臺灣博碩士論文加值系統

脂肪肝是三酸甘油酯代謝異常，使得肝細胞內堆積過多的脂肪顆粒，可能導致肝有關的疾病。咖啡酸（caffeic acid，3,4-dihydroxycinnamic acid or CA）分佈於蔬菜、紅酒、水果、全穀物和蜂蜜等物質中。結構上屬於多酚類化合物類，依據一些研究文獻的報導具有抗氧化、降血脂與保護肝臟等醫學功能。因此本實驗以高脂肪飲食(high fat diet; HFD)餵食小鼠，並於飼料中添加0.02%、0.08%咖啡酸，經六週後發現高脂肪餵食會使小鼠血清AST、ALT、TG、Cholersterol、Glucose升高及降低 HDL-C；而添加咖啡酸樣本之小鼠血清AST、ALT、TG、Cholersterol、Glucose降低並增加HDL-C。實驗時每週量測體重、肝臟重量及肝組織切片觀察，結果發現餵食0.08%咖啡酸樣本，肝臟之顏色及外觀皆己獲得改善、另外肝臟平均重量減輕、組織切片之脂肪空泡堆積明顯獲得改善了。0.08%咖啡酸可降低HFD所引起的肝臟脂肪堆積、降低肝臟損傷程度。又綜合血清生化值測定，0.08%咖啡酸可以降低HFD引起之脂肪肝而達到保肝的作用。

Fatty liver is a kind of triglyceride metabolic disorder that makes the liver cells accumulate excessive lipid particles. This may cause liver-related disease. Caffeic acid（3,4-dihydroxycinnamic acid or CA）is distributed in vegetables, red wine, fruits, whole grains﹐ honey and other substances. Ac-cording to the research literature
﹐phenolic compounds like caffeic acid has antioxidants and atte-nuates plasma lipids, so offering a medical protective function. In this experiment two groups of mice were fed a high fat diet（HFD）； the second groups given the high fat diet also contained a mixture of 0.02%, 0.08% caffeic acid, Six weeks later the mice fed only a high fat diet were found to have an increase in AST, ALT, TG, Cholersterol, Glucose while the HDL-C is decreased in value . The group given the high fat diet with caffeic acid were found to have a decrease in AST, ALT, TG, Cholersterol, Glucose while the HDL-C increased. Each week of the experiment body weight and liver weight were gauged along with liver tissue slice observation, the result being of 0.08% caffeic acid sample the color and outward appearance obtained improvement. The liver weight average reduced lipid vacuole accumulation of the tissue slice obviously improve. 0.08% caffeic acid may attenuate hepatic accumulation which high fat diet causes, reducing the liver extent of damage. Thus in the blood serum biochemistry value determination, 0.08% caffeic acid may attenuate the HFD-induced fatty liver and protect the liver.

目　　錄
中文摘要………………………………………………………………3
英文摘要………………………………………………………………4
縮寫檢索表……………………………………………………………6
緒論……………………………………………………………………7
研究目的………………………………………………………………28
研究架構………………………………………………………………29
實驗材料與方法………………………………………………………30
實驗結果………………………………………………………………37
討論……………………………………………………………………41
參考文獻………………………………………………………………45
實驗圖表………………………………………………………………51
附表……………………………………………………………………66

參考文獻
1.Neuschwander-Tetri BA, Caldwell SH：Nonalcoholic steatohepatitis：Summary of an AASLD Single Topic Conference. Hepatology 2003；37：1202-1219.
2.ANGULO：Nonalcoholic fatty liver disease. N Engl J Med 2002；346：1221-1231.
3.Rashid M, Roberts EA：Nonalcoholic steatohepatitis in children. J Pediatr Gastroenterol Nutr 2000；30：48-53.
4.Clark JM, Diehl AM：Nonalcoholic fatty liver disease：An un-derrecognized cause of cryptogenic cirrhosis.JAMA 2003；289：3000-3004.
5.Ratzui V, Bonhay L, Di Martino V, et al：Survival, liver failure, and hepatocellular carcinoma in obesityrelated cryptogenic cirrhosis. Hepatology 2002; 35:1485-1493.
6.Marrero JA, Fontana RJ, Su GL, Conjeevaram HS,Emick DM, Lok AS：NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology 2002；36：1349-1354.
7.Bugianesi E, Leone N, Vanni E, et al: Expanding the natural history of nonalcoholic steatohepatitis：From cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002；123：134-140.
8.Ludwig J, Viggiano TR, McGill DB, Oh BJ：Nonalcoholic steatohepatitis：Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55:434-8.
