代謝症候群包含腹部肥胖、高三酸甘油酯、低HDL與高血壓，若未經適當控制，則可能轉為第2型糖尿病或心血管疾病。許多研究提出非酒精性脂肪肝是代謝症候群的相關病症，會由單純的脂肪變性進展到肝炎、肝纖維化、肝硬化。有研究指出，芝麻素是PPAR-α天然配子，具促進脂肪酸氧化及抑制脂肪酸合成的作用。菊花桂花萃取物可以保護細胞免受自由基的傷害。故本研究探討這三種材料對非酒精性脂肪肝與代謝症候群的影響。
實驗一：在人類肝細胞 (HepG2) 模式中，以1 mM脂肪酸 (oleic acid, palmitic acid, stearic acid, linoleic acid and arachidonic acid, 1mM) 誘發脂肪堆積，發現芝麻素、菊花與桂花甲醇萃物均可降低肝細胞內三酸甘油酯堆積與oil red O染色，菊花與桂花甲醇萃物可抑制ROS生成量，具有抗氧化潛力。
以real-time PCR分析HepG2脂肪酸代謝相關基因，發現桂花甲醇萃取物抑制sterol regulatory element binding protein-1 (SREBP-1)、fatty acid synthase(FAS)、glycerol 3-phosphate acyltransferase (GPAT)、acyl-CoA oxidase (ACO) mRNA表現，促進acetyl-CoA carboxylase(ACC) mRNA表現，菊花甲醇萃取物抑制SREBP-1c、ACC 、FAS、GPAT、ACO mRNA表現，芝麻素抑制SREBP-1c與GPAT mRNA表現量。另以0.5 g/ml LPS刺激THP-1分泌促發炎激素做為誘發HepG2發炎模式，以real-time PCR分析HepG2 mRNA表現，實驗結果發現，菊花萃取物與芝麻素抑制TNFα, IL-1β, IL-6, IL-8, MCP-1與TGFβ mRNA表現量，桂花萃取物降低TNFα, IL-1β, IL-8 mRNA表現量。
實驗二、在動物模式方面，餵予雄性倉鼠高脂 (35%) 、高膽固醇 (1%) 飼料，同時投予0.3% 芝麻素、菊花甲醇萃取物或桂花甲醇萃取物，14天後犧牲。發現芝麻素對血脂、血中游離脂肪酸與血糖有下降趨勢但未達顯著，菊花甲醇萃取物則反而顯著增加血液三酸甘油酯與膽固醇之濃度。桂花甲醇萃取物顯著降低肝中膽固醇，菊花與桂花甲醇萃取物會顯著降低腎臟之相對重量。但此三種食材對體重增加量與腹睪脂肪量皆無顯著影響。
實驗三、將雄性倉鼠分為三組，對照組餵予AIN76配方飼料，另兩組分別餵予FFC飼料 (Fat 20%, Fructose 34%, Cholesterol 0.2% wt/wt) 與含有0.3% 桂花甲醇萃取物的FFC飼料，為期10週。發現FFC飲食顯著增加脾、副睪脂肪、腎、肝之相對重量，血中TC、TG與HDL-C與肝臟TC皆顯著增加，肝臟SOD活性則顯著下降，肝臟MCP-1含量顯著上升。肝臟切片以Oil Red O染色觀察到脂質堆積，以H&E染色發現有巨噬細胞入侵的發炎情形。桂花甲醇萃物對以上指標則無改善效果。
總結： 在體外實驗，芝麻素、菊花與桂花甲醇萃取物可顯著降低肝細胞脂肪堆積與發炎。以高脂 (35%)、高膽固醇 (1%) 餵予雄性倉鼠2週，僅見桂花甲醇萃物降低肝中膽固醇堆積。以較低脂肪 (20%) 膽固醇 (0.2%) 及高果糖 (34%) 餵予雄性倉鼠10週可誘發腹部肥胖、高血脂、肝臟發炎等代謝症候群相關病症，但桂花甲醇萃物並未改善代謝症候群。動物實驗未觀察到此三種材料在細胞實驗中顯現的效果，可能由於萃物劑量不足，或是萃物經由動物吸收代謝後降低效果所致。

Metabolic syndrome includes central obesity, hypertriglyceridemia, low serum level of high density lipoprotein-cholesterol and hypertension. It may turn to type II diabetes mellitus and cardiovascular disease without proper treatment. Many studies reveal that nonalcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome. NAFLD refers to a wide spectrum of liver disease ranging from simple fatty liver, to steatohepatitis, and to cirrhosis. The aim of this study was to investigate the effects of methanolic extracts of Osmanthus fragrans (OF) and Chrysanthemum morifolium (CR) and sesamin (SE) on NAFLD and metabolic syndrome in HepG2 cells and hamsters.

