資料載入中.....
|
請使用永久網址來引用或連結此文件:
http://libir.tmu.edu.tw/handle/987654321/36487
|
| 題名: | 十字花科蔬菜衍生物indole-3-carbinol對高脂飲食誘導肥胖相關疾病調節及其機制之探討 |
| 作者: | 張筱珮 |
| 貢獻者: | 藥學系(博士班) |
| 關鍵詞: | 十字花科蔬菜衍生物 肥胖 發炎反應 |
| 日期: | 2009 |
| 上傳時間: | 2010-10-21 10:25:19 (UTC+8) |
| 摘要: | 本研究欲探討十字花科蔬菜衍生物indole-3-carbinol (I3C)對於高脂飲食所誘導肥胖及其相關機制之影響，分為三部分進行。第一部分主要目的為觀察I3C對於高脂飲食誘導肥胖之臨床表徵及脂肪生成相關因子的影響；第二部分則探討I3C對於高脂飲食小鼠之血脂質、脂肪肝及肝臟中脂質相關代謝因子的影響；最後利用小鼠初代脂肪細胞與巨噬細胞RAW 264.7共同培養，模擬體內肥胖細胞發炎狀態，給予I3C是否可改善伴隨肥胖引起相關發炎介質之變化。C57BL/6小鼠隨機分為控制組 (B)、高脂飲食組 (HF)與高脂飲食並給與腹腔注射5 mg I3C/kg (HFI)三組，於給予12週後，結果顯示HF組體重、副睪脂肪皆高於其他兩組。相較於HF組，HFI組降低血清中血糖、三酸甘油酯、瘦體素和胰島素的濃度，增加葡萄糖耐受能力與adiponectin的濃度，以及減少脂肪組織中F4/80的表現。另外，給予I3C可降低脂肪組織中ACC mRNA和增加PPARγ蛋白質的含量。第二部分實驗結果顯示，HF組血清及肝臟中三酸甘油酯濃度顯著增加，而血清及糞便中膽固醇的濃度沒有顯著改變。HFI組在肝臟中的膽固醇含量顯著較控制組上升。HFI組肝臟中三酸甘油酯含量亦較HF組低，且I3C可以顯著降低由高脂飲食所誘導脂質相關代謝基因SREBP-1、ACC及HMGR mRNA與增加PPAR-α mRNA的表現。在脂肪細胞與巨噬細胞共同培養下，給予I3C可抑制iNOS mRNA的表現量，降低NO、MCP-1與IL-6之濃度，以及增加PPARγ mRNA的表現，並可抑制脂肪細胞之分化。綜合以上結果，本研究發現，I3C藉由改善血清中血糖、血脂和脂肪激素的含量，降低脂肪量、調控脂肪組織和肝臟中脂質代謝相關因子以及抑制肥胖細胞之發炎狀態，因而具有抑制肥胖的作用，此結果可支持十字花科蔬菜衍生物I3C於預防或治療肥胖相關疾病之應用。
The objective of this study was to investigate the effects of indole-3-carbinol (I3C), a compound derivated from cruciferous vegetables, on diet-induced obesity and its associated pathological conditions. The first study was to examine the effects of I3C on obesity and its related factors in high fat diet-induced obese (DIO) mice. Secondly, the effects of I3C on high-fat diet induced hepatic steatosis and on lipid metabolism associated genes were studied. Finally, the model of co-culture of adipocytes and macrophages was conducted to evaluate the anti-obesity activity mechanisms of I3C. For the first two studies, C57BL/6 mice were randomly divided into three groups, and received basal diet, high fat diet (HF), as well as high fat diet + 5 mg I3C/kg intraperitoneally (HFI) 3 times per week for 12 weeks. Results showed that body weight and epididymal adipose tissue weight were greater, and adipocytes were larger in the HF group than in the basal and HFI groups. Compared with the HF group, the HFI group had improved glucose tolerance, a higher serum adiponectin concentration, and lower serum glucose, triglyceride, insulin, and leptin concentrations, as well as less F4/80 expression in epididymal adipose tissue (p<0.001). Furthermore, I3C treatment decreased acetyl CoA carboxylase (ACC) mRNA expression (p<0.05) and increased peroxisome proliferators–activated receptor-γ (PPARγ) protein expression (p<0.05) in epididymal adipose tissue of DIO mice. In the second study, mice fed with high-fat diet had upregulation on serum lipid profiles and on hepatic TG accumulation. I3C reduced high fat diet-induced hepatic steatosis, glucose intolerance, lowered serum glucose, serum and hepatic triglyceride levels, and decreased expressions of sterol response element binding protein-1 (SREBP-1) and ACC mRNA, increased PPARα mRNA expressions in liver comparing to those of HF mice. However, no significant difference was observed in serum and fecal cholesterol levels between HFI and HF groups. As in macrophage and primary adipocyte co-culture study, I3C treatment decreased expression of inducible nitric oxide synthase (iNOS), lowered nitrite and interleukin-6 (IL-6) concentrations in medium, and enhanced mRNA expression of PPAR-γ. I3C also inhibited intracellular lipid accumulation in hypertrophic adipocytes, indicating an inhibition of adipocyte differentiation. In conclusion, I3C possesses anti-obesity activity as observed from decreased adiposity and infiltrated macrophages in epididymal adipose tissue of DIO mice. These reductions were associated with improved glucose tolerance and with modulated expression of adipokines and hepatic lipogenic-associated gene products. Besides, the possible mechanisms for anti-obesity effects of I3C may be involved in inhibition of macrophage-induced inflammatory changes and modulation expression of PPAR-γ and hepatic lipogenic genes. |
| 關聯: | 215頁 |
