以激素敏感性脂肪酶为靶点的天然减肥药物的初步筛选
|
摘要
目的：
肥胖症是危害人类健康的全球性疾病。肥胖增加人类患其他疾病的危险性，包括高血压，血脂异常(如高胆固醇，高甘油三酯)，2型糖尿病，冠心病，中风，胆囊疾病，骨关节炎，睡眠呼吸暂停，子宫内膜癌，乳腺癌，结肠癌等肿瘤和心理疾患。白色脂肪组织中脂肪的合成和分解与肥胖症的发生、发展关系密切。增加脂肪分解有助于减少脂肪细胞中甘油三酯的储存。激素敏感性脂肪酶(HSL)是脂肪分解过程中的主要限速酶，在脂肪分解过程中起重要的作用。通过细胞转染技术，将含人脂肪组织HSL基因启动子的荧光素酶表达质粒稳定转染小鼠3T3-L1前脂肪细胞中，并以此为工具，从众多中药天然化合物中寻找对HSL启动子活性有影响的药物，再通过动物实验观察药物对高脂膳食昆明小鼠体重、糖脂代谢的干预作用，及对小鼠体内白色脂肪组织HSL基因表达的影响，探讨以HSL为减肥药物筛选靶点的可行性。
方法：
1．建立含人脂肪组织HSL基因启动子的荧光素酶表达质粒的稳定转染小鼠3T3-L1前脂肪细胞株：以人基因组DNA为模版，克隆人脂肪组织HSL基因启动子序列(-697-+53bp)，将该片断插入到含荧光素报告基因的质粒载体pGL3-Basic-Luc中，得到含人HSL基因启动子序列(-697-+53bp)的荧光素酶表达质粒。然后用脂质体转染法，将该质粒转染到小鼠3T3-L1前脂肪细胞中，经筛选药物Geneticin(G418)筛选，获得表达荧光素酶的稳定转染单克隆小鼠3T3-L1前脂肪细胞株。
2．50％乙醇中药提取液(extracts of Chinese medical herbs，ECMH)对人HSL基因启动子活性的影响：含人HSL基因启动子序列的荧光素酶报告质粒，其荧
Objective:
Obesity is a major health problem in the world. Obese increases the risk of many diseases and health conditions, including hypertension , dyslipidemia (for example, high total cholesterol or high levels of triglycerides), Type 2 diabetes , coronary heart disease , stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, some cancers (endometrial, breast, and colon) and psychological stress. The lipogenese and lipolyse of white fat cell are closely associated with the development of obesity. Icreasing lipolyse can help to reduce the triglyceride store in adipocyt. Hormone sensitity lipase is the rate-limiting enzyme in lipolytic process, plays a key role in this course. The mice 3T3-L1 preadipocyte stably transfected by a luciferase expreeion plasmid which contains the adipose tissue HSL promoter was used as a tool to screening drugs. The aim of this study is to find herb which may influence the activity of the HSL promoter from the numerous natural compounds , then to observe the effects of these drugs on weight, metabolism of glucose and lipid of Kunming mice.
肥胖症是危害人类健康的全球性疾病。肥胖增加人类患其他疾病的危险性，包括高血压，血脂异常(如高胆固醇，高甘油三酯)，2型糖尿病，冠心病，中风，胆囊疾病，骨关节炎，睡眠呼吸暂停，子宫内膜癌，乳腺癌，结肠癌等肿瘤和心理疾患。白色脂肪组织中脂肪的合成和分解与肥胖症的发生、发展关系密切。增加脂肪分解有助于减少脂肪细胞中甘油三酯的储存。激素敏感性脂肪酶(HSL)是脂肪分解过程中的主要限速酶，在脂肪分解过程中起重要的作用。通过细胞转染技术，将含人脂肪组织HSL基因启动子的荧光素酶表达质粒稳定转染小鼠3T3-L1前脂肪细胞中，并以此为工具，从众多中药天然化合物中寻找对HSL启动子活性有影响的药物，再通过动物实验观察药物对高脂膳食昆明小鼠体重、糖脂代谢的干预作用，及对小鼠体内白色脂肪组织HSL基因表达的影响，探讨以HSL为减肥药物筛选靶点的可行性。
方法：
1．建立含人脂肪组织HSL基因启动子的荧光素酶表达质粒的稳定转染小鼠3T3-L1前脂肪细胞株：以人基因组DNA为模版，克隆人脂肪组织HSL基因启动子序列(-697-+53bp)，将该片断插入到含荧光素报告基因的质粒载体pGL3-Basic-Luc中，得到含人HSL基因启动子序列(-697-+53bp)的荧光素酶表达质粒。然后用脂质体转染法，将该质粒转染到小鼠3T3-L1前脂肪细胞中，经筛选药物Geneticin(G418)筛选，获得表达荧光素酶的稳定转染单克隆小鼠3T3-L1前脂肪细胞株。
2．50％乙醇中药提取液(extracts of Chinese medical herbs，ECMH)对人HSL基因启动子活性的影响：含人HSL基因启动子序列的荧光素酶报告质粒，其荧
Objective:
Obesity is a major health problem in the world. Obese increases the risk of many diseases and health conditions, including hypertension , dyslipidemia (for example, high total cholesterol or high levels of triglycerides), Type 2 diabetes , coronary heart disease , stroke, gallbladder disease, osteoarthritis, sleep apnea and respiratory problems, some cancers (endometrial, breast, and colon) and psychological stress. The lipogenese and lipolyse of white fat cell are closely associated with the development of obesity. Icreasing lipolyse can help to reduce the triglyceride store in adipocyt. Hormone sensitity lipase is the rate-limiting enzyme in lipolytic process, plays a key role in this course. The mice 3T3-L1 preadipocyte stably transfected by a luciferase expreeion plasmid which contains the adipose tissue HSL promoter was used as a tool to screening drugs. The aim of this study is to find herb which may influence the activity of the HSL promoter from the numerous natural compounds , then to observe the effects of these drugs on weight, metabolism of glucose and lipid of Kunming mice.
引文
1. Bray GA, Bellanger T. Epidemiology, trends, and morbidities of obesity and the metabolic syndrome. Endocrine. 2006, 29(1):109-18.
2. Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes Res. 2004, 12:1197-1211.
3. Kusunoki J, Kanatani A, Moller DE. Modulation of Fatty Acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome. Endocrine. 2006, 29(1):91-100.
4. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001, 104(4):531-543.
5. D. B. Hauseman, M. Digirolamo, T.J. Bartness et al. The biology of white adipocyte proliferation.Obesity Review. 2001, 2:239-254.
6. Cornelius P, Macdougald O, Land et al. Regulation of adipocyte development. Annu Rev Nutri 1994, 14:99-129
7. Konieczny S. F, et al. 5-azacytidine induction of stable mesodermal stem cell lineages from lOT1/2 cell. Ce11.1984, 38:791-800.