In experiment 1, the HepG2 cells were treated with a 1mM fatty acid (FA) mixture containing oleic, palmitic, stearic, linoleic and arachidonic acids, and co-incubated with or without OF, CR and SE for 24 hrs. We observed that OF, CR and SE significantly suppressed intracellular TG accumulation. Both OF and CR decreased ROS production in HepG2 cells. The expression of mRNA related to fatty acid metabolism in HepG2 cells was determined by quantitative real-time PCR. The results revealed that OF significantly decreased mRNA expression of sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthase(FAS), glycerol 3-phosphate acyltransferase (GPAT), and acyl-CoA oxidase (ACO) and increased mRNA expression of acetyl-CoA carboxylase(ACC). CR significantly decreased mRNA expression of SREBP-1c, ACC, FAS, GPAT, and ACO. SE significantly decreased mRNA expression of SREBP-1c and GPAT.
To assess the anti-inflammatory potential of OF, CR and SE, HepG2 cells were treated with conditioned medium from LPS-stimulated THP-1 macrophages as a source of pro-inflammatory cytokines and co-incubated with or without test samples for 48 hr, and then the mRNA expression of pro-inflammatory cytokines in HepG2 cells was determined by quantitative real-time PCR. The results revealed that CR and SE significantly decreased mRNA expression of TNFα, IL-1β, IL-6, IL-8, MCP-1, and TGFβ. Similar inhibitory effects on mRNA expression of TNFα, IL-1β and IL-8 were observed with OF.
In experiment 2, male hamsters were randomly divided into 4 groups and fed high fat high cholesterol diet (30% fat, 1% cholesterol) supplemented with or without 0.3% OF, CR or SE. After 14 days of feeding, the SE group seemed to have a lower level of serum TC, TG, NEFA and glucose but without statistical significance. The OF group significantly decreased the content of hepatic TC but the CR group significantly increased the level of serum TG and TC. There was no significant difference in body weight gain and the weight of epididymal fat pad among control, OF, CR and SE groups.

In experiment 3, male hamsters were divided into 3 groups (1) LF: low fat diet (5% fat, AIN76 diet)；(2) HF: high fat (HF) diet (20% fat, 34% fructose, 0.2% cholesterol)；(3) OF: HF diet supplemented with 0.3% OF. After 10 weeks feeding, the HF group had higher levels of serum TC, TG, HDL-C, hepatic TC, and MCP-1, and lower activity of hepatic SOD in comparison with the LF group. Liver sections revealed HF diets increased fat deposition from oil-red O stain and macrophage clusters from H&E stain. Therefore, metabolic syndrome was induced in this model. However, OF supplementation did not improve any of the above parameters.

In conclusion, OF, CR and SE prevent lipid accumulation and inflammation in HepG2 cells, but they do not improve metabolic syndrome in hamsters except a decreased level of hepatic TC by OF. The inconsistence may be due to (1) insufficient dosage of test samples, (2) low intestinal absorption or metabolic alteration of the effective components in hamster studies.

Abiru, S., Migita, K., Maeda, Y., Daikoku, M., Ito, M., Ohata, K., et al. (2006). Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis. Liver Int, 26(1), 39-45.
Adams, L. A., Angulo, P., & Lindor, K. D. (2005). Nonalcoholic fatty liver disease. CMAJ, 172(7), 899-905.
Adams, L. A., Sanderson, S., Lindor, K. D., & Angulo, P. (2005). The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol, 42(1), 132-138.
Ahmed, M. H., & Byrne, C. D. (2007). Modulation of sterol regulatory element binding proteins (SREBPs) as potential treatments for non-alcoholic fatty liver disease (NAFLD). Drug Discov Today, 12(17-18), 740-747.
Alberti, K. G., Zimmet, P., & Shaw, J. (2006). Metabolic syndrome--a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med, 23(5), 469-480.
Aronis, A., Madar, Z., & Tirosh, O. (2005). Mechanism underlying oxidative stress-mediated lipotoxicity: exposure of J774.2 macrophages to triacylglycerols facilitates mitochondrial reactive oxygen species production and cellular necrosis. Free Radic Biol Med, 38(9), 1221-1230.
Ashakumary, L., Rouyer, I., Takahashi, Y., Ide, T., Fukuda, N., Aoyama, T., et al. (1999). Sesamin, a sesame lignan, is a potent inducer of hepatic fatty acid oxidation in the rat. Metabolism, 48(10), 1303-1313.
Bagry, H. S., Raghavendran, S., & Carli, F. (2008). Metabolic syndrome and insulin resistance: perioperative considerations. Anesthesiology, 108(3), 506-523.
Barros, C. M., Lessa, R. Q., Grechi, M. P., Mouco, T. L., Souza, M. G., Wiernsperger, N., et al. (2007). Substitution of drinking water by fructose solution induces hyperinsulinemia and hyperglycemia in hamsters. Clinics, 62(3), 327-334.