| 描述: | (一)論文目次
Acknowledgements I
Abstract III
中文摘要 V
Abbreviations VII
Contents VIII
Figure of contents XII
Table of contents XIV
Chapter 1 Introduction 1
1.1 Obesity 1
1.2 Obesity related disorders 3
1.2.1 Metabolic syndrome 3
1.2.2 Non-alcoholic fatty liver disease (NAFLD) 5
1.3 Obesity and adipogenesis 6
1.3.1 Accumulation of triglycerides (TG) and free fatty acid 6
1.3.2 Adipocyte and adipogenesis 7
1.3.3 Regulation of adipogenesis 10
1.3.4 The regulation factors of lipid metabolism 15
1.4 Obesity and inflammation 19
1.5 Adipokines 19
1.6 Adipokines and inflammation in obesity 23
1.7 Regulation of inflammatory signaling 26
1.8 Cruciferous vegetable derivatives 29
1.9 Cruciferous vegetable derivatives in disease prevention 32
Chaptre 2 Scheme of the study 34
2.1 Outline of the experimental design 35
Chapter 3 Diet-induced obesity (DIO) mice model 38
3.1 Introduction 38
3.2 Materials and methods 40
3.2.1 Animals and diet 40
3.2.2 Measurement size, mass, and immunohistochemistry of the adipocytes 42
3.2.3 Measurement of serum glucose, triglyceride contents 42
3.2.4 Reverse transcriptase-polymerase chain reaction analysis and real-time PCR 43
3.2.5 Measurement of serum level of insulin, leptin, adiponectin, IL-6 45
MCP-1 and resistin 45
3.2.6 Immunoblotting analysis 46
3.2.7 Statistical analysis 46
3.3 Results 47
3.3.1. Body and organ weights 47
3.3.2. Biochemical measurements 47
3.3.3. Histopathology and macrophage accumulation of adipose tissue 48
3.3.4. Expression of lipid metabolism-associated factors 48
3.3.5. Adipokines 49
3.4 Discussion 69
Chapter 4 High-fat diet-induced fatty liver 75
4.1 Introduction 75
4.2 Materials and methods 77
4.2.1 Animals and diet 77
4.2.2 Measurements triglyceride and cholesterol content 79
4.2.3 Histopathology of the liver 79
4.2.4 Reverse transcriptase polymerase chain reaction analysis 79
4.2.5 Statistical analysis 82
4.3 Results 82
4.3.1 Effects of indole-3-carbinol on liver histopathology in HF-fed mice. 82
4.3.2 Effects of indole-3-carbinol on serum parameters, liver and feces lipid profiles.
83
4.3.3 Effects of indole-3-carbinol on lipid metabolism related genes in the liver. 83
4.4 Discussion 90
Chapter 5 Co-culture of macrophages and adipocytes 96
5.1 Introduction 96
5.2 Materials and methods 98
5.2.1 Reagents 98
5.2.2 Cell culture 98
5.2.2.1 Cell lines 98
5.2.2.2 Primary adipocyte culture 99
5.2.2.3 Adipocytes and macrophages co-culture model 100
5.2.3 Measurement of nitric oxide (NO) 100
5.2.4 Measurement of IL-6 and MCP-1 production 101
5.2.5 Reverse transcriptase polymerase chain reaction (RT-PCR) 101
5.2.6 Oil red O staining of 3T3-L1 adipocytes 102
5.2.7 Statistical analysis 103
5.3 Results 105
5.3.1 Effects of indole-3-carbinol on inflammatory mediators in co-culture cells 105
5.3.2 Effects of indole-3-carbinol on the expression of PPAR-γ mRNA 106
5.3.3 Effects of indole-3-carbinol on intracellular lipid accumulation. 107
5.4 Discussion 118
6. Conclusions 124
7. References 125
8. Published Articles and honors: (2003~2010) 144
(二)參考文獻
Adams LA and Angulo P. (2006) Treatment of non-alcoholic fatty liver disease. Postgrad Med J 82: 315-322.
Adams LA, Lymp JF, St Sauver J, et al. (2005) The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129: 113-121.
Ae Park S, Choi MS, Cho SY, et al. (2006) Genistein and daidzein modulate hepatic glucose and lipid regulating enzyme activities in C57BL/KsJ-db/db mice. Life Sci 79: 1207-1211.
Alexander DL, Ganem LG, Fernandez-Salguero P, Gonzalez F and Jefcoate CR. (1998) Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis. J Cell Sci 111: 3311-3322.
Andersson K, Gaudiot N, Ribiere C, et al. (1999) A nitric oxide-mediated mechanism regulates lipolysis in human adipose tissue in vivo. Br J Pharmacol 126: 1639-1645.
Auborn KJ, Fan S, Rosen EM, et al. (2003) Indole-3-carbinol is a negative regulator of estrogen. J Nutr 133: S2470-S2475.
Arita Y, Kihara S and Ouchi N. (1999) Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Comm 257: 79-83.