9.Adler M, Schaffner F：Fatty liver hepatitis and cirrhosis in obese patients.Am J Med 1979; 67:811-816.
10.Manton ND, Lipsett J, Moore DJ, Davidson GP, Bourne AJ, Couper RT：Non-alcoholic steatohepatitis in children and adolescents. Med J Aust 2000; 173：476-479.
11.Lee RG：Nonalcoholic steatohepatitis：A study of 49 patients. Hum Pathol 1989；20：594-598.
12.Ratziu V, Giral P, Charlotte F, et al:Liver fibrosis in over weight patients.Gastroenterology 2000；118：1117-1123.
13.Wang JT：Hepatitis C virus infection in Taiwan. Gastroenterol J Taiwan 1995；12：66.
14.Friedman LS：Alcoholic & nonalcoholic fatty liver disease. Current Medical Diagnosis & Treatment 2003, 42nd edition. New York, McGraw-Hill, 2003；15：644-645.
15.Weltman MD,Farrell GC, Hall P,Ingelman-Snndberg M,Liddle C.Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis .Hepatology 1998；27：128-33.
16.Lin SC, Shih SC, Kao CR, et al：Prevalence of antibodies to hepatitis C virus in patients with nonalcoholic fatty liver. Chung Hua I Hsueh Tsa Chih - Chinese Medical Journal 1995；56：80-85.
17.行政院衛生署。1997。高血脂防治手冊,國人血脂異常診療及預防指引。遠流出版公司，台北。
18.Brown, M.S. and Goldstein, J.L. Lipoprotein metabolism in the macrophage:Implications for cholesterol deposition in atherosclerosis. Annu. Rev. Biochem. 1983；52:223-261.
19.Lin, P.J. and Chang, C.H. Endothelium dyfunction in cardi-ovascular disease. Chang Gung Med. J. 1994；17：198-210.
20.Chait, A., Brazg, R.L., Tribble, D.L. and Krauss, R.M. Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern M. Am. J. Med. 1993；94：350-356.
21.Reaven, G.M., Chen, Y.D.I., Jeppesen, J., Maheux, P. and Krauss, R.M. Insulin resistance and hyperinsulinemia in indi-viduals with small, dense, low density lipoprotein particles. J. Clin. Invest. 1993；92：141-146.
22.Podolsky DK：Hepatic steatosis（fatty liver）and nonalcoholic steatohepatitis. Harrison''s Principles of Internal Medicine, 15th edition. New York：McGraw-Hill 2001；300：1767-1768.
23.Contos MJ, Cales W, Sterling RK, et al：Development of nonalcoholic fatty liver disease after orthotopic liver transplantation for cryptogenic cirrhosis. Liver Transpl 2001；7：363-373.
24.Basaranoglu M, Acbay O, Sonsuz A：A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999；31：384-384.
25.Lavine JE：Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000；136：734-738.
26.Hasegawa T, Yoneda M, Nakamura K, et al：Plasma trans-forming growth factor-（1 level and efficacy of）-tocopherol in patients with non-alcoholic steatohepatitis：a pilot study. Aliment Pharmacol Ther 2001；15：1667-1672.
27.Marchesini G, Brizi M, Bianchi G, et al：Metformin in non-alcoholic steatohepatitis. Lancet 2001；358：893-894.
28.Wakil, S. J., Stoops, J. K., and Joshi, V. C.. Fatty acid synthesis and its regulation. Annu. Rev. Biochem. 1983；52：537-579.
29.Wakil, S. J. Fatty acid synthase, a proficient multifunctional enzyme. Biochemistry 1989 ；28： 4523-4530.
30.Stoops, J. K., and Wakil, S. J. Animal fatty acid synthetase. A novel arrangement of the β-ketoacyl synthetase sites comprising domains of the two subunits. J. Biol. Chem. 1981；256：5128-5133.
31.Stoops, J. K., and Wakil, S. J. The reaction of chicken liver fatty acid synthetase with 5,5''-dithiobis（2-nitrobenzoic acid）Biochem. Biophys. Res. Commun. 1982：104：1018-1024.
32.Schreckenbach, T., Wobser, H., and Lynen, F.. The palmityl binding sites of fatty acid synthetase from yeast. Eur. J. Bio-chem. 1977；80：13-23
33.Rock, C. O., Goelz, S. E., and Cronan, J. E., Jr. Phospholipid synthesis in Escherichia coli. Characteristics of fatty acid transfer from acyl-acyl carrier protein to sn-glycerol 3-phosphate. J. Biol. Chem. 1981；256：736-742.