Basciano, H., Federico, L., & Adeli, K. (2005). Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab (Lond), 2(1), 5.
Basciano, H., Miller, A. E., Naples, M., Baker, C., Kohen, R., Xu, E., et al. (2009). Metabolic effects of dietary cholesterol in an animal model of insulin resistance and hepatic steatosis. Am J Physiol Endocrinol Metab, 297(2), E462-473.
Bastard, J. P., Maachi, M., Lagathu, C., Kim, M. J., Caron, M., Vidal, H., et al. (2006). Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw, 17(1), 4-12.
Bellentani, S., Saccoccio, G., Masutti, F., Croce, L. S., Brandi, G., Sasso, F., et al. (2000). Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med, 132(2), 112-117.
Bose, T., Alvarenga, J. C., Tejero, M. E., Voruganti, V. S., Proffitt, J. M., Freeland-Graves, J. H., et al. (2009). Association of monocyte chemoattractant protein-1 with adipocyte number, insulin resistance and liver function markers. J Med Primatol, 38(6), 418-424.
Byrne, C. D., Olufadi, R., Bruce, K. D., Cagampang, F. R., & Ahmed, M. H. (2009). Metabolic disturbances in non-alcoholic fatty liver disease. Clin Sci (Lond), 116(7), 539-564.
Carter-Kent, C., Zein, N. N., & Feldstein, A. E. (2008). Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: implications for treatment. Am J Gastroenterol, 103(4), 1036-1042.
Ceriello, A., & Motz, E. (2004). Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol, 24(5), 816-823.
Chakravarthy, M. V., Pan, Z., Zhu, Y., Tordjman, K., Schneider, J. G., Coleman, T., et al. (2005). "New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab, 1(5), 309-322.
Cheng, W., Li, J., You, T., & Hu, C. (2005). Anti-inflammatory and immunomodulatory activities of the extracts from the inflorescence of Chrysanthemum indicum Linne. J Ethnopharmacol, 101(1-3), 334-337.
Chitturi, S., Abeygunasekera, S., Farrell, G. C., Holmes-Walker, J., Hui, J. M., Fung, C., et al. (2002). NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology, 35(2), 373-379.
Chitturi, S., & Farrell, G. C. (2007). Fatty liver now, diabetes and heart attack later? The liver as a barometer of metabolic health. J Gastroenterol Hepatol, 22(7), 967-969.
Copaci, I., Micu, L., & Voiculescu, M. (2006). The role of cytokines in non-alcoholic steatohepatitis. A review. J Gastrointestin Liver Dis, 15(4), 363-373.
Cousin, S. P., Hugl, S. R., Wrede, C. E., Kajio, H., Myers, M. G., Jr., & Rhodes, C. J. (2001). Free fatty acid-induced inhibition of glucose and insulin-like growth factor I-induced deoxyribonucleic acid synthesis in the pancreatic beta-cell line INS-1. Endocrinology, 142(1), 229-240.
Crespo, J., Cayon, A., Fernandez-Gil, P., Hernandez-Guerra, M., Mayorga, M., Dominguez-Diez, A., et al. (2001). Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology, 34(6), 1158-1163.
Dandona, P., Aljada, A., & Bandyopadhyay, A. (2004). Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol, 25(1), 4-7.
Day, C. P., & James, O. F. (1998). Steatohepatitis: a tale of two "hits"? Gastroenterology, 114(4), 842-845.
Deji, N., Kume, S., Araki, S., Soumura, M., Sugimoto, T., Isshiki, K., et al. (2009). Structural and functional changes in the kidneys of high-fat diet-induced obese mice. Am J Physiol Renal Physiol, 296(1), F118-126.
Del Gaudio, A., Boschi, L., Del Gaudio, G. A., Mastrangelo, L., & Munari, D. (2002). Liver damage in obese patients. Obes Surg, 12(6), 802-804.
Diehl, A. M. (2004). Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. Clin Liver Dis, 8(3), 619-638, x.
Dixon, J. B., Bhathal, P. S., Jonsson, J. R., Dixon, A. F., Powell, E. E., & O'Brien, P. E. (2003). Pro-fibrotic polymorphisms predictive of advanced liver fibrosis in the severely obese. J Hepatol, 39(6), 967-971.
Du, J., Sun, L. N., Xing, W. W., Huang, B. K., Jia, M., Wu, J. Z., et al. (2009). Lipid-lowering effects of polydatin from Polygonum cuspidatum in hyperlipidemic hamsters. Phytomedicine, 16(6-7), 652-658.
Endo, M., Masaki, T., Seike, M., & Yoshimatsu, H. (2007). TNF-alpha induces hepatic steatosis in mice by enhancing gene expression of sterol regulatory element binding protein-1c (SREBP-1c). Exp Biol Med (Maywood), 232(5), 614-621.