Arkan MC, Hevener AL, Greten FR, et al. (2005) IKK-β links inflammation to obesity-induced insulin resistance. Nat Med 11: 191-198.
Barness LA, Opitz JM and Gilbert-Barness E (2007). Obesity: genetic, molecular, and environmental aspects". Am J Med Genet 143A: 3016-3034.
Bell MC, Crowley-Nowick P, Bradlow HL, et al. (2000) Placebo-controlled trial of indole-3-carbinol in the treatment of CIN. Gynecol Oncol 78: 123-129.
Bennett BL, Satoh Y and Lewis AJ. (2003) JNK: a new therapeutic target for diabetes. Curr Opin Pharmacol 3: 420-425.
Berg AH, Combs TP, Du X, Brownlee M and Scherer PE. (2002) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7: 947-953.
Berg AH and Scherer PE. (2005) Adipose tissue, inflammation, and cardiovascular disease. Circ Res 96: 939-949.
Berger JP. (2005) Role of PPARgamma, transcriptional cofactors, and adiponectin in the regulation of nutrient metabolism, adipogenesis and insulin action: view from the chair. Int J Obes 29 (Suppl 1):S3-S4.
Bernlohr DA, Coe NR and LiCata ZJ. (1999) Fatty acid trafficking in the adipocyte. Semin Cell Dev Biol 10: 43-49.
Bhathena SJ. (2000) Dietary fatty acids and fatty acid metabolism in diabetes. Chow CK, ed. Fatty acids in foods and their health implications. 2nd ed. New York: Marcel Dekker. p915-961.
Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC and Bradfield CA. (1991) Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8- tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci USA 88: 9543-9547.
Bluher S, Ziotopoulou M, Bullen JW Jr, et al. (2004) Responsiveness to peripherally administered melanocortins in lean and obese mice. Diabetes 53: 82-90.
Bray GA. (2004) Medical consequences of obesity. J Clin Endocrinol Metab 89: 2583-2589.
Brown MS and Goldstein JL. (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.Cell 89: 331-340
Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40: 1387-1395.
Bruun JM, Lihn AS, Pedersen SB and Richelsen B. (2005) MCP-1 release is higher in visceral than subcutaneous human adipose tissue. Implication of macrophages resident in the adipose tissue. J Clin Endocrinol Metab 90: 2282-2289.
Bryzgalova G., Lundholm L, Portwood N, et al (2008) Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab 295: E904-E912.
Bullo-Bonet M, Garcia-Lorda P and Lopez-Soriano FJ. (1999) Tumour necrosis factor, a key role in obesity. FEBS Letter 451: 215-219.
Caro JR, Sinha MK, Kolaczynski JW, et al. (1996) Leptin: the tale of an obesity gene. Diabetes. 45:1455–1461.
Chawla A, Barak Y, Nagy L, et al. (2001) PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 7: 48-52.
Chang HP, Tsai IH, Huang SY, et al. (2007) Study of contents of indole glucosinolates in fresh and pickled cruciferous vegetables cultivated in Taiwan. Nutr sci J 32: 102-107.
Chen YH, Dai HJ and Chang HP. (2003) Suppression of inducible nitric oxide production by indole and isothiocyanate derivatives from Brassica plants in stimulated macrophages. Planta Med 69: 696-700.
Chinni SR and Sarkar FH. (2002) Akt Inactivation Is a Key Event in Indole-3-carbinol-induced Apoptosis in PC-3 Cells. Clin Cancer Res 8: 1228-1234.
Christiansen T, Richelsen B and Bruun JM. (2005) Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. Int J Obes (Lond) 29: 146-150.
Chu R, Madison LD, Lin Y, et al. (1995) Thyroid hormone (T3) inhibits ciprofibrate-induced transcription of genes encoding beta-oxidation enzymes: cross talk between peroxisome proliferators and T3 signaling pathways. Proc Natl Acad Sci USA 92: 11593-7.
Cinti S. (2002) Adipocyte differentiation and transdifferentiation: Plasticity of the adipose organ. J Endocrinol Invest 25: 823-835.
Considine RV, Sinha MK, Heiman ML, et al. (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334: 292-295.
Crandall DL, Hausman GJ and Kral JG. (1997) A review of the microcirculation of adipose tissue: anatomic, metabolic, and angiogenic perspectives. Microcirculation 4:211-232.
Curat CA, Miranville A, Sengenes C, et al. (2004) From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes 53: 1285-1292.
Dandona P, Aljada A and Bandyopadhyay A. (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25: 4-7.
Degawa-Yamauchi MBJE, Juliar BE, Watson W, et al. (2003) Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab. 88: 5452-5455.
Deng QG, She H, Cheng JH, et al. (2005) Steatohepatitis induced by intragastric overfeeding in mice. Hepatology 42: 905-914.
Desvergne A and Wahli W. (1999) Peroxisome Proliferator-Activated Receptors: Nuclear Control of Metabolism. Endocrine Reviews 20: 649-88.
Desvergne B and Wahli W. (1994) PPAR: a key nuclear factor in nutrient/gene interactions. In: Bauerle P (ed) Inducible gene expression, vol 1. Birkhauser, Boston, p 142-176.