8. Dani C. Differentiation of embryonic stem cell into adipocyte in vitro, J Cell Science. 1997, 110:1279-1285.
9. Davies JI, Souness JE. The mechanisms of hormone and drugs actions on fatty acid release from adipose tissue. Rev Pure Appl Pharmacol Sci. 1996, 2:1-113.
10. Lilioja S, Foley J, Borgadus C, et al. Free fatty acid metabolism in man. In vivo, In vitro comparisons. Metabolism. 1986, 35(6):505-514.
11. Tischler ME, Goldberg AL. Leucine degradation and release of glutamine and alanine by adipose tissue, J Biol chem. 1980,255(17):8074-8081.12. Hirsch J, Goldrick R. Serial studies of human adipose tissue. I. Lipogenesis and free fatty acid uptake and release in small aspirated samples of subcutaneous fat. J Clin Invest. 1964 , 43:1776-1992.
13. Hirsch J, Frield SK, Edens N, et al. The fat cell. Med Clin North Am. 1989, 73(1): 83-96.
14. Kern PA, Ong JM, Saffari B, et al. The effects of weight loss on the activity and expression of adipose - tissue lipoprotein lipase in very obese humans. N Engl J Med. 1991, 322(15):1053-1059.
15.Rebuffe-Scrive M, Fat cell metabolism in different regions in women. Effect of menstrual cycle/pregnancy and latation. J Clin Invest. 1985, 75(6):1973-1976
16. Rebuffe-Scrive M, Marin P, Bjorntorp P. Effect of testosterone on abdominal adipose tissue in men. Int J Obes. 1991, 15(11):791-795
17. Langin D, Holm C, Lafontan M. Adipocyte hormone-sensitive lipase: a major regulator of lipid metabolism. Proc Nutr Soc. 1996, 55 (1B): 93-109.
18. Haemmerle G, Zimmermann R, Zechner R. Letting lipids go: hormone-sensitive lipase. Curr Opin Lipidol. 2003, 14(3):289-97.
19.Langin D, Dicker A, Tavernier G, Hoffstedt J. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes. 2005, 54(11): 3190-3197.
20. Haemmerle G, Zimmermann R, Hayn M, et al. Hormone -sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J Biol Chem. 2002, 227: 4806-4815.
21.Komaromy MC, Kraemer FB, Sztalryd C. Overexpression of hormone-sensitive lipase prevents triglyceride accumulation in adipocytes. J Clin Invest. 1995, 95(6):2652-2661.
22. Large V, Reynisdottir S, Langin D, et al. Decreased expression and
function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res. 1999, 40(11):2059-2066.
23. Langin D, Dicker A, Tavernier G. Adipocyte lipases and defect of lipolysis in human obesityDiabetes. 2005, 54(11):3190-3197.
24. Mairal A, Langin D, Arner P, Hoffstedt J. Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity. Diabetologia. 2006 May 10[Epub ahead of print]
25. Sztalryd C, Komaromy MC, Kraemer FB. Overexpression hormone-sensitive lipase prevents triglyceride accumulation in adipocyte. J Clin Invest. 1995, 95:2652-2661.
26. Wyatt SB, Winters KP, Dubbert PM. Overweight and obesity: prevalence, consequences, and causes of a growing public health problem. Am J Med Sci. 2006, 331(4): 166-174.
27．武阳丰，马冠生，胡永华，等．中国居民的超重和肥胖流行现状。中华预防医学杂志 2005，39(5)：316-320．
28．杜海洲．抗肥胖新药的研究与开发．医学信息．2005，8：20-22
29. Halford JC. Obesity drugs in clinical development. CurrOpin Investig Drugs. 2006, 7(4):312-318.
30. Carrel AL, Allen DB. Effects of growth hormone on adipose tissue. J Pediatr Endocrinol Metab. 2000. 13 Suppl, 2: 1003-1009.
31. Langin D. Adlpose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. Pharmacol Res. 2006, Mar 27. [Epub ahead of print]
32．吴大真等编．现代名中医肥胖治疗绝技．科学技术文献出版社．
33. Green H, O. Kehinde et al. An established preadipocyte cell line and its differentiation in culture. Ⅱ factors affecting the adipose convertsion. Cell. 1975,5:19-27.
34. Green H,O. Kehinde et al. Spontaneous heritable changes leading to??increase adipose conversion in 3T3 cells. Ce11.1976, 7:105-113.
35. Green H, Meuth M, et al. An established pre-adipose cell line and its differentiation in culture. Ce11.1974, 3:127-133.
36. Von Gierke. Uber fett metabolism. Ver Deutsch Ges Path 1906, 10:182-185.
37. D.B. Hauseman, M. Digirolamo, T.J. Bartness et al. The biology of white adipocyte proliferation.Obesity Review 2001, 2:239-254.
38．J．萨姆布鲁克，D．W．拉赛尔著，黄培堂等译，科学出版社。《分子克隆实验指南》(第三版)第17章：哺乳动物培养细胞的基因表达分析，P1347-1361．
39. Sekiya M, Osuga J, Okazaki H, at al. Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice. J. Biol. Chem. 2004, 279 (15): 15084-15090.
40. Shu Pei Wang, Nancy Laurin, Jean Himms-Hagen, et al. The Adipose Tissue Phenotype of Hormone-Sensitive Lipase Deficiency in Mice. Obesity Research. 2001, 9:119-128.
41. Jun-ichi Osuga, Shun Ishibashi, Teruaki Oka, at al. Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. PNAS. 2000, 97 (2): 787-792.
42. Zimmermann R, Strauss JG, Haemmerle G, et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004, 19; 306(5700):1383-1386.
43. Zechner R, Strauss JG, Haemmerle G, et al. Lipolysis: pathway under construction. Curr Opin Lipidol. 2005, 16(3):333-40.1. Hauseman DB, Digirolamo M, Bartness TJ,et al. The biology of white adipocyte proliferation.Obesity Review. 2001, 2:239-154.
2. Komaromy MC, Kraemer FB,Sztalryd C. Overexpression of hormone-sensitive lipase prevents triglyceride accumulation in adipocytes. J Clin Invest.??1995, 95(6): 2652-2661.
3. Large V, Reynisdottir S, Langin D, et al. Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res. 1999,40(11):2059-2066.
4. Carrel AL, Allen DB. Effects of growth hormone on adipose tissue. J Pediatr Endocrinol Metab. 2000,13 Suppl 2: 1003-1009.
5. Sekiya M, Osuga J, Okazaki H, at al. Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice. J. Biol. Chem..2004, 279 (15): 15084-15090.