Eriksson, J. W. (2007). Metabolic stress in insulin's target cells leads to ROS accumulation - a hypothetical common pathway causing insulin resistance. FEBS Lett, 581(19), 3734-3742.
Evans, J. L., Goldfine, I. D., Maddux, B. A., & Grodsky, G. M. (2002). Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev, 23(5), 599-622.
Evans, J. L., Maddux, B. A., & Goldfine, I. D. (2005). The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal, 7(7-8), 1040-1052.
Fan, C. Y., Pan, J., Chu, R., Lee, D., Kluckman, K. D., Usuda, N., et al. (1996). Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl-coenzyme A oxidase gene. J Biol Chem, 271(40), 24698-24710.
Feinstein, R., Kanety, H., Papa, M. Z., Lunenfeld, B., & Karasik, A. (1993). Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem, 268(35), 26055-26058.
Fitzgerald, S. M., Henegar, J. R., Brands, M. W., Henegar, L. K., & Hall, J. E. (2001). Cardiovascular and renal responses to a high-fat diet in Osborne-Mendel rats. Am J Physiol Regul Integr Comp Physiol, 281(2), R547-552.
Flegal, K. M., Carroll, M. D., Ogden, C. L., & Johnson, C. L. (2002). Prevalence and trends in obesity among US adults, 1999-2000. JAMA, 288(14), 1723-1727.
Foufelle, F., & Ferre, P. (2002). New perspectives in the regulation of hepatic glycolytic and lipogenic genes by insulin and glucose: a role for the transcription factor sterol regulatory element binding protein-1c. Biochem J, 366(Pt 2), 377-391.
Fungwe, T. V., Cagen, L., Wilcox, H. G., & Heimberg, M. (1992). Regulation of hepatic secretion of very low density lipoprotein by dietary cholesterol. J Lipid Res, 33(2), 179-191.
Galis, Z. S. (2004). Role of oxidant stress in vascular proteolysis. International Congress Series, 1262, 490-493.
Glue, C., Hansen, J. B., Schjerling, P., Jinquan, T., & Poulsen, L. K. (2002). LPS-induced cytokine production in the monocytic cell line THP-1 determined by multiple quantitative competitive PCR (QC-PCR). Scand J Clin Lab Invest, 62(6), 405-412.
Grattagliano, I., Palmieri, V. O., Portincasa, P., Moschetta, A., & Palasciano, G. (2008). Oxidative stress-induced risk factors associated with the metabolic syndrome: a unifying hypothesis. J Nutr Biochem, 19(8), 491-504.
Gregoire, F. M., Zhang, Q., Smith, S. J., Tong, C., Ross, D., Lopez, H., et al. (2002). Diet-induced obesity and hepatic gene expression alterations in C57BL/6J and ICAM-1-deficient mice. Am J Physiol Endocrinol Metab, 282(3), E703-713.
Grundy, S. M. (2004). Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab, 89(6), 2595-2600.
Gupte, P., Amarapurkar, D., Agal, S., Baijal, R., Kulshrestha, P., Pramanik, S., et al. (2004). Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol, 19(8), 854-858.
Haas, J. T., & Biddinger, S. B. (2009). Dissecting the role of insulin resistance in the metabolic syndrome. Curr Opin Lipidol, 20(3), 206-210.
Halliwell, B. (1999). Antioxidant defence mechanisms: from the beginning to the end (of the beginning). Free Radic Res, 31(4), 261-272.
Hammond, L. E., Gallagher, P. A., Wang, S., Hiller, S., Kluckman, K. D., Posey-Marcos, E. L., et al. (2002). Mitochondrial glycerol-3-phosphate acyltransferase-deficient mice have reduced weight and liver triacylglycerol content and altered glycerolipid fatty acid composition. Mol Cell Biol, 22(23), 8204-8214.
Hannah, V. C., Ou, J., Luong, A., Goldstein, J. L., & Brown, M. S. (2001). Unsaturated fatty acids down-regulate srebp isoforms 1a and 1c by two mechanisms in HEK-293 cells. J Biol Chem, 276(6), 4365-4372.
Haukeland, J. W., Damas, J. K., Konopski, Z., Loberg, E. M., Haaland, T., Goverud, I., et al. (2006). Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol, 44(6), 1167-1174.
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002). SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest, 109(9), 1125-1131.
Hotamisligil, G. S. (2006). Inflammation and metabolic disorders. Nature, 444(7121), 860-867.
Hotamisligil, G. S., Shargill, N. S., & Spiegelman, B. M. (1993). Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science, 259(5091), 87-91.
Houstis, N., Rosen, E. D., & Lander, E. S. (2006). Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature, 440(7086), 944-948.