Dunn SE and LeBlanc GA. (1994) Hypocholesterolemic properties of plant indoles Inhibition of acyl-CoA:cholesterol acyltransferase activity and reduction of serum LDL/VLDL cholesterol levels. by glucobrassicin derivatives. Biochem Pharmacol 47: 359-364.
Fan JG. (2007) Relationship between hepatic SCD-1 expression and ATP content in rats with nonalcoholic fatty liver caused by fat-rich diet. J Hepatol 46: A342
Fassahauer M and Paschke R. (2003) Regulation of adipocytokines and insulin resistance. Diabetologia 46: 1594-603.
Fenwick GR, Heaney RK and Mullin WJ. (1987) Glucosionolates and their breakdown products in food and food plants. Crit Rev Food Sci Nutr 18: 123-194.
Flier JS. (1995) The adipocyte: storage depot or node on the energy information superhighway? Cell 80: 15-18.
Freytag SO, Paielli DL and Gilbert JD. (1994) Ectopic expression of the CCAAT/enhancer-binding protein a promotes the adipogenic program in a variety of mouse fibroblastic cells. Genes Dev 8: 1654-1663.
Fried SK, Bunkin DA and Greenberg AS. (19989) Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83: 847-850.
Frühbeck G, Gómez-Ambrosi J, Muruzábal FJ and Burrell MA. (2001) The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 280: E827-E847.
Gao Z, Hwang D and Bataille F. (2002) Serine phosphorylation of insulin receptor substrate 1 by inhibitor κB kinase complex. J Biol Chem 277: 48115-48121.
Gao Z, Zuberi A, Quon MJ, Dong Z and Ye J. (2003) Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor treated cells through targeting multiple serine kinases. J Biol Chem 278: 24944-24950.
Garlid KD, Jaburek M and Jezek P. (1998) The mechanism of proton transport mediated by mitochondrial uncoupling proteins. FEBS Lett 428: 10-14.
Gasic S, Tian B and Green A. (1999) Tumor necrosis factor alpha stimulates lipolysis in adipocytes by decreasing Gi protein concentrations. J Biol Chem 274: 6770-6775.
Gaudiot N, Jaubert A M, Charbonnier E, et al. (1998) Modulation of white adipose tissue lipolysis by nitric oxide. J Biol Chem 273: 13475-13481.
Gauthier MS, Favier R and Lavoie JM. (2006) Time course of the development of non-alcoholic hepatic steatosis in response to high-fat diet-induced obesity in rats. Br J Nutr 95: 273-281.
Gibbs DF, Warner RL, Weiss SJ, Johnson KJ and Varani J. (1999) Characterization of matrix metalloproteinases produced by rat alveolar macrophages. Am J Respir Cell Mol Biol 20: 1136-1144.
Goldberg IJ and Ginsberg HN. (2006) Ins and outs modulating hepatic triglyceride and development of nonalcoholic fatty liver disease. Gastroenterol 130: 1343-1346.
Green H, Kehinde O. (1974) Sublines of mouse 3T3 cells that accumulate lipid. Cell : 113-116.
Gregoire FM, Smas CM and Sul HS. (1998) Understanding adipocyte differentiation. Physiol Rev 78: 783-809.
Gruchow HM, Anderson AJ, Barboriak JJ and Sobocinski KA. (1988) Postmenopausal use of estrogen and occlusion of coronary arteries. Am Heart J 115: 954-963.
Gu L, Okada Y, Clinton SK, et al. (1998) Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 2: 275-281.
Harkins JM, Moustaid-Moussa N, Chung YJ, et al. (2004) Expression of interleukin-6 is greater in preadipocytes than in adipocytes of 3T3-L1 cells and C57BL/6J and ob/ob mice. J Nutr 134: 2673-2677.
He W, Barak Y, Hevener A and Olson P. (2003) Adipose-specific peroxisome proliferators- activated receptor gamma knockout caused insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci USA 100: 15715-15717.
Horton JD, Bashmakov Y, Shimomura I and Shimano H. (1998) Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci USA 95: 5987-5992.
Horton JD. (2002) Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis. Biochem Soc Trans 30: 1091-1095.
Hotamisligil GS, Shargill NS and Spiegelman BM. (1993) Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259: 87-91.
Hotamisligil GS and Spiegelman BM. (1994) Tumor necrosis factor α: a key component of the obesity-diabetes link. Diabetes 43: 1271-1278.
Hotamisligil GS, Arner P, Caro JF, Atkinson RL and Spiegelman BM. (1995) Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J. Clin Invest 95: 2409-2415.
Hotamisligil GS, Johnson RS, Distel RJ, et al. (1996) Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 274: 1377-1379.
Hotamisligil GS. (2003) Inflammatory pathways and insulin action. Int J Obesity 27: S53-S55.
Hotamisligil GS, Shargill NS and Spiegelman BM. (2003) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259: 87-91.
Hu E, Liang P and Spiegelman BM. (1996) AdipoQ is a novel adiposespecific gene dysregulated in obesity. J Biol Chem 271: 10697-10703.
Hwang JT, Park IJ, Shin JI, et al. (2005) Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase. Biochem Biophys Res Commun 338: 694-699.
Issemann I and Green S (1990). Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347: 645-650.
Iverius PH and Ostrund-Lindqvist AM. (1986) Preparation, characterization, and measurement of lipoprotein lipase. Methods Enzymol 129: 691-704.