6. Shu Pei Wang, Nancy Laurin, Jean Himms-Hagen, et alo The Adipose Tissue Phenotype of Hormone-Sensitive Lipase Deficiency in Mice.Obesity Research. 2001, 9:119-128.
7. Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Bimer-Gruenberger R, Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004, 19;306(5700):1383-1386.
8. Mairal A, Langin D, Amer P, Hoffstedt J. Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity. Diabetologia. 2006 May 10[Epub ahead of print]
9. Haemmerle G, Zimmermann R, Zechner R.Letting lipids go: hormone-sensitive lipase. Curr Opin Lipidol. 2003,14(3):289-297.
10. John C. Khoo, Karen Reue, Daniel Steinberg, et al. Expression of hormone-sensitive lipase mRNA in macrophages. J Lipid Res.1998, 34: 1993-1969.
11．刘星霞，缪兵，李府，等．胚胎干细胞诱生的胰岛素分泌细胞分泌胰岛素的研究，世界华人消化杂志．2004，12(8)：1857-1860．
12．朱愉，多秀瀛．实验动物的疾病模型(第一版)，天津科技出版社，1997：258．
13．范晓，韩丽君．我国常见海藻营养成分分析．中国海洋药物，1993，12(4)：32-38．
14．西泽一俊，刘长发．海藻的生理活性物质．中国海洋药物，1993，12(1)：47-51．
15. Liu QY, Meng QY.Therapeutic effect of Seaweed Polysaccharide from Sargassum??confusum on sarcoma s180 in mice and its mechanism. Ai Zheng. 2005, 24(12): 1469-1473.
16. Park P J, Heo S J, Park E J, et al. Reactive oxygen scavenging effect of enzymatic extracts from Sargassum thunbergii. J Agric Food Chem. 2005, 53(17): 6666-6672
17. Huang ZX, Mei XT, Xu DH, et al. Protective effects of polysacchride of Spirulina platensis and Sargassarn thunbeergii on vascular of alloxan induced diabetic rats. Zhongguo Zhong Yao Za Zhi. 2005, 30(3):211-215.
18．程志清，严建伟．海藻提取物对实验性高脂大鼠模型的药效学研究．中国现代应用药学．1998，15(5)：9-10
19. Kim, SO, Yun, SJ, JUNG B, et al, Hypolipidemic effects of crude extract ofadlay seed (Coix lachrymajobi var. mayuen) in obesity rat fed high fat diet: relations of TNF-alpha and leptin mRNA expressions and serum lipid levels. Life Sci. 2004, 75(11):1391-1404.
20．张春海 毛缜 马丽，等．泽泻水提取物、醇提取物对小鼠脂代谢影响的比较．徐州师范大学学报：自然科学版．2005，23(2)：68-70．
21. KIM CH, KIM MS, YOUN JY, et al. Lipolysis in skeletal muscle is decreased in high-fat-fed rats. Metabolism, 2003-52(12): 1586-1592.
22．谭正怀、莫正纪、陈岷，等．西布曲明对金硫葡萄糖诱导肥胖动物模型的影响．中国药理学通报，2003，19：(10)：60．
23. Nagao T, Ostuka H, Kohda H, et al. Benzoxazineone from Coix lachruma-jobi L vat. ma-yuen. Phutochemistry. 1985, 24 (2):2959-2962.
24. Hsu HY, Lin BF, Lin JY, et al. Suppression of allergic reactions by dehulled adlay in association with the balance of TH1/TH2 cell responses. J Agric Food Chem. 2003, 51(13):3763-3769.
25. Shih CK, Chiang W, Kuo ML. Effects of adlay on azoxymethane-induced colon carcinogenesis in rats. Food Chem Toxicol. 2004, 42(8): 1339-1347.
26. Yu YM, Chang WC, Liu CS, et al. Effect of young barley leaf extract and adlay on plasma lipids and LDL oxidation in hyperlipidemic smokers. Biol Pharm Bull. 2004, 27(6):802-805.
27. Huang BW, Chiang MT, Yao HT, et al. The effect of adlay oil on plasma lipids,??insulin and leptin in rat. Phytomedicine. 2005, 12(6-7):433-439.1. Yeaman SJ.Hormone-sensitive lipase-a multipurpose enzyme in lipid metabolism. Biochim Biophys Acta. 1990, 1052(l):128-32.
2. Fredrikson G, Stralfors P, Nilsson NO, et al. Hormone-sensitive lipase of rat adipose tissue. Purification and some properties. J Biol Chem. 1981 , 256(12):6311-20.
3. Yeaman SJ. Hormone-sensitive lipase~new roles for an old enzyme. Biochem J. 2004,379(Pt 1):11-22.
4. Kraemer FB, Shen WJ. Hormone sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. J Lipid Res. 2002, 43: 1585-1594.
5. Shen WJ, Liang Y, Hong R, et al. Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase. J Biol Chem. 2001, 276:49443-49448.
6. Anthonsen MW, Ronnstrand L, Wernstedt C,et al. Indentification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitr. J Biol Chem. 1998,273:215-221.
7. Mulder H, Hoist LS, Svensson H, et al. Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in β-cells. Diabetes. 1999, 48:228-232.
8. Lindvall H, Nevsten P, Strom K, et al. A novel hormone-sensitive lipase isoform expressed in pancreatic beta-cells. J Biol Chem.2004,279:3828-3826.
9. Hoist LS, Langin D, Mulder H,et al. Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase. Genomics. 1996, 35(3):441-447.
10. Watt M J, Stellingwerff T, Heigenhauser G J F, et al. Effects of plasma adrenaline on hormone-sensitive lipase at rest and during moderate exercise in human skeletal muscle. J Physiol.2003,550:325-332.
11. Haemmerle G, Zimmermann R, Zechner R.Letting lipids go: hormone-sensitive lipase. Curr Opin Lipidol. 2003 , 14(3):289-297.
12. Shen WJ, Patel S, Hong R. Hormone-sensitive lipase functions as an oligomer. Biochemistry. 2000, 39(9):2392-2398.
13.Fredrikson G, Tornqvist H, Belfrage P. Hormone-sensitive lipase and monoacylglycerol lipase are both required for complete degradation of adipocyte triacylglycerol. Biochim Biophys Acta. 1986, 876(2):288-293.
14. Holm C, Osterlund T, Laurell H,et al. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Annu Rev Nutr. 2000, 20:365-393.
15. Londos C, Brasaemle DL, Gruia-Gray J, et al.Perilipin: unique proteins associated with intracellular neutral lipid droplets in adipocytes and steroidogenic cells. Biochem Soc Trans. 1995, 23(3):611-615.
16. Greenberg AS, Shen WJ, Muliro K, et al. Stimulation of lipolysis and hormone sensitive lipase via the extracellular signal regulated kinase pathway. J Biol Chem.2001,276:45456-45461.