Hu, C. Q., Chen, K., Shi, Q., Kilkuskie, R. E., Cheng, Y. C., & Lee, K. H. (1994). Anti-AIDS agents, 10. Acacetin-7-O-beta-D-galactopyranoside, an anti-HIV principle from Chrysanthemum morifolium and a structure-activity correlation with some related flavonoids. J Nat Prod, 57(1), 42-51.
Hussain, M. M., Shi, J., & Dreizen, P. (2003). Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res, 44(1), 22-32.
Ide, T., Ashakumary, L., Takahashi, Y., Kushiro, M., Fukuda, N., & Sugano, M. (2001). Sesamin, a sesame lignan, decreases fatty acid synthesis in rat liver accompanying the down-regulation of sterol regulatory element binding protein-1. Biochim Biophys Acta, 1534(1), 1-13.
Iritani, N., Komiya, M., Fukuda, H., & Sugimoto, T. (1998). Lipogenic enzyme gene expression is quickly suppressed in rats by a small amount of exogenous polyunsaturated fatty acids. J Nutr, 128(6), 967-972.
James, O. F., & Day, C. P. (1998). Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance. J Hepatol, 29(3), 495-501.
Jang, E. M., Choi, M. S., Jung, U. J., Kim, M. J., Kim, H. J., Jeon, S. M., et al. (2008). Beneficial effects of curcumin on hyperlipidemia and insulin resistance in high-fat-fed hamsters. Metabolism, 57(11), 1576-1583.
Jarrar, M. H., Baranova, A., Collantes, R., Ranard, B., Stepanova, M., Bennett, C., et al. (2008). Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther, 27(5), 412-421.
Jeng, K. C., Hou, R. C., Wang, J. C., & Ping, L. I. (2005). Sesamin inhibits lipopolysaccharide-induced cytokine production by suppression of p38 mitogen-activated protein kinase and nuclear factor-kappaB. Immunol Lett, 97(1), 101-106.
Jiang, T., Wang, Z., Proctor, G., Moskowitz, S., Liebman, S. E., Rogers, T., et al. (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(37), 32317-32325.
Karalis, K. P., Giannogonas, P., Kodela, E., Koutmani, Y., Zoumakis, M., & Teli, T. (2009). Mechanisms of obesity and related pathology: linking immune responses to metabolic stress. FEBS J, 276(20), 5747-5754.
Kelley, G. L., Allan, G., & Azhar, S. (2004). High dietary fructose induces a hepatic stress response resulting in cholesterol and lipid dysregulation. Endocrinology, 145(2), 548-555.
Khan, B., Wilcox, H. G., & Heimberg, M. (1989). Cholesterol is required for secretion of very-low-density lipoprotein by rat liver. Biochem J, 258(3), 807-816.
Khan, M. M., Saxena, R., Puri, A., KHanna, A. K., Chander, R., & Saxena, J. K. (2008). Regulation of glycogen metabolism by anti-dyslipidemic action of gemfibrozil and cholestyramine in a dyslipidemic-diabetic hamster model. Med Chem Res, 17, 245-257.
Kiso, Y., Tsuruoka, N., Kidokoro, A., Matsumoto, I., & Abe, K. (2005). Sesamin ingestion regulates the transcription levels of hepatic metabolizing enzymes for alcohol and lipids in rats. Alcohol Clin Exp Res, 29(11 Suppl), 116S-120S.
Klover, P. J., Zimmers, T. A., Koniaris, L. G., & Mooney, R. A. (2003). Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes, 52(11), 2784-2789.
Kohjima, M., Enjoji, M., Higuchi, N., Kato, M., Kotoh, K., Nakashoma, M., et al. (2008). The effect of unsaturated fatty acid on lipid metabolism. In Vitro Cell.Dev.Biol.
Latasa, M. J., Moon, Y. S., Kim, K. H., & Sul, H. S. (2000). Nutritional regulation of the fatty acid synthase promoter in vivo: sterol regulatory element binding protein functions through an upstream region containing a sterol regulatory element. Proc Natl Acad Sci U S A, 97(19), 10619-10624.
Lee do, Y., Choi, G., Yoon, T., Cheon, M. S., Choo, B. K., & Kim, H. K. (2009). Anti-inflammatory activity of Chrysanthemum indicum extract in acute and chronic cutaneous inflammation. J Ethnopharmacol, 123(1), 149-154.
Lee, H. H., Lin, C. T., & Yang, L. L. (2007). Neuroprotection and free radical scavenging effects of Osmanthus fragrans. J Biomed Sci, 14(6), 819-827.
Lee, W. J., Ou, H. C., Wu, C. M., Lee, I. T., Lin, S. Y., Lin, L. Y., et al. (2009). Sesamin mitigates inflammation and oxidative stress in endothelial cells exposed to oxidized low-density lipoprotein. J Agric Food Chem, 57(23), 11406-11417.