Jay MA and Ren J. (2007) Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus. Curr Diabetes Rev 3: 33-39.
Jernås M, Palming J, Sjöholm K, et al. (2006) Seperation of human adipocytes by size: hypertrophic fat cells display distinct gene expression. FASEB J 20: 1540-1542.
Jiang C, Ting AT and Seed B. (1998) PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391: 82-86.
Jiang T, Wang Z and Proctor G. (2005) Diet-induced obesity in C57BL/6J mice causes increased renal lipid accumulation and glomerulosclerosis via a sterol regulatory element-binding protein-1c-dependent pathway. J Biol Chem 280: 32317-32325.
Kaneki M, Shimizu N, Yamada D and Chang K. (2007) Nitrosative stress and pathogenesis of insulin resistance. Antioxid Redox Signal 9: 319-329.
Kapur S, Marcotte B and Marette A. (1999) Mechanism of adipose tissue iNOS induction in endotoxemia. Am J Physiol Endocrinol Metab 276: E635-E641.
Kelley DE and Goodpaster BH. (2001) Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance. Diabetes Care 24: 933-941.
Khor TO, Keum YS and Lin W. (2006) Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC-3 prostate xenografts in immunodeficient mice. Cancer Res 66: 613-621.
Kim S, Sohn I, Lee YS and Lee YS. (2005) Hepatic gene expression profiles are altered by genistein supplementation in mice with diet-induced obesity. J Nutr 135: 33-41.
Kim YS and Milner JA. (2005) Targets for indole-3-carbinol in cancer prevention. J Nutr Biochem 16: 65-73.
Kotzka J, Koponen A. Njamen D, et al. (2000) Sterol regulator element bonding proteins SREBP-1 and SREBP-2 are link to map kinase cascade. J Lipid Res 41: 99-108.
Kotzka J, Muller-Wieland D, Koponen A, et al. (1998) ADD1/SREBP-1c mediates insulin-induced gene expression. Biochem Biophy Res Commun 249: 375-379.
Kovacs P and Stumvoll M. (2005) Fatty acids and insulin resistance in muscle and liver. Clin Endocrinol Metab 19: 625-635.
Krssak M, Falk PK, Dresner A, et al. (1999) Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42: 113-116.
Kubo Y, Kaidzu S, Nakajima I, Takenouchi K and Nakamura F. (2000) Organization of extracellular matrix components during differentiation of adipocytes in long-term culture. In Vitro Cell Dev Biol Anim 36: 38-44
Kuri-Harcuch W, Arguello C and Marsch-Moreno MB. (1984) Extracellular matrix production by mouse 3T3–F442A cells during adipose differentiation in culture. Differentiation 28: 173-178
Lau DC, Dhillon B, Yan H, Szmitko PE and Verma S. (2005) Adipokines: molecular links between obesity and atherosclerosis. Am J Physiol Heart Circ Physiol 288: H2031-H2041.
LeBlanc GA, Stuart JD, Dunn SE and Baldwin WS. (1994) Effect of the plant compound indole-3-carbinol on hepatic cholesterol homoeostasis. Food Chem Toxicol 32: 633-639.
Li AC and Palinski W. (2006) Peroxisome proliferator-activated receptors: how their effects on macrophages can lead to the development of a new drug therapy against atherosclerosis. Annu Rev Pharmacol Toxicol 46: 1-39.
Libermann TA and Baltimore D. (1990) Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol 10: 2327-2334.
Lieber C, Leo M, Mak K, et al. (2004) Model of nonalcoholic steatohepatitis. Am J Clin Nutr 79: 502-509.
Lin FT and Lane MD. (1994) CCAAT/enhancer binding protein α is sufficient to initiate the 3T3-L1 adipocyte differentiation program. Proc Natl Acad Sci USA 91: 8757-8761.
Lin J, Della-Fera MA and Baile CA. (2005) Green tea polyphenol epigallocatechin gallate inhibits adipogenesis and induces apoptosis in 3T3-L1 adipocytes. Obes Res 13: 982-990.
Liu S, Manson JE and Lee IM. (2000) Fruit and vegetable intake and risk of cardiovascular disease: the Women’s Health Study. Am J Clin Nutr 72: 922-928.
London RM and George J. (2007) Pathogenesis of NASH: animal models. Clin Liver Dis 11: 55-74.
Lowell BB and Flier JS. (1997) Brown adipose tissue, ß3 -adrenergic receptors, and obesity. Annu Rev Med 48: 307-316.
Lyon CJ, Evans CJ, Bill BR, Law RE and Hsueh WA. (2003) Minireview: adiposity, inflammation, and atherogenesis. Endocrinol 144: 2195-2200.
McAlindon TE, Gulin J, Chen T, et al. (2001) Indole-3-carbinol in women with SLE: effect on estrogen metabolism and disease activity. Lupus 10: 779-783.
Maffei M, Halaas J and Ravussin E. (1995) Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1: 1155-1161.
Magaña MM, Lin SS, Dooley K A and Osborne TF. (1997) Sterol regulation of acetyl coenzyme A carboxylase promoter requires two interdependent binding sites for sterol regulatory element binding proteins. J Lipid Res 38: 1630-1638.