17. Smith F, Rouet P, Lucas S, et al. Transcriptional regulation of adipocyte hormone-sensitive lipase by glucose. Diabetes.2002, 51:293-300.
18. Berraondo B, Martinez JA. Free Fatty Acids Are Involved in the Inverse Relationship between Hormone-Sensitive Lipase (HSL) Activity and Expression in Adipose Tissue after High-Fat Feeding or β3-Adrenergic Stimulatio. Obes Res. 2000,8:255-261.
19. Large V, Arner P, et al. Hormone-sensitive lipase and activity in relation to lipolysis in human fat cell. J Lipid Res. 1998 , 39:1688-1695.
20. Sztalryd C, Komaromy MC, Kraemer FB. Overexpression hormone-sensitive lipase prevents triglyceride accumulation in adipocyte. J Clin Invest. 1995, 95:2652-2661.
21. Large V, Reynisdottir S, Langin D, et al. Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res. 1999,40:2059-2066.
22. Haemmerle G, Zimmermann R, Hayn M, et al. Hormone-sensitive lipase
deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J Biol Chem. 2002, 277(7):4806-4815.
23. Osuga J, Ishibashi S, Oka T, Yagyu H, et al Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. PNAS. 2000,18;97(2):787-792.
24. Raclot T, Holm C, Langin D.Fatty acid specificity of hormone-sensitive lipase. Implication in the selective hydrolysis of triacylglycerols. J Lipid Res. 2001 Dec;42(12):2049-2057.
25. Zimmermann R, Strauss JG, Haemmerle G, et al. Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase. Science.2004: 306 (5700): 1383-1386.
26. Villena JA,Roy S, Sarkadi-Nagy E,et al. Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids. J Biol Chem, 2004. 279(45):47066-47075.
27. Jenkins CM, Mancuso DJ, Yan W, et al. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem. 2004,279(47):48968-48975.
28. Langin D, Dicker A, Tavernier G Adipocyte lipases and defect of lipolysis in human obesity. Diabetes. 2005 , 54(ll):3190-3197.
29. Mairal A, Langin D, Arner P, Hoffstedt J. Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity. Diabetologia. 2006 May 10[Epub ahead of print]
30. Haemmerle G, Zimmermann R, Strauss JG, et al. Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle. J Biol Chem. 2002,277(15):12946-12952.
31. Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G,et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science.
2006 , 312(5774):734-737.
32. Suzuki J, Shen WJ, Nelson BD,et al. Absence of cardiac lipid accumulation in transgenic mice with heart-specific HSL overexpression. Am J Physiol Endocrinol Metab. 2001, 281(4):E857-866.
33. Tavintharan S, Kashyap ML. The benefits of niacin in atherosclerosis. Curr Atheroscler Rep. 2001, 3 (l):74-82.
34. Aktories K, Schultz G, Jakobs KH. Adenylate cyclase inhibition and GTPase stimulation by somatostatin in S49 lymphoma cyc- variants are prevented by islet-activating protein. FEBS Lett. 1983 , 158(1):169-173.
35. Green A, Milligan G, Dobias SB Gi down-regulation as a mechanism for heterologous desensitization in adipocytes. J Biol Chem. 1992 , 267(5):3223-3229.
36. Brown MS, HO YK, Goldstein JL. The cholesteryl ester cycle in macrophage foam cells. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters.J Biol Chem. 1980 ,255(19):9344-9352.
37. Krause BR, Hartman AD. Adipose tissue and cholesterol metabolism. J Lipid Res. 1984, 25(2):97-110.
38. Escary JL,Choy HA, Reue K, etal. Hormone-sensitive lipase overexpression increases cholesteryl ester hydrolysis in macrophage foam cells. Arterioscler Thromb Vasc Biol. 1998,18(6):991-998.
39. Okazaki H, Osuga J, Tsukamoto K, et al . Elimination of cholesterol ester from macrophage foam cells by adenovirus-mediated gene transfer of hormone-sensitive lipase. J Biol Chem. 2002,277(35):31893-31899.
40. Escary JL,Choy HA, Reue K, et al. Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages.J Lipid Res. 1999,40(3):397-404.
41.Contreras JA. Hormone-sensitive lipase is not required for cholesteryl ester hydrolysis in macrophages.Biochem Biophys Res Commun. 2002, 292(4):900-903.
42. Li H,Brochu M,Wang SP,et al. Hormone-sensitive lipase deficiency in mice
causes lipid storage in the adrenal cortex and impaired corticosterone response to corticotropin stimulation. Endocrinology. 2002, 143(9):3333-3340.
43. 78 Kraemer FB,Shen WJ, Natu V,et al. Adrenal neutral cholesteryl ester hydrolase: identification, subcellular distribution, and sex differences. Endocrinology. 2002, 143(3):801-806.
44. Chung S, Wang SP, Pan L, et al. Infertility and testicular defects in hormone-sensitive lipase-deficient mice. Endocrinology. 2001 ,142(10):4272-4281.
45. Lufkin T, Lohnes D, Mark M, et al. High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc Natl Acad Sci U S A. 1993,90(15):7225-7229 .
46. Kastner P, Mark M, Leid M, et al. Abnormal spermatogenesis in RXR beta mutant mice.: Genes Dev. 1996,10(1 ):80-92.
47. Grober J, Lucas S, Sorhede-Winzell M, et al. Hormone-sensitive lipase is a cholesterol esterase of the intestinal mucosa. J Biol Chem. 2003,278(8):6510-6515.
48. Boden G Free fatty acids and insulin secretion in humans. Curr Diab Rep. 2005, 5(3): 167-170.
49. McGarry JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 2002, 51(1):7-18.
50. Spiegelman Bruce M, Flier JS. Obesity and the regulation of energy baIance.Cell.2001,104:531-534.
51.Klannemark M, Orho M, Langin D,et al. The putative role of the hormone-sensitive lipase gene in the pathogenesis of Type II diabetes mellitus and abdominal obesity. Diabetologia. 1998 ,41(12): 1516-1522
52. Gupta G, Cases JA, She L, et al. Ability of insulin to modulate hepatic glucose production in aging rats is impaired by fat accumulation. Am J Physiol Endocrinol Metab. 2000,278(6):E985-991.
53. McGarry JD, Dobbins RL. Fatty acids, lipotoxicity and insulin secretion. Diabetologia. 1999,42(2):128-38.
54. Zhou YP, Grill VE. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest. 1994,93(2):870-876.
55. Reynisdottir S, Angelin B, Langin D. Adipose tissue lipoprotein lipase and hormone-sensitive lipase. Contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome. Arterioscler Thromb Vasc Biol. 1997,17(10):2287-2292.