Leung, N., Naples, M., Uffelman, K., Szeto, L., Adeli, K., & Lewis, G. F. (2004). Rosiglitazone improves intestinal lipoprotein overproduction in the fat-fed Syrian Golden hamster, an animal model of nutritionally-induced insulin resistance. Atherosclerosis, 174(2), 235-241.
Lin, C. L., Huang, H. C., & Lin, J. K. (2007). Theaflavins attenuate hepatic lipid accumulation through activating AMPK in human HepG2 cells. J Lipid Res, 48(11), 2334-2343.
Lin, D. S., & Connor, W. E. (1980). The long term effects of dietary cholesterol upon the plasma lipids, lipoproteins, cholesterol absorption, and the sterol balance in man: the demonstration of feedback inhibition of cholesterol biosynthesis and increased bile acid excretion. J Lipid Res, 21(8), 1042-1052.
Lin, M. H., Lu, S. C., Huang, P. C., Liu, Y. C., & Liu, S. Y. (2005). A high-cholesterol, n-3 polyunsaturated fatty acid diet causes different responses in rats and hamsters. Ann Nutr Metab, 49(6), 386-391.
Linden, D., William-Olsson, L., Ahnmark, A., Ekroos, K., Hallberg, C., Sjogren, H. P., et al. (2006). Liver-directed overexpression of mitochondrial glycerol-3-phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation. FASEB J, 20(3), 434-443.
Lundgren, M., Svensson, M., Lindmark, S., Renstrom, F., Ruge, T., & Eriksson, J. W. (2007). Fat cell enlargement is an independent marker of insulin resistance and 'hyperleptinaemia'. Diabetologia, 50(3), 625-633.
Mao, J., DeMayo, F. J., Li, H., Abu-Elheiga, L., Gu, Z., Shaikenov, T. E., et al. (2006). Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci U S A, 103(22), 8552-8557.
Marchesini, G., Brizi, M., Bianchi, G., Tomassetti, S., Bugianesi, E., Lenzi, M., et al. (2001). Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes, 50(8), 1844-1850.
Marchesini, G., Bugianesi, E., Forlani, G., Cerrelli, F., Lenzi, M., Manini, R., et al. (2003). Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology, 37(4), 917-923.
Matsuzaka, T., Shimano, H., Yahagi, N., Amemiya-Kudo, M., Okazaki, H., Tamura, Y., et al. (2004). Insulin-independent induction of sterol regulatory element-binding protein-1c expression in the livers of streptozotocin-treated mice. Diabetes, 53(3), 560-569.
Matsuzawa-Nagata, N., Takamura, T., Ando, H., Nakamura, S., Kurita, S., Misu, H., et al. (2008). Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism, 57(8), 1071-1077.
Maurizio, P., & Novo, E. (2005). Nrf1 gene expression in the liver: a single gene linking oxidative stress to NAFLD, NASH and hepatic tumours. J Hepatol, 43(6), 1096-1097.
Meigs, J. B., Larson, M. G., Fox, C. S., Keaney, J. F., Jr., Vasan, R. S., & Benjamin, E. J. (2007). Association of oxidative stress, insulin resistance, and diabetes risk phenotypes: the Framingham Offspring Study. Diabetes Care, 30(10), 2529-2535.
Miyazaki, M., Kim, Y. C., Gray-Keller, M. P., Attie, A. D., & Ntambi, J. M. (2000). The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1. J Biol Chem, 275(39), 30132-30138.
Miyazawa, M., & Hisama, M. (2003). Antimutagenic activity of flavonoids from Chrysanthemum morifolium. Biosci Biotechnol Biochem, 67(10), 2091-2099.
Mokdad, A. H., Ford, E. S., Bowman, B. A., Dietz, W. H., Vinicor, F., Bales, V. S., et al. (2003). Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA, 289(1), 76-79.
Moon, P. D., Jeong, H. J., Um, J. Y., Kim, H. M., & Hong, S. H. (2007). LPS-induced inflammatory cytokine production was inhibited by HyungbangJihwangTang through blockade of NF-kappaB in peripheral blood mononuclear cells. Int J Neurosci, 117(9), 1315-1329.
Morise, A., Mourot, J., Boue, C., Combe, N., Amsler, G., Gripois, D., et al. (2006). Gender-related response of lipid metabolism to dietary fatty acids in the hamster. Br J Nutr, 95(4), 709-720.
Munday, M. R. (2002). Regulation of mammalian acetyl-CoA carboxylase. Biochem Soc Trans, 30(Pt 6), 1059-1064.
Musso, G., Gambino, R., Bo, S., Uberti, B., Biroli, G., Pagano, G., et al. (2008). Should nonalcoholic fatty liver disease be included in the definition of metabolic syndrome? A cross-sectional comparison with Adult Treatment Panel III criteria in nonobese nondiabetic subjects. Diabetes Care, 31(3), 562-568.
