burns. Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutr Clin Pract 2011;26: 565–576. [38] Yamaguchi, S.; Koda, N.; Eto, Y.; Aoki, K. J. Pediatr. 1985;106: 620–622. [39] Vinaixa M, Rodriguez MA, Rull A, Beltran R, Blade C, Brezmes J, et al. Metabo-lomic assessment of the effect of dietary cholesterol in the progressive develop-ment of fatty liver disease. J Proteome Res 2010;9:2527–2538. [40] van Ginneken V, Verhey E, Poelmann R, Ramakers R, van Dijk KW, Ham L, et al. Metabolomics (liver and blood profiling) in a mouse model in response to fasting: a study of hepatic steatosis. Biochim Biophys Acta 2007;1771:1263–1270. [41] Hyde MJ, Griffin JL, Herrera E, Byrne CD, Clarke L, Kemp PR. Delivery by Caesarean section, rather than vaginal delivery, promotes hepatic steatosis in pig-lets. Clin Sci (Lond) 2010;118:47–59. [42] Barr J, Vazquez-Chantada M, Alonso C, Perez-Cormenzana M, Mayo R, Galan A, et al. Liquid chromatography–mass spectrometry-based parallel metabolic profiling of human and mouse model serum reveals putative biomarkers associated with the progression of non-alcoholic fatty liver disease. J Proteome Res 2010;9:4501–4512. [43] Toye AA, Dumas ME, Blancher C, Rothwell AR, Fearnside JF, Wilder SP, et al. Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice. Diabetologia 2007;50:1867–1879. [44] Noguchi Y, Young JD, Aleman JO, Hansen ME, Kelleher JK, Stephanopoulos G. Tracking cellular metabolomics in lipoapoptosis- and steatosis-developing liver cells. Mol Biosyst 2011;7:1409–1419. [45] Griffin JL, Scott J, Nicholson JK. The influence of pharmacogenetics on fatty liver disease in the Wistar and Kyoto rats: a combined transcriptomic and metabonomic study. J Proteome Res 2007;6:54–61. [46] Wishart DS, Frolkis A, Knox C, et al., SMPDB: The Small Molecule Pathway Database. Nucleic Acids Res. 2010 Jan;38(Database issue):D480-7. [47] Jewison T, Su Y, Disfany FM, et al., SMPDB 2.0: Big Improvements to the Small Molecule Pathway Database Nucleic Acids Res. 2013 Submitted. [48] Schauder P, Zavelberg D, Langer K, Herbertz L. Sex-specific differences in plas-ma branched-chain keto acid levels in obesity. Am J Clin Nutr. 1987;46:58 – 60. [49] Caballero B, Wurtman RJ. Differential effects of insulin resistance on leucine and glucose kinetics in obesity. Metabolism. 1991;40:51 – 8. [50] Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, et al. A branched-chain amino acid-related meta-bolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009;9:311 – 26. [51] Huffman KM, Shah SH, Stevens RD, Bain JR, Muehlbauer M, Slentz CA, Tanner CJ, Kuchibhatla M, Houmard JA, Newgard CB, et al. Relationships between cir-culating metabolic intermediates and insulin action in overweight to obese, inac-tive men and women. Diabetes Care. 2009;32:1678 – 83. [52] Fiehn O, Garvey WT, Newman JW, Lok KH, Hoppel CL, Adams SH. Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women. PLoS ONE. 2010;5:e15234. [53] Gall WE, Beebe K, Lawton KA, Adam KP, Mitchell MW, Nakhle PJ, Ryals JA, Milburn MV, Nannipieri M, Camastra S, et al. alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE. 2010;5:e10883. [54] Menge BA, Schrader H, Ritter PR, Ellrichmann M, Uhl W, Schmidt WE, Meier JJ. Selective amino acid deficiency in patients with impaired glucose tolerance and type 2 diabetes. Regul Pept. 2010;160:75 – 80. [55] Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL, Ilkayeva OR, Wenner BR, Bain JR, Lee JJ, et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabeto-logia. 