56. Magre J,Laurell H,Fizames C, et al. Human hormone-sensitive lipase: genetic mapping, identification of a new dinucleotide repeat, and association with obesity and NIDDM. Diabetes. 1998,47(2):284-286.
57. Pihlajamaki J, Valve R, Karjalainen L, et al. The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance. Eur J Clin Invest. 2001, 31(4):302-308.
58. Stumvoll M, Wahl HG, Jacob S, et al. Two novel prevalent polymorphisms in the hormone-sensitive lipase gene have no effect on insulin sensitivity of lipolysis and glucose disposal. J Lipid Res. 2001,42(ll):1782-1788.
59. Wang SP, Laurin N, Himmis HJ, et al. The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice. Obes Res. 2001,9(2): 119-128.
60. Kim JK, Fillmore JJ, Chen Y, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. PNAS. 2001,98(13):7522-7527.
61. Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest. 2002,32 Suppl 3:14-23.
62. Roduit R, Masiello P, Wang SP, et al. A role for hormone-sensitive lipase in glucose stimulated insulin secretion. Diabetes, 2001,50:1970-1975.
63. Kelpe CL, Johnson LM,Poitout V. Increasing triglyceride synthesis inhibits glucose-induced insulin secretion in isolated rat islets of langerhans: a study using adenoviral expression of diacylglycerol acyltransferase. Endocrinology. 2002 ,143(9):3326-3332.
64. Pihlajamaki J, Valve R, Karjalainen L, et al. The hormone sensitive lipase gene in??familial combined hyperlipidemia and insulin resistance. Eur J Clin Invest.2001, 31:302-308.
65. Ylitalo K, Large V, Pajukanta P,et al. Reduced hormone-sensitive lipase activity is not a major metabolic defect in Finnish FCHL families. Atherosclerosis. 2000,153(2):373-381.
66. Stumvoll M, Wahl HG, Jacob S, et al. Two novel prevalent polymorphisms in the hormone-sensitive lipase gene have no effect on insulin sensitivity of lipolysis and glucose disposal. J Lipid Res. 2001,42:1782-1788.
67. Talmud P, Palmen J, Luan J, et al. Variation in the promoter of the human hormone sensitive lipase gene shows gender specific effects on insulin and lipid levels: results from the Ely study. Biochim Biophys Acta. 2001,1537:239-244.
68. Large V, Reynisdottir S, Langin D, et al. Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res. 1999,40:2059-2065.
69. Imbeault P, Vidal H, Tremblay A, et al.Age-related differences in messenger ribonucleic acid expression of key proteins involved in adipose cell differentiation and metabolism. J Clin Endocrinol Metab.2001,86:828-833.
70. Hoffstedt J, Arner P, Schalling M,et al. A Common Hormone Sensitive Lipase i6 Gene Polymorphism Is Associated With Decreased Human Adipocyte Lipolytic Function. Diabetes.2001,50:2410-2413.
2. Bays HE. Current and investigational antiobesity agents and obesity therapeutic treatment targets. Obes Res. 2004, 12:1197-1211.
3. Kusunoki J, Kanatani A, Moller DE. Modulation of Fatty Acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome. Endocrine. 2006, 29(1):91-100.
4. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001, 104(4):531-543.
5. D. B. Hauseman, M. Digirolamo, T.J. Bartness et al. The biology of white adipocyte proliferation.Obesity Review. 2001, 2:239-254.
6. Cornelius P, Macdougald O, Land et al. Regulation of adipocyte development. Annu Rev Nutri 1994, 14:99-129
7. Konieczny S. F, et al. 5-azacytidine induction of stable mesodermal stem cell lineages from lOT1/2 cell. Ce11.1984, 38:791-800.
8. Dani C. Differentiation of embryonic stem cell into adipocyte in vitro, J Cell Science. 1997, 110:1279-1285.
9. Davies JI, Souness JE. The mechanisms of hormone and drugs actions on fatty acid release from adipose tissue. Rev Pure Appl Pharmacol Sci. 1996, 2:1-113.
10. Lilioja S, Foley J, Borgadus C, et al. Free fatty acid metabolism in man. In vivo, In vitro comparisons. Metabolism. 1986, 35(6):505-514.
11. Tischler ME, Goldberg AL. Leucine degradation and release of glutamine and alanine by adipose tissue, J Biol chem. 1980,255(17):8074-8081.12. Hirsch J, Goldrick R. Serial studies of human adipose tissue. I. Lipogenesis and free fatty acid uptake and release in small aspirated samples of subcutaneous fat. J Clin Invest. 1964 , 43:1776-1992.
13. Hirsch J, Frield SK, Edens N, et al. The fat cell. Med Clin North Am. 1989, 73(1): 83-96.
14. Kern PA, Ong JM, Saffari B, et al. The effects of weight loss on the activity and expression of adipose - tissue lipoprotein lipase in very obese humans. N Engl J Med. 1991, 322(15):1053-1059.
15.Rebuffe-Scrive M, Fat cell metabolism in different regions in women. Effect of menstrual cycle/pregnancy and latation. J Clin Invest. 1985, 75(6):1973-1976
16. Rebuffe-Scrive M, Marin P, Bjorntorp P. Effect of testosterone on abdominal adipose tissue in men. Int J Obes. 1991, 15(11):791-795
17. Langin D, Holm C, Lafontan M. Adipocyte hormone-sensitive lipase: a major regulator of lipid metabolism. Proc Nutr Soc. 1996, 55 (1B): 93-109.
18. Haemmerle G, Zimmermann R, Zechner R. Letting lipids go: hormone-sensitive lipase. Curr Opin Lipidol. 2003, 14(3):289-97.
19.Langin D, Dicker A, Tavernier G, Hoffstedt J. Adipocyte lipases and defect of lipolysis in human obesity. Diabetes. 2005, 54(11): 3190-3197.
20. Haemmerle G, Zimmermann R, Hayn M, et al. Hormone -sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J Biol Chem. 2002, 227: 4806-4815.
21.Komaromy MC, Kraemer FB, Sztalryd C. Overexpression of hormone-sensitive lipase prevents triglyceride accumulation in adipocytes. J Clin Invest. 1995, 95(6):2652-2661.
22. Large V, Reynisdottir S, Langin D, et al. Decreased expression and
function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res. 1999, 40(11):2059-2066.
23. Langin D, Dicker A, Tavernier G. Adipocyte lipases and defect of lipolysis in human obesityDiabetes. 2005, 54(11):3190-3197.
24. Mairal A, Langin D, Arner P, Hoffstedt J. Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity. Diabetologia. 2006 May 10[Epub ahead of print]
25. Sztalryd C, Komaromy MC, Kraemer FB. Overexpression hormone-sensitive lipase prevents triglyceride accumulation in adipocyte. J Clin Invest. 1995, 95:2652-2661.