Maiyoh GK, Kuh JE, Casaschi A and Theriault AG. (2007) Cruciferous indole-3-carbinol inhibits apolipoprotein B secretion in HepG2 cells. J Nutr 137: 2185-2189.
McGarry JD and Brown NF. (1997) The mitochondrial carnitine palmitoyl transferase system: from concept to molecular analysis. Eur J Biochem 244: 1-14.
Menendez JA and Lupu R. (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7: 763-777.
Miyazaki Y, Mahankali A, Wajcberg E, et al. (2004) Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 89: 4312-4319.
Moustaid N and Sul HS. (1991) Regulation of expression of the fatty acid synthase gene in3T3-L1 cells by differentiation and triiodothyronine. J Biol Chem 266: 18550-18554.
Naaz A, Yellayi S, Zakroczymski MA, et al. (2003) The soy isoflavone genistein decreases adipose deposition in mice. Endocrinol 144: 3315–3320.
Nakajima I, Yamaguchi T, Ozutsumi K and Aso H. (1998) Adipose tissue extracellular matrix: newly organized by adipocytes during differentiation. Differentiation 63: 193-200.
Nakayama H, Otabe S, Ueno T, et al. (2007) Transgenic mice expressing nuclear sterol regulatory element–binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis. Metabolism 56:470-475.
Nedvídková J, Smitka K, Kopský V and Hainer V (2005). Adiponectin, an adipocyte-derived protein. Physiol Res 54: 133–140.
Nguyen MTA, Satoh H and Favelyukis S. (2005) JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem 280: 35361-35371.
Neuschwander-Tetri BA, Brunt EM, Wehmeier KR and Bacon BR. (2003) Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38: 1008-1017.
Odegaard JI, Ricardo-Gonzalez RR. Goforth MH, et al. (2007) Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447: 1116-1120.
Orasanu G, Ziouzenkova O, Devchand PR, et al. (2008) The peroxisome proliferator-activated receptorgamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha dependent manner in vitro and in vivo in mice. J Am Coll Cardiol 52: 869-881.
Osborne TF. (2000) Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J Biol Chem 275: 32379 -32382.
Otto TC and Lane MD. (2005) Adipose development: from stem cell to adipocyte. Crit Rev Biochem Mol Biol 40: 229-42.
Ouchi N, Kihara S, Arita Y, et al. (2000) Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation 102: 1296-1301.
Pairault J and Green H. (1976) A study of the adipose conversion of suspended 3T3 cells by using glycerophosphate dehydrogenase as differentiation marker. Proc Natl Acad Sci USA 76: 5128-5142.
Pan DA, Lillioja S, Kriketos AD, et al. (1997) Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 46: 983-988.
Perreault M and Marette A. (2001) Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med 7: 1138-1143.
Pickup JC and Crook MA. (1998) Is type II diabetes mellitus a disease of the innate immune system. Diabetologia 41: 1241-1248.
Prins JB, Niesler CU, Winterford CM, et al. (1997) Tumor necrosis factor-alpha induces apoptosis of human adipose cells. Diabetes 46: 1939-1944.
Privat C, Lantoine F, Bedioui F, et al. (1997) Nitric oxide production by endothelial cells: comparison of three methods of quantification. Life Sci 61: 1193-1202.
Promrat K, Lutchman G, Uwaifo GI, et al. (2004) A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39:188-196.
Puglisi MJ and Fernandez ML. (2008) Modulation of C-reactive protein, tumor necrosis factor-alpha, and adiponectin by diet, exercise, and weight loss. J Nutr 138: 2293-2296.
Qin H and Powell-Coffman JA. (2004) The Caenorhabditis elegans aryl hydrocarbon receptor, AHR-1, regulates neuronal development. Dev Biol 270: 64-75.
Qin H, Zhai Z and Powell-Coffman JA (2006) The Caenorhabditis elegans AHR-1 transcription complex controls expression of soluble guanylate cyclase genes in the URX neurons and regulates aggregation behavior. Dev Biol 298: 606-615.
Rajala MW and Scherer PE. (2003) Minireview: The adipocyte- at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144: 3765-3773.
Ramírez-Zacarías JL, Castro-Muñozledo F and Kuri-Harcuch W. (1992) Quantitation of adipose conversion and triglyceride by staining intercytoplasmic lipids with Oil Red O. Histochemistry 97: 493-497.
Randle PJ, Garland PB, Hales CN and Newsholme EA. (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1: 785-789.
Raubenheimer PJ, Nyirenda MJ and Walker BR. (2006) A choline-deficient diet exacerbates fatty liver but attenuates insulin resistance and glucose intolerance in mice fed a high-fat diet. Diabetes 55: 2015-2020.
Ren D, Collingwood TN, Rebar EJ, Wolffe AP and Camp HS. (2002) PPARgamma knockdown by engineered transcription factors: exogenous PPARgamma2 but not PPARgamma1 reactivates adipogenesis. Genes Dev 16: 27-32.
Renaldi O, Pramono B, Sinorita H, et al (2009). Hypoadiponectinemia: a risk factor for metabolic syndrome. Acta Med Indones 41: 20-24.
Ribière C, Jaubert AM, Gaudiot N, et al. (1996) White adipose tissue nitric oxide synthase: a potential source for NO production. Biochem Biophys Res Commun 222: 706-712.
Ricote M, Li AC, Willson TM, et al. (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391: 79-82.
Ricote M, Huang J, Fajas L, et al. (1998) Expression of the peroxisome proliferator-activated receptorγ (PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci USA 95:7614-7619.
Rosen ED and Spiegelman BM. (2000) Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 16: 145-171.
Rosen ED, Sarraf P, Troy AE, et al. (1999) PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4: 611-617.
Rosen ED, Walkey CJ, Puigserver P and Spiegelman BM. (2004) Transcriptional regulation of adipogenesis. Genes & Development 14: 1293-1307.
Safe S and Krishnan V. (1995) Cellular and molecular biology of aryl hydrocarbon (Ah) receptor-mediated gene expression. Arch Toxical Suppl 17: 99-115.
Salpeter SR, Walsh JME, Ormiston TM, et al. (2006) Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab 72: 922-928.
Samuel VT, Liu ZX and Qu X. (2004) Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 279: 32345-32353.
Sang QX. (1998) Complex role of matrix metalloproteinases in angiogenesis. Cell Res 8: 171-177.
Saravanan N, Haseeb A, Ehtesham N and Nnissa G. (2005) Differential effects of dietary saturated and trans-fatty acids on expression of genes associated with insulin sensitivity in rat adipose tissue. Eur J Endocrinol 153: 159-165.
Schoonjans, K, Watanabe M, Suzuki H, et al. (1995) Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter. J Biol Chem 270: 19269-19276.
Shaban Z, El-Shazly S, Abdelhady S, et al. (2004) Down regulation of hepatic PPARalpha function by AhR ligand. J Vet Med Sci 66: 1377-1386.
Shi H, Kokoeva MJ, Inouye K, et al. (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116: 3015-3025.
Shibata R, Sato K and Pimentel DR. (2005) Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK- and COX-2-dependent mechanisms. Nat Med 11: 1096-1103.
Shimabukuro M, Ohneda M, Lee Y and Unger RH. (1997) Role of nitric oxide in obesity induced β cell disease. J Clin Invest 100: 290-295.
Shimano H, Horton JD, Hammer RE, et al. (1996) Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 98: 1575-1584.
Shoelson SE, Lee J and Goldfine AB. (2006) Inflammation and insulin resistance. J Clin Invest 116: 1793-1801.
Shoelson SE, Herrero L and Naaz A. (2007) Obesity, inflammation, and insulin resistance. Gastroenterol 132: 2169-2180.
Souza SC, Palmer HJ, Kang YH, et al. (2003) TNF-alpha induction of lipolysis is mesiated through activation of the extracellular signal related kinase pathway in 3T3-L1 adipocyte. J Cellular Biochem 89: 1077-1086.
Spiegelman BM, Choy L, Hotamisligil GS, et al. (1993) Regulation of adipocyte gene expression in differentiation and syndromes of obesity/diabetes. J Biol Chem 268: 6823-6826
Spiegelman BM and Flier JS. (2001) Obesity and the regulation of energy balance. Cell 104: 531-543.
Spiegelman BM, Hu E, Kim JB and Brun R. (1997) PPAR gamma and the control of adipogenesis. Biochimie 79: 111-112.
Steppan CM. (2001) The hormone resistin links obesity to diabetes. Nature. 409: 307-312.
Suganami T, Nishida J and Ogawa Y. (2005) A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 25: 2062-2068.
Suzawa M, Takada I, Yanagisawa J, et al. (2003) Cytokines suppress adipogenesis and PPAR-gamma function through the TAK1/TAB1/NIK cascade. Nat Cell Biol 5: 224-230.
Svegliati-Baroni G, Candelaresi C, Saccomanno S, et al. (2006) A model of insulin resistance and nonalcoholic steatohepatitis in rats: role of peroxisome proliferator-activated receptor-α and n-3 polyunsaturated fatty acid treatment on liver injury Am J Pathol 169: 846-860.
Takada Y, Andreeff M and Bharat B. (2005) Aggarwal Indole-3-carbinol suppresses NF-κB and IκBα kinase activation, causing inhibition of expression of NF-κB-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells. Blood 106: 641-649.
Takahashi N, Kawada T, Yamamoto T, et al. (2002) Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma. J Biol Chem 277: 16906-16912.
Tcheronv A, Calles-Escandon J, Sites CK and Poehlman ET. (1998) Menopause, central body fatness, and insulin resistance: effects of hormone-replacement therapy. Coron Artery Dis 5: 733-748.
Tontonoz P, Hu E and Spiegelman BM. (1994) Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79: 1147-1156.
Tontonoz P, Kim JB, Graves RA and Spiegelman BM. (1993) ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation. Mol Cell Biol 13: 4753-4759.
Trayhurn P and Wood IS. (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr 92: 347-355.
Trayhurn P and Wood IS. (2005) Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans 33: 1078-1081.
Tsai JT, Liu HT and Chen YH. (2010) Suppression of Inflammatory Mediators by Cruciferous Vegetable-Derived Indole-3-Carbinol and Phenylethyl Isothiocyanate in Lipopolysaccharide-Activated Macrophages. Mediators Inflamm 2010: 293642.
Uysal KT, Scheja L, Wiesbrock SM, Bonner-Weir B and Hotamisligil GS. (2000) Improved glucose and lipid metabolism in genetically obese mice lacking aP2. Endocrinol 141: 3388-3396.
Vallett SM, Sanchez HB, Rosenfeld JM and Osborne TF. (1996) A Direct Role for Sterol Regulatory Element Binding Protein in Activation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Gene. J Biol Chem 271: 12247-12253.
van Raalte DH, Li M, Pritchard PH and Wasan KM. (2004) Peroxisome proliferator- activated receptor (PPAR)-alpha: a pharmacological target with a promising future. Pharm Res 21: 1531-1538.
Verhoeven DT, Goldbohm RA, van Poppel G, et al. (1996) Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiol Biomarkers Prev 5: 733-748.
Verhoeven DT, Verhagan H, Goldbohm RA, et al. (1997) A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chem Biol Interac 103: 79-129.
Verkerk R, Van der Gaag MS, Dekker M and Jongen WM. (1997) Effects of processing conditions on glucosinolates in cruciferous vegetables. Cancer Lett 114: 193-194.
Vitseva OI, Tanriverdi K, Tchkonia TT, et al. (2008) Inducible toll-like receptor and NF-κB regulatory pathway expression in human adipose tissue. Obesity 16: 932-937.
von Knethen A and Brune B. (2003) PPARgamma – an important regulator of monocyte/macrophage function. Arch Immunol Ther Exp 51: 219-226.
Wang N, Finegold MJ, Bradley A, et al. (1995) Impaired energy homeostasis in C/EBPa knockout mice. Science 269: 1108-1112.
Wang Y, Rangan GK, Goodwin B, et al. (2000) Lipopolysaccharide-induced MCP-1 gene expression in rat tubular epithelial cells is nuclear factor-κB dependent. Kidney Int 57: 2011-2022.
Wasserman F. (1965) Handbook of Physiology. American Physiology Society, Washington, DC.
Watt MJ, Heigenhauser GJ, Spriet LL. (2002) Intramuscular triacylglycerol utilization in human skeletal muscle during exercise: is there a controversy? J Appl Physiol 93: 1185-1195.
Weisberg SP, McCann D, Desai M, et al. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112: 1796-1808.
Wellen KE and Hotamisligil GS. (2005) Inflammation, stress, and diabetes. J Clin Invest 116: 1813-1822.
Wellen KE and Hotamisligil GS. (2003) Obesity-induced inflammatory changes in adipose tissue. J Clin Invest 112: 1785-1788.
Weng JR, Tsai CH, Kulp SK and Chen CS. (2008) Indole-3-carbinol as a chemopreventive and anti-cancer agent. Cancer Lett 262: 153-163.
Westerveld HE. (1998) Estrogens and postprandial lipid metabolism. Atherosclerosis. 141: S105-S107.
Wilkinson WO, Min HY, Claffey KP, et al. (1990) Control of the adipsin gene in adipocyte differentiation. Identification of distinct nuclear factors binding to single- and double-stranded DNA. J Biol Chem 265: 477-482.
Wisse BE. (2004) The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 15: 2792-2800.
Xie QW, Kashiwabara Y, Nathan C. (1994) Role of transcription factor NF-kappa/Rel in induction of nitric oxide synthase. J Biol Chem 269: 4705-4708.
Xu H, Barnes GT, Yang Q, et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112: 1821-1830.
Yamamoto Y, Yoshimasa Y, Koh M, et al. (2000) Constitutively active mitogen-activated protein kinase kinase increases GLUT1 expression and recruits both GLUT1 and GLUT4 at the cell surface in 3T3–L1 adipocytes. Diabetes 49: 332-339.
Yamauchi T, Kamon J, Waki H, et al. (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7: 941-946.
Yu YH and Ginsberg NH. (2005) Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue. Circulation Res 96: 1042-1052.
Yudkin JS, Kumari M, Humphries SE, et al (2000) Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148: 209-214.
Yudkin JS, Stehouwer CD, Emeis JJ and Coppack SW. (1999) C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 19: 972-978.
Zamboni M, Armellini F and Turcato E. (1994) Relationship between visceral fat, steroid hormones and insulin sensitivity in premenopausal obese women. J Intern Med 236: 521-527.
Zamboni M, Armellini F and Cominacini L. (1994) Obesity and regional body-fat distribution in men: separate and joint relationships to glucose tolerance and plasma lipoproteins. Am J Clin Nutr 60: 682-687.
Zamboni M, Zoico E, and Fantin F. (2004) Relation between leptin and metabolic syndrome in elderly women. J Gerontol Biol Sci Med Sci 59: 396-400.
Zangani D, Darcy KM, Masso-Welch PA, et al. (1999) Multiple differentiation pathways of rat mammary stromal cells in vitro: acquisition of a fibroblast, adipocyte or endothelial phenotype is dependent on hormonal and extracellular matrix stimulation. Differentiation 64: 91-101.
Zeyda M, Stulnig TM. (2009) Obesity, inflammation, and insulin resistance--a mini-review. Gerontology 55: 379-386.
Zhang Y, Proenca R, Maffei M, et al. (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372: 425-432.
Zou Y, Li J, Lu C, et al. (2006) High fat emulsion-induced rat model of nonalcoholic steatohepatitis. Life Sci 79: 1100-1107. |
| 顯示於類別: | [藥學系] 博碩士論文
|
在TMUIR中所有的資料項目都受到原著作權保護.
|