2010;53:757 – 67. [56] Adibi SA. Influence of dietary deprivations on plasma concentration of free ami-no acids of man. J Appl Physiol. 1968;25:52 – 7. [57] Felig P, Marliss E, Cahill GF Jr. Plasma amino acid levels and insulin secretion in obesity. N Engl J Med. 1969;281:811 – 6. [58] Zeng M, Liang Y, Li H, Wang M, Wang B, Chen X, Zhou N, Cao D, Wu J. Plasma metabolic fingerprinting of childhood obesity by GC/MS in conjunction with mul-tivariate statistical analysis. J Pharm Biomed Anal. 2010;52:265 – 72. [59] Wijekoon EP, Skinner C, Brosnan ME, Brosnan JT. Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes. Can J Physiol Pharmacol. 2004;82:506 – 14. [60] She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab. 2007;293:E1552 – 63. [61] Kuzuya T, Katano Y, Nakano I, Hirooka Y, Itoh A, Ishigami M, Hayashi K, Hon-da T, Goto H, Fujita Y, et al. Regulation of branched-chain amino acid catabolism in rat models for spontaneous type 2 diabetes mellitus. Biochem Biophys Res Commun. 2008;373:94 – 8. [62] Bajotto G, Murakami T, Nagasaki M, Sato Y, Shimomura Y. Decreased enzyme activity and contents of hepatic branched-chain alpha-keto acid dehydrogenase complex subunits in a rat model for type 2 diabetes mellitus. Metabolism. 2009;58:1489 – 95. [63] Doisaki M, Katano Y, Nakano I, Hirooka Y, Itoh A, Ishigami M, Hayashi K, Goto H, Fujita Y, Kadota Y, et al. Regulation of hepatic branched-chain alpha-keto acid dehydrogenase kinase in a rat model for type 2 diabetes mellitus at different stag-es of the disease. Biochem Biophys Res Commun. 2010;393:303 – 7. [64] Lehninger, A.L. Lehninger principles of biochemistry (4 th ed.). New York: W.H Freeman 2005. [65] Salway, J.G. Metabolism at a glance (3 rd ed.). Alden, Mass. : Blackwell Pub 2004. [66] Chao LT, Wu CF, Sung FY et al. Insulin, glucose and hepatocellular carcinoma risk in male hepatitis B carriers: results from 17-year follow-up of a population-based cohort. Carcinogenesis 2011; 32: 876–881. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/57105 | - |
dc.description.abstract | 背景:非酒精性脂肪肝病是指在沒有過度飲酒的情況下,肝臟內過多脂肪囤積的ㄧ種現象。近十年間,非酒精性脂肪肝病廣泛且快速的影響到全球人類。其中造成非酒精性脂肪肝病的主要危險因子包括糖尿病與肥胖。本研究的目的是透過代謝體學去探討人體內代謝小分子在B型肝炎帶原者身上,在與肥胖相關肝癌發展中所扮演的角色為何。
材料方法:本研究針對711名過重和肥胖的B型肝炎帶原者,研究在進入世代研究時人體內代謝小分子與肥胖相關肝癌發展中及肝生化指標之間的相關性。 結果:使用PLS-DA模型,從22個辨識出來的代謝小分子中,找出區分有無非酒精性脂肪肝病及肝生化指標之重要因子,並且挑出12個區分三酸甘油脂是否異常增加的重要代謝小分子,評估三酸甘油脂異常增加、脂肪肝與肝硬化之風險。控制年齡、吸菸與喝酒習慣與追蹤之肝生化指標後,有4個個高度表現代謝小分子,包括丙酮、低密度脂蛋白與極低密度脂蛋白和不飽和脂肪,與脂肪肝達統計上顯著正相關,但卻與肝硬化呈現顯著負相關;而低度表現的8個代謝小分子,包括檸檬酸、肌酸、beta葡萄糖、麩醯胺酸、甲醇、脯氨酸、酪氨酸和纈氨酸,與脂肪肝達統計上顯著負相關,但卻與肝硬化呈現顯著正相關。而這12個代謝小分子與肝癌都沒有達統計上顯著相關。 結論:本研究初步的結果顯示代謝小分子和三酸甘油脂異常增加與肥胖相關肝臟疾病之間的關聯。但是這些代謝小分子和肥胖相關肝臟疾病之間的關係並不一致。 | zh_TW |
dc.description.abstract | Background: Nonalcoholic fatty liver disease (NAFLD) occurs due to excessive fat accumulation in the liver cells, which is becoming an increasingly common cause of hepatic disease. Obesity and related metabolic syndrome increase the risk of NAFLD. The purpose of this study was to understand the mechanisms underlying the relationship between abnormal metabolism and obesity-related liver diseases in hepatitis B, with the use of metabolomics approach.