26. Wyatt SB, Winters KP, Dubbert PM. Overweight and obesity: prevalence, consequences, and causes of a growing public health problem. Am J Med Sci. 2006, 331(4): 166-174.
27．武阳丰，马冠生，胡永华，等．中国居民的超重和肥胖流行现状。中华预防医学杂志 2005，39(5)：316-320．
28．杜海洲．抗肥胖新药的研究与开发．医学信息．2005，8：20-22
29. Halford JC. Obesity drugs in clinical development. CurrOpin Investig Drugs. 2006, 7(4):312-318.
30. Carrel AL, Allen DB. Effects of growth hormone on adipose tissue. J Pediatr Endocrinol Metab. 2000. 13 Suppl, 2: 1003-1009.
31. Langin D. Adlpose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. Pharmacol Res. 2006, Mar 27. [Epub ahead of print]
32．吴大真等编．现代名中医肥胖治疗绝技．科学技术文献出版社．
33. Green H, O. Kehinde et al. An established preadipocyte cell line and its differentiation in culture. Ⅱ factors affecting the adipose convertsion. Cell. 1975,5:19-27.
34. Green H,O. Kehinde et al. Spontaneous heritable changes leading to??increase adipose conversion in 3T3 cells. Ce11.1976, 7:105-113.
35. Green H, Meuth M, et al. An established pre-adipose cell line and its differentiation in culture. Ce11.1974, 3:127-133.
36. Von Gierke. Uber fett metabolism. Ver Deutsch Ges Path 1906, 10:182-185.
37. D.B. Hauseman, M. Digirolamo, T.J. Bartness et al. The biology of white adipocyte proliferation.Obesity Review 2001, 2:239-254.
38．J．萨姆布鲁克，D．W．拉赛尔著，黄培堂等译，科学出版社。《分子克隆实验指南》(第三版)第17章：哺乳动物培养细胞的基因表达分析，P1347-1361．
39. Sekiya M, Osuga J, Okazaki H, at al. Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice. J. Biol. Chem. 2004, 279 (15): 15084-15090.
40. Shu Pei Wang, Nancy Laurin, Jean Himms-Hagen, et al. The Adipose Tissue Phenotype of Hormone-Sensitive Lipase Deficiency in Mice. Obesity Research. 2001, 9:119-128.
41. Jun-ichi Osuga, Shun Ishibashi, Teruaki Oka, at al. Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. PNAS. 2000, 97 (2): 787-792.
42. Zimmermann R, Strauss JG, Haemmerle G, et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004, 19; 306(5700):1383-1386.
43. Zechner R, Strauss JG, Haemmerle G, et al. Lipolysis: pathway under construction. Curr Opin Lipidol. 2005, 16(3):333-40.1. Hauseman DB, Digirolamo M, Bartness TJ,et al. The biology of white adipocyte proliferation.Obesity Review. 2001, 2:239-154.
2. Komaromy MC, Kraemer FB,Sztalryd C. Overexpression of hormone-sensitive lipase prevents triglyceride accumulation in adipocytes. J Clin Invest.??1995, 95(6): 2652-2661.
3. Large V, Reynisdottir S, Langin D, et al. Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res. 1999,40(11):2059-2066.
4. Carrel AL, Allen DB. Effects of growth hormone on adipose tissue. J Pediatr Endocrinol Metab. 2000,13 Suppl 2: 1003-1009.
5. Sekiya M, Osuga J, Okazaki H, at al. Absence of hormone-sensitive lipase inhibits obesity and adipogenesis in Lep ob/ob mice. J. Biol. Chem..2004, 279 (15): 15084-15090.
6. Shu Pei Wang, Nancy Laurin, Jean Himms-Hagen, et alo The Adipose Tissue Phenotype of Hormone-Sensitive Lipase Deficiency in Mice.Obesity Research. 2001, 9:119-128.
7. Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Bimer-Gruenberger R, Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 2004, 19;306(5700):1383-1386.
8. Mairal A, Langin D, Amer P, Hoffstedt J. Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity. Diabetologia. 2006 May 10[Epub ahead of print]
9. Haemmerle G, Zimmermann R, Zechner R.Letting lipids go: hormone-sensitive lipase. Curr Opin Lipidol. 2003,14(3):289-297.
10. John C. Khoo, Karen Reue, Daniel Steinberg, et al. Expression of hormone-sensitive lipase mRNA in macrophages. J Lipid Res.1998, 34: 1993-1969.
11．刘星霞，缪兵，李府，等．胚胎干细胞诱生的胰岛素分泌细胞分泌胰岛素的研究，世界华人消化杂志．2004，12(8)：1857-1860．
12．朱愉，多秀瀛．实验动物的疾病模型(第一版)，天津科技出版社，1997：258．
13．范晓，韩丽君．我国常见海藻营养成分分析．中国海洋药物，1993，12(4)：32-38．
14．西泽一俊，刘长发．海藻的生理活性物质．中国海洋药物，1993，12(1)：47-51．
15. Liu QY, Meng QY.Therapeutic effect of Seaweed Polysaccharide from Sargassum??confusum on sarcoma s180 in mice and its mechanism. Ai Zheng. 2005, 24(12): 1469-1473.
16. Park P J, Heo S J, Park E J, et al. Reactive oxygen scavenging effect of enzymatic extracts from Sargassum thunbergii. J Agric Food Chem. 2005, 53(17): 6666-6672
17. Huang ZX, Mei XT, Xu DH, et al. Protective effects of polysacchride of Spirulina platensis and Sargassarn thunbeergii on vascular of alloxan induced diabetic rats. Zhongguo Zhong Yao Za Zhi. 2005, 30(3):211-215.
18．程志清，严建伟．海藻提取物对实验性高脂大鼠模型的药效学研究．中国现代应用药学．1998，15(5)：9-10
19. Kim, SO, Yun, SJ, JUNG B, et al, Hypolipidemic effects of crude extract ofadlay seed (Coix lachrymajobi var. mayuen) in obesity rat fed high fat diet: relations of TNF-alpha and leptin mRNA expressions and serum lipid levels. Life Sci. 2004, 75(11):1391-1404.
20．张春海 毛缜 马丽，等．泽泻水提取物、醇提取物对小鼠脂代谢影响的比较．徐州师范大学学报：自然科学版．2005，23(2)：68-70．
21. KIM CH, KIM MS, YOUN JY, et al. Lipolysis in skeletal muscle is decreased in high-fat-fed rats. Metabolism, 2003-52(12): 1586-1592.
22．谭正怀、莫正纪、陈岷，等．西布曲明对金硫葡萄糖诱导肥胖动物模型的影响．中国药理学通报，2003，19：(10)：60．
23. Nagao T, Ostuka H, Kohda H, et al. Benzoxazineone from Coix lachruma-jobi L vat. ma-yuen. Phutochemistry. 1985, 24 (2):2959-2962.