34.McGarry, J. D., and Foster, D. W. Regulation of hepatic fatty acid oxidation and ketone body productior. Annu. Rev. Biochem. 1980；49：395-420.
35.Saija A, Tomaino A, Cascio RL, Trombetta D, Proteggente A, Pasquale A, Uccella N, Bonina F. Ferulic and caffeic acids as potential protective agents against photooxidative skin damage. J Sci Food Agr 1999；79：476- 480.
36.Saija A, Tomaino A, Trombetta D, Pasquale A, Uccella N, Barbuzzi T, Paolino D, Bonina F. In vitro and in vivo evaluation of caffeic and ferulic acids as topical photoprotective agents.Int J Pharm 2000 ；199：39- 47.
37.Bhat SH, Azmi AS, Hadi SM.. Prooxidant DNA breakage in-duced by caffeic acid in human peripheral lymphocytes: In-volvement of endogenous copper and a putative mechanism for anticancer properties. Toxicol Appl Pharmacol 2007；218（3）：249- 255.
38.Won Jun Lee and Bao Ting Zhu. Inhibition of DNA methylation by caffeic acid and chlorogenic acid,two common cate-chol-containing coffee polyphenols .Carcinogenesis 2006；27(2)：269–277.
39.Sroka Z, and Cisowski W. Hydrogen peroxide scavenging, antioxidant and anti-radical activity of some phenolic acids. Food Chem Toxicol 2003；41(6)：753–758.
40.Rhinkus SJ, and Taylor RT. Analysis of Hydrogen Peroxidei in Freshly Prepared Coffees. Food Chem Toxic 1990；28：323- 331.
41.Gülçin İ. Antioxidant activity of caffeic acid （3,4-dihydroxycinnamic acid）.Toxicology 2006；217（2/3）：213–220.
42.Cheng JC, Dai F, Zhou B, Yang L, Liu ZL. Antioxidant activity of hydroxycinnamic acid derivatives in human low density lipoprotein：Mechanism and structure–activity relationship. Food Chem 2007；104（1）：132–139.
43.Meyer AS, Heinonen M, Frankel EN.. Antioxidant interactions of catechin, cyanidin,caffeic acid, quercetin, and ellagic acid on human LDL oxidation. Food Chem 1998；61（1/2）：71-75.
44.Janbaza KH, Saeedb SA, Gilani AH.. Studies on the protective effects of caffeic acid and quercetin on chemical-induced he-patotoxicity in rodents. Phytomedicine 2004；11：424- 430.
45.Pérez-Alvarez V, Bobadilla RA, Muriel P. Structure– hepato-protective activity relationship of 3,4-dihydroxycinnamic acid （caffeic acid）derivatives. J Appl Toxicol 2001；21：527- 531.
46.Staniforth,V.,Chiu,K.-T.and Yang,N.-S. Caffeic Acid Sup-presses UVB Radiation-Induced Expression of Interleukin-10 and Activation of Mitogen-Activated Protein Kinases in Mouse.Carcinogenesis, 2006；27（9)：1803-1811.
47.Peng-Gao LI, Jin-Wen XU, Katsumi IKEDA, Akira KOBAYA-KAWA,Yasuyo KAYANO, Takahiko MITANI, Takao IKAMI, and Yukio YAMORI Caffeic Acid Inhibits Vascular Smooth Muscle Cell Proliferation Induced by Angiotensin II in Stroke-Prone Spontaneously Hypertensive Rats .Hypertens Res 2005；28：369–377.
48.Formiguera, X.﹐Canton, A. Obesity：epidemiology and clinical aspects. Best Pract. Res. Clin. Gastroenterol. 2004；18, 1125–1146.
49.Banga JD. Coagulation and fibrinolysis in diabetes. Semin Vasc Med. 2002 ;2, 75-86.
50.Polednak AP. Trends in incidence rates for obesity-associated cancers in the US. Cancer Detect Prev. 2003；27, 415-21.
51.Mika Sekiya, Ako Hiraishi, Maiko Touyama and Kazuichi Sa-kamoto. Oxidative stress induced lipid accumulation via SREBP1c activation in HepG2 cells. Biochemical and Biophysical Research Communications. 2008；375, 602-607
52.Un Ju Jung, Mi-Kyung Lee, Yong Bok Park, Seon-Min Jeon, and Myung-Sook Choi. Antihyperglycemic and Antioxidant Properties of Caffeic Acid in db/db Mice JPET 2006；318, 476–483.