Materials and methods: Study subjects included a total of 711 overweight or obese men with hepatitis B, who were recruited from a cohort study of civil servants. Information on demographics, lifestyle habits, and medical history was obtained from a structured questionnaire. Metabolomics profiles of baseline serum samples were deter-mined using 1H nuclear magnetic resonance (NMR)-based metabolomics assay. Partial least squares discriminant analysis (PLS-DA) was applied to analyze the profiling data to identify the distinguishing metabolites of dyslipidemia and liver biochemical and ultrasonographic abnormalities as well as hepatocellular carcinoma. Results: A total of 22 metabolites was identified, 12 of which were important for classification of triglycerides (TG) abnormality, including 4 that were up-regulated and 8 that were down-regulated in participants with TG abnormality. The up-regulation of 4 metabolites, including acetone, VLDL/LDL (CH3-(CH2)n), VLDL/LDL (CH3-(CH2)n) and unsaturated lipid, tend to be positively associated with fatty liver but were significantly, inversely associated with liver cirrhosis. The down-regulation of 8 metabolites, including citrate, creatine, beta-glucose, glutamine, methanol, proline, tyrosine and valine, tend to be inversely associated with fatty liver but significantly, positively associated with liver cirrhosis. On the other hand, none of these 12 metabolites were significantly associated with hepatocellular carcinoma. Conclusion: Our preliminary results showed an association between elevated TG and an altered metabolite signature. The altered metabolites in relation to TG abnormality revealed no consistent patterns in any type of liver abnormalities. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T06:35:04Z (GMT). No. of bitstreams: 1 ntu-103-R01849009-1.pdf: 513382 bytes, checksum: 29321480e591883609717c1eea28d0ba (MD5) Previous issue date: 2014 | en |
dc.description.tableofcontents | 誌謝………………………………………………………………………………… i
中文摘要…………………………………………………………………………… ii Abstract…………………………………………………………………………… iii Contents…………………………………………………………………………… v Introduction………………………………………………………………………… 1 Epidemiology of NAFLD………………………………………………………… 1 Diagnosis of NAFLD……………………………………………………………… 3 Metabolomics……………………………………………………………………… 3 Materials and methods…………………………………………………………… 6 Database…………………………………………………………………………… 6 1H NMR Spectroscopic Analysis of Blood Serum…………………………… 6 NMR Spectral Preprocessing…………………………………………………… 7 Statistical Analysis………………………………………………………………… 8 Results……………………………………………………………………………… 9 Baseline Characteristics of Study Participants………………………………… 9 BMI and Liver Abnormalities……………………………………………………… 9 Correlation between Metabolites………………………………………………… 9 Identification of Important Metabolites in Discriminating Liver Abnormalities… 9 TG and Liver Abnormalities……………………………………………………… 10 Association between Metabolites in relation to TG Abnormality and Fatty Liver and Liver Cirrhosis………………………………………………………………… 10 Biochemical Features Assayed during Follow-up in Fatty Liver, Liver Cirrhosis and HCC…………………………………………………………………………… 11 Discussion………………………………………………………………………… 12 BCAA Degradation………………………………………………………………… 13 Ketone Body Metabolism………………………………………………………… 13 Lipid Metabolism…………………………………………………………………… 13 Glucose-Alanine Cycle…………………………………………………………… 14 Arginine and Proline Metabolism………………………………………………… 14 Abnormal TG-related Metabolites and Liver Abnormalities…………………… 14 References………………………………………………………………………… 16 | |
dc.language.iso | en | |
dc.title | 分析B型肝炎帶原者體內代謝小分子與肥胖相關肝臟疾病間關係:前瞻研究 | zh_TW |
dc.title | Prospective Analysis of Small Metabolites and Obesity-Related Liver Disease in Hepatitis B | en |
dc.type | Thesis | |
dc.date.schoolyear | 102-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 林靖愉(Ching-Yu Lin) | |
dc.contributor.oralexamcommittee | 蔡孟勳(Meng-Hsun Tsai),劉貞佑(Chen-Yu Liu) | |
dc.subject.keyword | 肥胖,非酒精性脂肪肝病,代謝質體學, | zh_TW |
dc.subject.keyword | Obesity,NAFLD,Metabolomics, | en |
dc.relation.page | 33 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2014-08-04 | |
dc.contributor.author-college | 公共衛生學院 | zh_TW |
dc.contributor.author-dept | 流行病學與預防醫學研究所 | zh_TW |
顯示於系所單位: | 流行病學與預防醫學研究所 |
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