24. Hsu HY, Lin BF, Lin JY, et al. Suppression of allergic reactions by dehulled adlay in association with the balance of TH1/TH2 cell responses. J Agric Food Chem. 2003, 51(13):3763-3769.
25. Shih CK, Chiang W, Kuo ML. Effects of adlay on azoxymethane-induced colon carcinogenesis in rats. Food Chem Toxicol. 2004, 42(8): 1339-1347.
26. Yu YM, Chang WC, Liu CS, et al. Effect of young barley leaf extract and adlay on plasma lipids and LDL oxidation in hyperlipidemic smokers. Biol Pharm Bull. 2004, 27(6):802-805.
27. Huang BW, Chiang MT, Yao HT, et al. The effect of adlay oil on plasma lipids,??insulin and leptin in rat. Phytomedicine. 2005, 12(6-7):433-439.1. Yeaman SJ.Hormone-sensitive lipase-a multipurpose enzyme in lipid metabolism. Biochim Biophys Acta. 1990, 1052(l):128-32.
2. Fredrikson G, Stralfors P, Nilsson NO, et al. Hormone-sensitive lipase of rat adipose tissue. Purification and some properties. J Biol Chem. 1981 , 256(12):6311-20.
3. Yeaman SJ. Hormone-sensitive lipase~new roles for an old enzyme. Biochem J. 2004,379(Pt 1):11-22.
4. Kraemer FB, Shen WJ. Hormone sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. J Lipid Res. 2002, 43: 1585-1594.
5. Shen WJ, Liang Y, Hong R, et al. Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase. J Biol Chem. 2001, 276:49443-49448.
6. Anthonsen MW, Ronnstrand L, Wernstedt C,et al. Indentification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitr. J Biol Chem. 1998,273:215-221.
7. Mulder H, Hoist LS, Svensson H, et al. Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in β-cells. Diabetes. 1999, 48:228-232.
8. Lindvall H, Nevsten P, Strom K, et al. A novel hormone-sensitive lipase isoform expressed in pancreatic beta-cells. J Biol Chem.2004,279:3828-3826.
9. Hoist LS, Langin D, Mulder H,et al. Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase. Genomics. 1996, 35(3):441-447.
10. Watt M J, Stellingwerff T, Heigenhauser G J F, et al. Effects of plasma adrenaline on hormone-sensitive lipase at rest and during moderate exercise in human skeletal muscle. J Physiol.2003,550:325-332.
11. Haemmerle G, Zimmermann R, Zechner R.Letting lipids go: hormone-sensitive lipase. Curr Opin Lipidol. 2003 , 14(3):289-297.
12. Shen WJ, Patel S, Hong R. Hormone-sensitive lipase functions as an oligomer. Biochemistry. 2000, 39(9):2392-2398.
13.Fredrikson G, Tornqvist H, Belfrage P. Hormone-sensitive lipase and monoacylglycerol lipase are both required for complete degradation of adipocyte triacylglycerol. Biochim Biophys Acta. 1986, 876(2):288-293.
14. Holm C, Osterlund T, Laurell H,et al. Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Annu Rev Nutr. 2000, 20:365-393.
15. Londos C, Brasaemle DL, Gruia-Gray J, et al.Perilipin: unique proteins associated with intracellular neutral lipid droplets in adipocytes and steroidogenic cells. Biochem Soc Trans. 1995, 23(3):611-615.
16. Greenberg AS, Shen WJ, Muliro K, et al. Stimulation of lipolysis and hormone sensitive lipase via the extracellular signal regulated kinase pathway. J Biol Chem.2001,276:45456-45461.
17. Smith F, Rouet P, Lucas S, et al. Transcriptional regulation of adipocyte hormone-sensitive lipase by glucose. Diabetes.2002, 51:293-300.
18. Berraondo B, Martinez JA. Free Fatty Acids Are Involved in the Inverse Relationship between Hormone-Sensitive Lipase (HSL) Activity and Expression in Adipose Tissue after High-Fat Feeding or β3-Adrenergic Stimulatio. Obes Res. 2000,8:255-261.
19. Large V, Arner P, et al. Hormone-sensitive lipase and activity in relation to lipolysis in human fat cell. J Lipid Res. 1998 , 39:1688-1695.
20. Sztalryd C, Komaromy MC, Kraemer FB. Overexpression hormone-sensitive lipase prevents triglyceride accumulation in adipocyte. J Clin Invest. 1995, 95:2652-2661.
21. Large V, Reynisdottir S, Langin D, et al. Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res. 1999,40:2059-2066.
22. Haemmerle G, Zimmermann R, Hayn M, et al. Hormone-sensitive lipase
deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis. J Biol Chem. 2002, 277(7):4806-4815.
23. Osuga J, Ishibashi S, Oka T, Yagyu H, et al Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. PNAS. 2000,18;97(2):787-792.
24. Raclot T, Holm C, Langin D.Fatty acid specificity of hormone-sensitive lipase. Implication in the selective hydrolysis of triacylglycerols. J Lipid Res. 2001 Dec;42(12):2049-2057.
25. Zimmermann R, Strauss JG, Haemmerle G, et al. Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase. Science.2004: 306 (5700): 1383-1386.
26. Villena JA,Roy S, Sarkadi-Nagy E,et al. Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids. J Biol Chem, 2004. 279(45):47066-47075.
27. Jenkins CM, Mancuso DJ, Yan W, et al. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem. 2004,279(47):48968-48975.
28. Langin D, Dicker A, Tavernier G Adipocyte lipases and defect of lipolysis in human obesity. Diabetes. 2005 , 54(ll):3190-3197.
29. Mairal A, Langin D, Arner P, Hoffstedt J. Human adipose triglyceride lipase (PNPLA2) is not regulated by obesity and exhibits low in vitro triglyceride hydrolase activity. Diabetologia. 2006 May 10[Epub ahead of print]
30. Haemmerle G, Zimmermann R, Strauss JG, et al. Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle. J Biol Chem. 2002,277(15):12946-12952.
31. Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G,et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science.
2006 , 312(5774):734-737.
32. Suzuki J, Shen WJ, Nelson BD,et al. Absence of cardiac lipid accumulation in transgenic mice with heart-specific HSL overexpression. Am J Physiol Endocrinol Metab. 2001, 281(4):E857-866.
33. Tavintharan S, Kashyap ML. The benefits of niacin in atherosclerosis. Curr Atheroscler Rep. 2001, 3 (l):74-82.
34. Aktories K, Schultz G, Jakobs KH. Adenylate cyclase inhibition and GTPase stimulation by somatostatin in S49 lymphoma cyc- variants are prevented by islet-activating protein. FEBS Lett. 1983 , 158(1):169-173.