Musso, G., Gambino, R., & Cassader, M. (2009). Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res, 48(1), 1-26.
Novo, E., & Parola, M. (2008). Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair, 1(1), 5.
Ouyang, X., Cirillo, P., Sautin, Y., McCall, S., Bruchette, J. L., Diehl, A. M., et al. (2008). Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol, 48(6), 993-999.
Pérez-Palacios, T., Ruiz, J., Martín, D., Muriel, E., & Antequera, T. (2008). Comparison of different methods for total lipid quantification in meat and meat products. Food Chemistry, 110(4), 1025-1029.
Pawlak, K., Pawlak, D., & Mysliwiec, M. (2007). Serum matrix metalloproteinase-2 and increased oxidative stress are associated with carotid atherosclerosis in hemodialyzed patients. Atherosclerosis, 190(1), 199-204.
Portincasa, P., Grattagliano, I., Palmieri, V. O., & Palasciano, G. (2005). Nonalcoholic steatohepatitis: recent advances from experimental models to clinical management. Clin Biochem, 38(3), 203-217.
Rajagopalan, S., Meng, X. P., Ramasamy, S., Harrison, D. G., & Galis, Z. S. (1996). Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest, 98(11), 2572-2579.
Reaven, G. M. (1988). Banting lecture 1988. Role of insulin resistance in human disease. Diabetes, 37(12), 1595-1607.
Repa, J. J., Liang, G., Ou, J., Bashmakov, Y., Lobaccaro, J. M., Shimomura, I., et al. (2000). Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev, 14(22), 2819-2830.
Rizvi, F., Puri, A., Bhatia, G., Khanna, A. K., Wulff, E. M., Rastogi, A. K., et al. (2003). Antidyslipidemic action of fenofibrate in dyslipidemic-diabetic hamster model. Biochem Biophys Res Commun, 305(2), 215-222.
Roberts, C. K., & Sindhu, K. K. (2009). Oxidative stress and metabolic syndrome. Life Sci, 84(21-22), 705-712.
Savage, D. B., Choi, C. S., Samuel, V. T., Liu, Z. X., Zhang, D., Wang, A., et al. (2006). Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest, 116(3), 817-824.
Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L., et al. (2000). Role of LXRs in control of lipogenesis. Genes Dev, 14(22), 2831-2838.
Sekiya, M., Hiraishi, A., Touyama, M., & Sakamoto, K. (2008). Oxidative stress induced lipid accumulation via SREBP1c activation in HepG2 cells. Biochem Biophys Res Commun.
Shimano, H., Horton, J. D., Shimomura, I., Hammer, R. E., Brown, M. S., & Goldstein, J. L. (1997). Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest, 99(5), 846-854.
Shimomura, I., Bashmakov, Y., & Horton, J. D. (1999). Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem, 274(42), 30028-30032.
Shoelson, S. E., Lee, J., & Goldfine, A. B. (2006). Inflammation and insulin resistance. J Clin Invest, 116(7), 1793-1801.
Singh, G., Gupta, P., Rawat, P., Puri, A., Bhatia, G., & Maurya, R. (2007). Antidyslipidemic activity of polyprenol from Coccinia grandis in high-fat diet-fed hamster model. Phytomedicine, 14(12), 792-798.
Sirato-Yasumoto, S., Katsuta, M., Okuyama, Y., Takahashi, Y., & Ide, T. (2001). Effect of sesame seeds rich in sesamin and sesamolin on fatty acid oxidation in rat liver. J Agric Food Chem, 49(5), 2647-2651.
Sullivan, M. P., Cerda, J. J., Robbins, F. L., Burgin, C. W., & Beatty, R. J. (1993). The gerbil, hamster, and guinea pig as rodent models for hyperlipidemia. Lab Anim Sci, 43(6), 575-578.
Surampudi, P. N., John-Kalarickal, J., & Fonseca, V. A. (2009). Emerging concepts in the pathophysiology of type 2 diabetes mellitus. Mt Sinai J Med, 76(3), 216-226.
Taniguchi, C. M., Kondo, T., Sajan, M., Luo, J., Bronson, R., Asano, T., et al. (2006). Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab, 3(5), 343-353.
Tarabra, E., Giunti, S., Barutta, F., Salvidio, G., Burt, D., Deferrari, G., et al. (2009). Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes. Diabetes, 58(9), 2109-2118.
Tarantino, G., Saldalamacchia, G., Conca, P., & Arena, A. (2007). Non-alcoholic fatty liver disease: further expression of the metabolic syndrome. J Gastroenterol Hepatol, 22(3), 293-303.
Taslim, S., & Tai, E. S. (2009). The relevance of the metabolic syndrome. Ann Acad Med Singapore, 38(1), 29-25.
Tiedge, M., Lortz, S., Drinkgern, J., & Lenzen, S. (1997). Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes, 46(11), 1733-1742.
Tilg, H., & Diehl, A. M. (2000). Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med, 343(20), 1467-1476.
Tilg, H., & Moschen, A. R. (2008). Insulin resistance, inflammation, and non-alcoholic fatty liver disease. Trends Endocrinol Metab, 19(10), 371-379.
Tomita, K., Tamiya, G., Ando, S., Ohsumi, K., Chiyo, T., Mizutani, A., et al. (2006). Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut, 55(3), 415-424.
Tripathi, S., Bruch, D., & Kittur, D. S. (2008). Ginger extract inhibits LPS induced macrophage activation and function. BMC Complement Altern Med, 8, 1.
Umeda-Sawada, R., Ogawa, M., Nakamura, M., & Igarashi, O. (2001). Effect of sesamin on mitochondrial and peroxisomal beta-oxidation of arachidonic and eicosapentaenoic acids in rat liver. Lipids, 36(5), 483-489.
Urakawa, H., Katsuki, A., Sumida, Y., Gabazza, E. C., Murashima, S., Morioka, K., et al. (2003). Oxidative stress is associated with adiposity and insulin resistance in men. J Clin Endocrinol Metab, 88(10), 4673-4676.
Wang, P. R., Guo, Q., Ippolito, M., Wu, M., Milot, D., Ventre, J., et al. (2001). High fat fed hamster, a unique animal model for treatment of diabetic dyslipidemia with peroxisome proliferator activated receptor alpha selective agonists. Eur J Pharmacol, 427(3), 285-293.
Wang, X. X., Jiang, T., Shen, Y., Adorini, L., Pruzanski, M., Gonzalez, F. J., et al. (2009). The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria. Am J Physiol Renal Physiol, 297(6), F1587-1596.
Wieckowska, A., Papouchado, B. G., Li, Z., Lopez, R., Zein, N. N., & Feldstein, A. E. (2008). Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol, 103(6), 1372-1379.
Wisse, B. E. (2004). The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol, 15(11), 2792-2800.
Wouters, K., van Gorp, P. J., Bieghs, V., Gijbels, M. J., Duimel, H., Lutjohann, D., et al. (2008). Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatology, 48(2), 474-486.
Xu, Z., Chen, L., Leung, L., Yen, T. S., Lee, C., & Chan, J. Y. (2005). Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc Natl Acad Sci U S A, 102(11), 4120-4125.
Yoshikawa, T., Shimano, H., Amemiya-Kudo, M., Yahagi, N., Hasty, A. H., Matsuzaka, T., et al. (2001). Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol, 21(9), 2991-3000.
Zeyda, M., & Stulnig, T. M. (2009). Obesity, inflammation, and insulin resistance--a mini-review. Gerontology, 55(4), 379-386.
Zhang, L., Perdomo, G., Kim, D. H., Qu, S., Ringquist, S., Trucco, M., et al. (2008). Proteomic analysis of fructose-induced fatty liver in hamsters. Metabolism, 57(8), 1115-1124.
Zhang, W., Patil, S., Chauhan, B., Guo, S., Powell, D. R., Le, J., et al. (2006). FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem, 281(15), 10105-10117.
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature, 372(6505), 425-432.
Zhang, Z., Wang, H., Jaio, R., Peng, C., Wong, Y. M., Yeung, V. S. Y., et al. (2009). Choosing hasmter but not rats as model for studying plasma cholesterol-lowering activity of functional foods. Mol. Nutr. Food Res., 53, 921-930.
Ziegler, O., Quilliot, D., Guerci, B., & Drouin, P. (2001). [Macronutrients, fat mass, fatty acid flux and insulin sensitivity]. Diabetes Metab, 27(2 Pt 2), 261-270.
Zimmet, P., Magliano, D., Matsuzawa, Y., Alberti, G., & Shaw, J. (2005). The metabolic syndrome: a global public health problem and a new definition. J Atheroscler Thromb, 12(6), 295-300.
Zimmet, P., Shaw, J., & Alberti, K. G. (2003). Preventing Type 2 diabetes and the dysmetabolic syndrome in the real world: a realistic view. Diabet Med, 20(9), 693-702.

曾文楷, 陳宜嫻, & 官常慶. (2009). 菊花萃取物於抗氧化、抑制黑色素生成及抗致突變的研究. 臺灣農業化學與食品科學(47卷1期), 8.
黃福龍 (2005). 台灣產桂花之安全性、抗致敏性氣喘及護肝功能之評估. 中華醫事
學院.
高秋華 (2007). 數種植物性雌激素對代謝症候群的影響 國立台灣師範大學人類發展與家庭學系營養科學教育組碩士論文