35. Green A, Milligan G, Dobias SB Gi down-regulation as a mechanism for heterologous desensitization in adipocytes. J Biol Chem. 1992 , 267(5):3223-3229.
36. Brown MS, HO YK, Goldstein JL. The cholesteryl ester cycle in macrophage foam cells. Continual hydrolysis and re-esterification of cytoplasmic cholesteryl esters.J Biol Chem. 1980 ,255(19):9344-9352.
37. Krause BR, Hartman AD. Adipose tissue and cholesterol metabolism. J Lipid Res. 1984, 25(2):97-110.
38. Escary JL,Choy HA, Reue K, etal. Hormone-sensitive lipase overexpression increases cholesteryl ester hydrolysis in macrophage foam cells. Arterioscler Thromb Vasc Biol. 1998,18(6):991-998.
39. Okazaki H, Osuga J, Tsukamoto K, et al . Elimination of cholesterol ester from macrophage foam cells by adenovirus-mediated gene transfer of hormone-sensitive lipase. J Biol Chem. 2002,277(35):31893-31899.
40. Escary JL,Choy HA, Reue K, et al. Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages.J Lipid Res. 1999,40(3):397-404.
41.Contreras JA. Hormone-sensitive lipase is not required for cholesteryl ester hydrolysis in macrophages.Biochem Biophys Res Commun. 2002, 292(4):900-903.
42. Li H,Brochu M,Wang SP,et al. Hormone-sensitive lipase deficiency in mice
causes lipid storage in the adrenal cortex and impaired corticosterone response to corticotropin stimulation. Endocrinology. 2002, 143(9):3333-3340.
43. 78 Kraemer FB,Shen WJ, Natu V,et al. Adrenal neutral cholesteryl ester hydrolase: identification, subcellular distribution, and sex differences. Endocrinology. 2002, 143(3):801-806.
44. Chung S, Wang SP, Pan L, et al. Infertility and testicular defects in hormone-sensitive lipase-deficient mice. Endocrinology. 2001 ,142(10):4272-4281.
45. Lufkin T, Lohnes D, Mark M, et al. High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice. Proc Natl Acad Sci U S A. 1993,90(15):7225-7229 .
46. Kastner P, Mark M, Leid M, et al. Abnormal spermatogenesis in RXR beta mutant mice.: Genes Dev. 1996,10(1 ):80-92.
47. Grober J, Lucas S, Sorhede-Winzell M, et al. Hormone-sensitive lipase is a cholesterol esterase of the intestinal mucosa. J Biol Chem. 2003,278(8):6510-6515.
48. Boden G Free fatty acids and insulin secretion in humans. Curr Diab Rep. 2005, 5(3): 167-170.
49. McGarry JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 2002, 51(1):7-18.
50. Spiegelman Bruce M, Flier JS. Obesity and the regulation of energy baIance.Cell.2001,104:531-534.
51.Klannemark M, Orho M, Langin D,et al. The putative role of the hormone-sensitive lipase gene in the pathogenesis of Type II diabetes mellitus and abdominal obesity. Diabetologia. 1998 ,41(12): 1516-1522
52. Gupta G, Cases JA, She L, et al. Ability of insulin to modulate hepatic glucose production in aging rats is impaired by fat accumulation. Am J Physiol Endocrinol Metab. 2000,278(6):E985-991.
53. McGarry JD, Dobbins RL. Fatty acids, lipotoxicity and insulin secretion. Diabetologia. 1999,42(2):128-38.
54. Zhou YP, Grill VE. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J Clin Invest. 1994,93(2):870-876.
55. Reynisdottir S, Angelin B, Langin D. Adipose tissue lipoprotein lipase and hormone-sensitive lipase. Contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome. Arterioscler Thromb Vasc Biol. 1997,17(10):2287-2292.
56. Magre J,Laurell H,Fizames C, et al. Human hormone-sensitive lipase: genetic mapping, identification of a new dinucleotide repeat, and association with obesity and NIDDM. Diabetes. 1998,47(2):284-286.
57. Pihlajamaki J, Valve R, Karjalainen L, et al. The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance. Eur J Clin Invest. 2001, 31(4):302-308.
58. Stumvoll M, Wahl HG, Jacob S, et al. Two novel prevalent polymorphisms in the hormone-sensitive lipase gene have no effect on insulin sensitivity of lipolysis and glucose disposal. J Lipid Res. 2001,42(ll):1782-1788.
59. Wang SP, Laurin N, Himmis HJ, et al. The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice. Obes Res. 2001,9(2): 119-128.
60. Kim JK, Fillmore JJ, Chen Y, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. PNAS. 2001,98(13):7522-7527.
61. Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Eur J Clin Invest. 2002,32 Suppl 3:14-23.
62. Roduit R, Masiello P, Wang SP, et al. A role for hormone-sensitive lipase in glucose stimulated insulin secretion. Diabetes, 2001,50:1970-1975.
63. Kelpe CL, Johnson LM,Poitout V. Increasing triglyceride synthesis inhibits glucose-induced insulin secretion in isolated rat islets of langerhans: a study using adenoviral expression of diacylglycerol acyltransferase. Endocrinology. 2002 ,143(9):3326-3332.
64. Pihlajamaki J, Valve R, Karjalainen L, et al. The hormone sensitive lipase gene in??familial combined hyperlipidemia and insulin resistance. Eur J Clin Invest.2001, 31:302-308.
65. Ylitalo K, Large V, Pajukanta P,et al. Reduced hormone-sensitive lipase activity is not a major metabolic defect in Finnish FCHL families. Atherosclerosis. 2000,153(2):373-381.
66. Stumvoll M, Wahl HG, Jacob S, et al. Two novel prevalent polymorphisms in the hormone-sensitive lipase gene have no effect on insulin sensitivity of lipolysis and glucose disposal. J Lipid Res. 2001,42:1782-1788.
67. Talmud P, Palmen J, Luan J, et al. Variation in the promoter of the human hormone sensitive lipase gene shows gender specific effects on insulin and lipid levels: results from the Ely study. Biochim Biophys Acta. 2001,1537:239-244.
68. Large V, Reynisdottir S, Langin D, et al. Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects. J Lipid Res. 1999,40:2059-2065.
69. Imbeault P, Vidal H, Tremblay A, et al.Age-related differences in messenger ribonucleic acid expression of key proteins involved in adipose cell differentiation and metabolism. J Clin Endocrinol Metab.2001,86:828-833.
70. Hoffstedt J, Arner P, Schalling M,et al. A Common Hormone Sensitive Lipase i6 Gene Polymorphism Is Associated With Decreased Human Adipocyte Lipolytic Function. Diabetes.2001,50:2410-2413.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |