黄连素对模型大鼠脂联素的影响及其联合他汀类药物的降脂研究
|
摘要
目的1.研究黄连素对非酒精性脂肪肝大鼠脂联素及脂联素受体的影响。2.研究辛伐他汀(Simvastatin,SIMVA)联合黄连素(Berberine,BBR)治疗高脂血症的降脂作用。
方法1.在动物实验研究中,32只大鼠随机分为对照组(8只,普通饲料喂养)和模型组(24只,高脂饲料喂养)。高脂饲料喂养8周后,建立非酒精性脂肪肝大鼠模型,然后用黄连素和辛伐他汀干预治疗8周,以辛伐他汀组作阳性对照组,8周后,分别检测大鼠血清肝肾功、血脂、血清脂联素(Adiponectin,APN),及大鼠肝脏HE染色和脂联素受体(Adiponectin receptor,AdipoR)的表达。2.在临床研究中,将99例高脂血症患者随机分成三组,即A组(SIMVA组):生活方式干预加辛伐他汀治疗组;B组(BBR组):生活方式加黄连素治疗组;C组(SIMVA+BBR组):生活方式干预加辛伐他汀与黄连素治疗组;连续治疗8周后,观察患者在治疗前后的体重指数、血脂、肝肾功能等变化。
结果1.动物实验研究表明黄连素和辛伐他汀干预治疗8周后血清脂联素水平较高脂组明显升高(P<0.05),肝脏组织AdipoR1-mRNA表达与高脂组相比差异无统计学意义(P>0.05),AdipoR2-mRNA表达与高脂组相比差异有显著统计学意义(P<0.01)。2.在临床研究中发现联合用药组疗效明显优于单一用药组,显效病例数是SIMVA组的一倍,有效率达100%;SIMVA组治疗前后总胆固醇(Total cholesterol,TC)、低密度脂蛋白(Low-density lipoprotein,LDL-c)值差异有统计学意义(P<0.01),BBR组和BBR+SIMVA组治疗前后比较TC、甘油三酯(Triglyceride,TG)和LDL-c差异显著(P<0.01);三组间比较,联合治疗组降低TC、TG、LDL-c较SIMVA组或BBR组差异有显著性统计学意义(P<0.01),联合治疗组治疗期间未见明显毒副作用。
结论1.黄连素和辛伐他汀都可以通过上调AdipoR2-mRNA的表达,升高血清脂联素,有效改善胰岛素抵抗,降低血脂,改善肝功。2.临床上辛伐他汀联合黄连素较等同剂量辛伐他汀或黄连素更能有效降低血脂,黄连素作为他汀降脂药的理想补充剂给高脂血症患者提供了一种新的治疗方式。
Objective: To investigate the effects of berberine on serum adiponectin and expression of adiponectin receptormin liver of NAFLD rats.To study the therapeutic effects of combination of simvastatin with berberine on the patients with hyperlipemia.
Methods:In animal trial,third-two SD rats were randomized into 2 groups:cont- rol group (n=8,on normal diet) and NAFLD group (n=24,on high-fat diet).The NAFLD model was induced by an oral administ ration of high fat diet.A 8-week berberine and simvastatin intervention was given to established NAFLD rats. After 8 weeks of treatment,the Blood lipid,liver and kidney functionswere detected and compared,and the expression of adiponectin accepter mRNA and protein examined with reverse Real-time fluorescent quantitative PCR and ELISA respectively.In clinical trial,a total of 99 patients with hyperlipidemia in our hospital were divided into 3 groups.Group A: SIMVA,Group B:BBR,Group C: combination of BBR with SIMVA.After 8 weeks of treatment,the Blood lipid,liver and kidney functions in the three groups were detected and compared.
Results:In animal trial,The serum adiponectin in the model group were decreased,and were all significantly lower than those in the control group (P<0.05).Compared with the pre-intervention level,the plasma concentration of APN was upgraded (P<0.01),while the expression of adiponectin accepter-1 mRNA has notable statistics significance after berberine and simvastatin treatment for 8 weeks(P>0.05).The expression of adiponectin accepter-2 mRNA has statistics significance Compared with the pre-intervention level(P<0.01).After 8weeks of treatment,in the treatment of the patients with hyperlipemia,combination of BBR with SIMVA was more effective than that of the SIMVA or BBR monotherapy,whose markedly effective cases was 1-fold higher than SIMVA alone.The total effective rate of group C was 100%.Serum TC、TG were significantly different before and after simvastatin treatment(P<0.01).Combination therapy reduced serum TC、TG and LDL-c,the level of them were all signifycantly lower than after simvastatin single-used in the hyperlipemia patients(P<0.01).Compare the three groups,in decreasing TC、TG、LDL-c,group C were more effective than group A or group B,which has notable statistics significance (P<0.01).
Conclusion: Intervention with berberine and simvastatin was shown to increase the serum adiponectin and adiponectin accepter-2 mRNA in liver.As compared with monotherapies,the combination showed an improved lipid-lowering effect with reduction of serum lipid.The combination therapy display a new and effective regimen for hyperlipemia.
方法1.在动物实验研究中,32只大鼠随机分为对照组(8只,普通饲料喂养)和模型组(24只,高脂饲料喂养)。高脂饲料喂养8周后,建立非酒精性脂肪肝大鼠模型,然后用黄连素和辛伐他汀干预治疗8周,以辛伐他汀组作阳性对照组,8周后,分别检测大鼠血清肝肾功、血脂、血清脂联素(Adiponectin,APN),及大鼠肝脏HE染色和脂联素受体(Adiponectin receptor,AdipoR)的表达。2.在临床研究中,将99例高脂血症患者随机分成三组,即A组(SIMVA组):生活方式干预加辛伐他汀治疗组;B组(BBR组):生活方式加黄连素治疗组;C组(SIMVA+BBR组):生活方式干预加辛伐他汀与黄连素治疗组;连续治疗8周后,观察患者在治疗前后的体重指数、血脂、肝肾功能等变化。
结果1.动物实验研究表明黄连素和辛伐他汀干预治疗8周后血清脂联素水平较高脂组明显升高(P<0.05),肝脏组织AdipoR1-mRNA表达与高脂组相比差异无统计学意义(P>0.05),AdipoR2-mRNA表达与高脂组相比差异有显著统计学意义(P<0.01)。2.在临床研究中发现联合用药组疗效明显优于单一用药组,显效病例数是SIMVA组的一倍,有效率达100%;SIMVA组治疗前后总胆固醇(Total cholesterol,TC)、低密度脂蛋白(Low-density lipoprotein,LDL-c)值差异有统计学意义(P<0.01),BBR组和BBR+SIMVA组治疗前后比较TC、甘油三酯(Triglyceride,TG)和LDL-c差异显著(P<0.01);三组间比较,联合治疗组降低TC、TG、LDL-c较SIMVA组或BBR组差异有显著性统计学意义(P<0.01),联合治疗组治疗期间未见明显毒副作用。
结论1.黄连素和辛伐他汀都可以通过上调AdipoR2-mRNA的表达,升高血清脂联素,有效改善胰岛素抵抗,降低血脂,改善肝功。2.临床上辛伐他汀联合黄连素较等同剂量辛伐他汀或黄连素更能有效降低血脂,黄连素作为他汀降脂药的理想补充剂给高脂血症患者提供了一种新的治疗方式。
Objective: To investigate the effects of berberine on serum adiponectin and expression of adiponectin receptormin liver of NAFLD rats.To study the therapeutic effects of combination of simvastatin with berberine on the patients with hyperlipemia.
Methods:In animal trial,third-two SD rats were randomized into 2 groups:cont- rol group (n=8,on normal diet) and NAFLD group (n=24,on high-fat diet).The NAFLD model was induced by an oral administ ration of high fat diet.A 8-week berberine and simvastatin intervention was given to established NAFLD rats. After 8 weeks of treatment,the Blood lipid,liver and kidney functionswere detected and compared,and the expression of adiponectin accepter mRNA and protein examined with reverse Real-time fluorescent quantitative PCR and ELISA respectively.In clinical trial,a total of 99 patients with hyperlipidemia in our hospital were divided into 3 groups.Group A: SIMVA,Group B:BBR,Group C: combination of BBR with SIMVA.After 8 weeks of treatment,the Blood lipid,liver and kidney functions in the three groups were detected and compared.
Results:In animal trial,The serum adiponectin in the model group were decreased,and were all significantly lower than those in the control group (P<0.05).Compared with the pre-intervention level,the plasma concentration of APN was upgraded (P<0.01),while the expression of adiponectin accepter-1 mRNA has notable statistics significance after berberine and simvastatin treatment for 8 weeks(P>0.05).The expression of adiponectin accepter-2 mRNA has statistics significance Compared with the pre-intervention level(P<0.01).After 8weeks of treatment,in the treatment of the patients with hyperlipemia,combination of BBR with SIMVA was more effective than that of the SIMVA or BBR monotherapy,whose markedly effective cases was 1-fold higher than SIMVA alone.The total effective rate of group C was 100%.Serum TC、TG were significantly different before and after simvastatin treatment(P<0.01).Combination therapy reduced serum TC、TG and LDL-c,the level of them were all signifycantly lower than after simvastatin single-used in the hyperlipemia patients(P<0.01).Compare the three groups,in decreasing TC、TG、LDL-c,group C were more effective than group A or group B,which has notable statistics significance (P<0.01).
Conclusion: Intervention with berberine and simvastatin was shown to increase the serum adiponectin and adiponectin accepter-2 mRNA in liver.As compared with monotherapies,the combination showed an improved lipid-lowering effect with reduction of serum lipid.The combination therapy display a new and effective regimen for hyperlipemia.
引文
1.曾民德.脂肪肝[J].中华消化杂志,1999 ,19(2):120-122.
2. Marchesini G,Brizi M ,Bianchi G,et al.Nonalcoholic fatty liver disease:a feature of the metabolic syndrome[J].Diabetes,2001,50(8):1844-1850.
3. Zeng MD.Pathogenesis and two“hits”hypothesis of fatty liver[J].Chinese Journal of Digestion,2002,22(9):167-168.
4. Christopher L,Gentile,Michael,J,et al.The Role of Fatty Acids in the Develop- ment and Progression of Nonalcoholic Fatty Liver Disease[J]. The Journal of Nutritional Biochemistry,2008,19(9):567-576.
5.耿东升,刘发,小檗碱药理作用研究进展[J].解放军药学学报,1997(1),13:26-28.
6.耿建东.黄连素的抗炎与免疫调节作用[J].解放军药学学报,2000,16(6):317-319.
7.谢培凤,周晖,高彦彬.小檗碱治疗Ⅱ型糖尿病40例治疗观察[J].中国临床保健杂志,2005,8(5):402-404.
8.魏敬、吴锦丹、蒋建东等.盐酸小檗碱治疗Ⅱ型糖尿病合并脂肪肝的临床研究[J].中西医结合肝病杂志,2004,14(6):334-336.
9. Wei-Jia Kong,Jin Wei,Parveen Abidi, et al .Berberine is a novel cholesterol lowering drug working through a unique mechanism distinct from statins[J]. Nature Medicine 2004,10(12):1344-1351.
10.王庆斌,高芳,岳桂华等.黄连素治疗高脂血症39例[J].滨州医学院学报,2001,24(2):157.
11.钟岚,范建高,王国良,等.肥胖、高脂血症性脂肪性肝炎模型的建立[J].实验动物科学与管理,2000,17(2):16-20.
12. Ronti T,Lupattelli G,Mannarino E.The endocrine function of adipose tissue:an update[J].Clin Endocrinol(Oxf),2006,64 (4):355-365.
13.赵宝珍,武艳丽,郗光霞,等.罗格列酮对糖耐量受损大鼠血清脂联素和肝脏脂联素受体表达的影响[J].中国药物与临床,2008,8(5):351-354.
14. Oh D K,Ciaraldi T,Henry R R.Adiponectin in health and disease[J].Diabetes Obes Metab 2007,9(3):282-289.
15. Hui JM,Hodge A.Farrell GC,et a1.Beyond insulin resistance in NASH: TNF- alpha or adiponectin? [J].Hepatology,2004.40(1):46-54.
16. Yoon D,Lee SH.Park HS,et a1.Hypoadiponectinemia and insulin resistance are associated with nonalcoholic fatty liver disease[J].Korean Med Sci,2005,20(3):421-426.
17. Zhang BJ,Xu D,Guo Y,et al.Protection by and anti-oxidant mechanism of berberine against rat liver fibrosis induced by multiple hepatotoxic factors[J]. Clinical and Experimental Pharmacology and Physiology.2008, 35(3):303-309.
18. Schulze MB,Rimm EB,Shai I,et al.Relationship between adiponectin and glycemic control,blood lipids,and inflamma-tory markers in men with type 2 diabetes[J].Diabetes Care,2004,7(27):1680-1687.
19. Beylot M ,Pinteur C,Peroni O. Expression of the adiponectin receptors AdipoR1 and AdipoR2 in lean rats and in obese Zucker rats[J].Metabolism,2006,55(3):396-401.
20.魏文青.脂联素的研究现状与展望[J].标记免疫分析与临床.2007,14(2):122-125.
21. Aygun C ,Sent urk O,Hulagu S,et al.Serum levels of hepato-protective peptide adiponectin in non-alcoholic fatty liver disease[J].Eur J Gast roenterol Hepatol ,2006 ,18 (2):175-180.
22. Wolf A M,Wolf D,Avila M A,et al.Up-regulation of the Anti-inflammatory adipokine adiponectin in acute liver failure in mice[J].Hepatol ,2006 ,44 (3):537-543.
23.中国成人血脂异常防治指南制订联合委员会.中国成人血脂异常防治指南.中华心血管病杂志,2007,35(5)390-419.
24.谢兴辉.中西药结合治疗混合性高脂血症的研究[J].现代中西药结合杂志,2009,18,(17):1971-1974.
25.中华人民共和国卫生部.中药新药临床研究指导原则:第2辑[S].1995:171.
26.祁哲,陈纪林,刘雪梅,等.辛伐他汀20mg治疗冠心病合并中度原发性高胆固醇血症疗效分析[J].中国实用内科,2002, 22(4):229-230.
27. Endo A. The discovery development of HMG-COA reuctase inhibitor.[J] Lipid Res,1991,33(1):569.
28. Zhang BJ,Xu D,Guo Y,et al.Protection by and anti-oxidant mechanism of berberine against rat liver fibrosis induced by multiple hepatotoxic factors[J].Clinical and Experimental Pharmacology and Physiology ,2008, 35 (3):303-309.
29.罗根艳,宫剑滨,汗俊军,等.急性冠状动脉综合征患者血浆低密度脂蛋白免疫复合物的变化及意义[J].医学研究生学报,2007,20(7):723-726.
30.罗根艳,官剑滨,汪俊军,等.复杂冠状动脉病变患者血清低密度脂蛋白免疫复合物的变化及意义[J].医学研究生学报2007,20(9):934-937.
31. Goldstein JL,Brown MS.Regulation of the mevalonate pathway [J]. Nature,1990 343,(6257):425-430.
32. Sholtz CL,Peeters AV,Hoogendijk CF,d a1.Mutation 59。C tin repeat 2 of the LDL receptor promoter:regulation in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia [J]. Hum Mol Genet,1999,8(1):2025-2030.
33. Hoogendijk CF.Scholtz CL,Pimstone SM,et.al.Allelic variation in the promoter region of the LDL receptor gene:analysis of an African-specific variant in the FP2 cis-acting regulatory element[J].Mol Cell Probes,2003,17(4):175-178.
34. Hobbs HH,Brown MS,Goldenstein JL.Molecular genetics of the LDL receptor gene in familial hypereholest erolemia[J].Hum Mutat,1992,1(6):445-466.
35. Cheng Huang,Yuebo Zhang,Zhenwei Gong,et.al.Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARγpathway[J].Biochemical and Biophysical Research Communications,2006,348(2):571-578.
36. Wei-Jia Kong, Jin Wei, Zeng-Yan Zuo, Yue-Ming Wang, et al.Combination of simvastatin with berberine improves the lipid-lowering efficacy[J]. Metabolism Clinical and Experimental,2008,57(8):1029-1037.
1. Choudhury J.Sanyal AJ.Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease[J].Clin liver Dis,2004,14(8):575- 594.
2. Zigman JM,Elmquist JK.Minireview:From anorexia to obesity-the yin and yang of body weight control[J].Endocrinology,2003,144(9):3749-3756.
3. Barouch LA,Berkowitz DE,Harrison RW,et al.Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice[J].Circulation,2003,108(6):754-759.
4. Kazuyuki T,Ryo S,Masashi A.et a1.Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) a) mouse liver[J].Biol Chem,2001,276:3837-3840.
5. Kim KO.Park SH,Hen TH,et al.Relationship between the severity of Iiver damage and the serum leptin level for normleo holic fatty liver disease[J].Korean Hepatol,2005,11:51-58.
6. Angulo P,Alba LM,Petrovic LM,et al.Leptint ,insulin resistance,and liver fibrosis in human nonalcoholic fatty liver disease[J].Hepatol,2004,41:943-949.
7. Berg AH,Combs TP,Scherer PE.Acrp30/adipnectin:an adipocutokine regulating glucose and lipid metabolism[J].Trends Endocrinol Metbolism,2002,13(1):84-89.
8. Wang Y,Xu A,kNIGHTc,Xu LY,Cooper GJ.Hydruxyltion nd glycosylation of the four conserved lysine residues in the collgenous domain of adiponectin: potential role in the modulation of its insulin-sensitizing activity[J].Biol,2002,227(22):521-529.
9. Yoda-Murakami M,Taniguchi M,Takahashi K,et al.Change in expression of GBP28/adiponectin in cabon tetrachloride administrated mouse liver[J].Biochm Biopgus Res Commun,2001,285(2):372-377.
10. Pajvani UB,Du X,Combs TP,et al.Complex distribution,not absolute amount ofadiponectin,correlates with thizolidinedione mediated improvement in insulin sensitivity[J].BiolChem,2004,279(13):152-162.
11. Pajvani UB,Du X,Combs TP,et al.Structure-Function Studies of the Adiponectin secreted Hormone Acrp30/Adiponectin[J].Biol Chem,2003,178(11):73-85.
12. Tsao TS,Tomas E,Murrey HE,Hug C,et al.Role of Disulfide bonds in Acrp30/ Adiponectin Structure and Signaling Specificity[J].Biol Chem,2003, 278(50): 810-817.
13. Yamamchi T,Kamon T,Minokoshi Y,et al.Adiponectin stimulates glucose utilize- tion and fatty-cid oxidation by activating AMP-acivated protein kinase[J].Nature Medicine,2002,8(11):288-295.
14. Wu X,Motoshima H,Mahadev K,Stalker TJ,et al.Involvement of AMP-activted protetin kinase in glucose uptake stimulated by the globular domain of adiponectin in primry rat adipocytes[J].Dibetes,2003,52(2):355-363.
15. Kern PA,Di Gregorio GB,Lu T,et al.Adiponectin expression from human adipose tissue relation to obesity,insulin resistance,and tumor necrosis factor-expression[J].Diadtes,2003,52(7):779-785.
16. Tsou PL,Jiang YD,Chang CC,et al.Sex related differences between adiponectin and insulin resistance in shoolchidldern[J].Diabetes Care,2004,27(2):308-313.
17. Zietz B,Herfarth H,Panl G,et al.Adiponectin represents an independent cardiovascular risk factor prediceing serum HDL-cholesterol levels in type 2 diabetes[J].FBES Lett,2003,545(23):102-104.
18. Krakoff J,Funahashi T,Stehoumer CD,et al.Inflammtory markers,adiponectin,and risk of type 2 diabetes in the Pima Indian[J].Diabetes Care,2003,26(6):745-751.
19. Viengchareun S,Christina M,Laurent P,et a1. Brown adipocyes are novel sites of expression and regulation of adiponectin and resistin[J].FEBS Letters,2002,532(3):345-350.
20. Yang G,Li L,Tang Y,et a1.Short-term pioglitazone treatment prevents free fatty acid-induced hepatic insulin resistance in normal rats:possible role of the resistin and adiponectin[J].Biochem Biophys Res Commun,2006,339(4):1190-1196.
21. Maeda N,Takahaslhi M,Funahashi T,et a1.PPAR gamma ligands increase expression and plasma concentrations of adiponectin , an adipose-derived protein[J].Diabetes,2001,50(9):2094-2099.
22. Combs TP , Wagner JA , Berger J , et al . Induction of adipocyte complement-reIated protein of 30kDa by PPAR gamma agonists:a potential mechanism of insuIin sensitization[J].Endocrinology,2002,143(3):998-1007.
23. Fasshauer M,KralIsch S,Klier M,et a1.Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes[J].Biochem Biophys Res Commun,2003,301(4):1045-1050.
24. Nishizawa H,Shimomura I,Kishida K,et a1.Androgens decrease plasma adiponectin,an insulin-sensitizing adipocyte-derived protein[J].Diabetes,2002,51(9):2734-2741.
25. Zeng Q,Isobe K,Fu L,et al.Effects of exercise on adiponectin and adiponectin receptor levels in rats[J].Life Sci,2007,80(5):454-459.
26. Lin E,Phillips LS,Ziegler TR,et a1.Increases in adiponectin predict improved liver,but not peripheral,insulin sensitivity in severely obese women during weight loss[J].Diabetes,2007,56(3):735-742.
27. Wolf AM,Wolf D,Avila MA,et a1.Up-regulation of the anti-infiammatory adipokine adiponectin in acute liver failure in mice[J].J Hepatol,2006,44(3):537-543.
28. Yoda Murakami M,Taniguchi M,Takahashi K,et a1.Change in expression of GBP28/adiponectin in carbon tetrachloride-administrated mouse liver[J]. Bioch- a) em Biophys Res Commun,2001,285(2):372-377.
29. Steppan CM,Bailey ST,Bhats,et a1.The hormone resistin kinks obesity to diabetes[J].Nature,2001,409(6818):307-12.
30. Banerjee RR.Lazar MA.Dimerization of resistin and resistin-like molecules is determined by a single cysteine[J]Biol Chem,2001,276(28):25970-25973.
31. Chosh S,Singh AK,arunn B,Mukhopadhyay S,at a1.The genotic organization of mouse resistin reveals major differences from the human resistin:functional implications[J].Gene,2003.305(1):27.
32. Kleiner DE,Brunt EM,Van Natta M,et a1.Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology,2005,4 l(6):1313-1321.
33. McTernan CL,McTernan PG,Harte AL,et a1.Resistin,central obesity,and type 2 Diabetes.Lancet,2002,359(9300):46-47.
34. Bajaj M,Suraamornkul S,Hardies LJ,et a1.Plasma resistin concentration,hepatic fat content , and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients.Int J Obes Relat Metab Disord,2004,28(6):783-789.
35. Banerjee RR,Rangwala SM,Shapiro JS,et a1.Regulation of fasted blood glucose by resistin.Science,2004,303(5661):l195-1198.
36. Pagano C,Soardo G,Pilon C,et a1.Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance.J Clin Endocrinol Metab,2006,9 l(3):1081-1086.
37. Gaillard I,ClauserE,Corvol P.Structure of the human angiotensinogen gene [J]. DNA,1989,8(2):87-99.
38.竹井谦之等.脂肪因子同肝脏的相关性.日本医学介绍,2007,28(4):152-153.
1. Wei-Jia Kong,Jin Wei,Parveen Abidi,et al .Berberine is a novel cholesterol- lowering drug working through a unique mechanism distinct from statins.[J].Nature Medicine, 2004,10(2):1344-1351.
2.魏敬、蒋建东、吴锦丹等.盐酸小檗碱调脂的研究[J].中华糖尿病杂志,2005,13(1):49-51.
3.谢兴辉.中西药结合治疗混合性高脂血症的研究[J].现代中西药结合杂志,2009,18,(17):1971-1974.
4.中华人民共和国卫生部.中药新药临床研究指导原则:第2辑[S].1995:171.
5.祁哲,陈纪林,刘雪梅,等.辛伐他汀20mg治疗冠心病合并中度原发性高胆固醇血症疗效分析[J].中国实用内科,2002, 22(4):229–230.
6.叶任高、陆再英等.人民卫生出版社内科学,2005(6):821-831.
7. Endo A. The discovery development of HMG-COA reuctase inhibitor.[J] Lipid Res,1991,33(1):569.
8. Zhang BJ,Xu D,Guo Y,et al.Protection by and anti-oxidant mechanism of berberine against rat liver fibrosis induced by multiple hepatotoxic factors[J].Clinical and Experimental Pharmacology and Physiology , 2008,35(3): 303-309.
9.罗根艳,宫剑滨,汗俊军,等.急性冠状动脉综合征患者血浆低密度脂蛋白免疫复合物的变化及意义[J].医学研究生学报,2007,20(7):723-726.
10.罗根,,官剑滨,汪俊军,等.复杂冠状动脉病变患者血清低密度脂蛋白免疫复合物的变化及意义[J].医学研究生学报2007,20(9):934-937.
11. Goldstein JL,Brown MS.Regulation of the mevalonate pathway [J].Nature,1990, 343,(6257):425-430.
12. Sholtz CL,Peeters AV,Hoogendijk CF,d a1.Mutation-59C-t in repeat 2 of the LDL receptor promoter:regulation in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia[J].Hum Mol Genet,1999,8(1):2025-2030.
13. Hoogendijk CF.Scholtz CL,Pimstone SM,et.al.Allelic variation in the promoter region of the LDL receptor gene:analysis of an African-specific variant in the FP2 cis-acting regulatory element[J].Mol Cell Probes,2003,17(4):175-18.
14. Hobbs HH,Brown MS,Goldenstein JL.Molecular genetics of the LDL receptor gene in familial hypereholest erolemia[J].Hum Mutat,1992,1(6):445-466.
15. Cheng Huang,Yuebo Zhang,Zhenwei Gong,et.al.Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARγpathway [J].Biochemical and Biophysical Research Communications,2006,348(2):571-578.
16. Wei-Jia Kong, Jin Wei, Zeng-Yan Zuo, Yue-Ming Wang, et al.Combination of simvastatin with berberine improves the lipid-lowering efficacy[J]. Metabolism Clinical and Experimental,2008,57(8):1029-1037.
2. Marchesini G,Brizi M ,Bianchi G,et al.Nonalcoholic fatty liver disease:a feature of the metabolic syndrome[J].Diabetes,2001,50(8):1844-1850.
3. Zeng MD.Pathogenesis and two“hits”hypothesis of fatty liver[J].Chinese Journal of Digestion,2002,22(9):167-168.
4. Christopher L,Gentile,Michael,J,et al.The Role of Fatty Acids in the Develop- ment and Progression of Nonalcoholic Fatty Liver Disease[J]. The Journal of Nutritional Biochemistry,2008,19(9):567-576.
5.耿东升,刘发,小檗碱药理作用研究进展[J].解放军药学学报,1997(1),13:26-28.
6.耿建东.黄连素的抗炎与免疫调节作用[J].解放军药学学报,2000,16(6):317-319.
7.谢培凤,周晖,高彦彬.小檗碱治疗Ⅱ型糖尿病40例治疗观察[J].中国临床保健杂志,2005,8(5):402-404.
8.魏敬、吴锦丹、蒋建东等.盐酸小檗碱治疗Ⅱ型糖尿病合并脂肪肝的临床研究[J].中西医结合肝病杂志,2004,14(6):334-336.
9. Wei-Jia Kong,Jin Wei,Parveen Abidi, et al .Berberine is a novel cholesterol lowering drug working through a unique mechanism distinct from statins[J]. Nature Medicine 2004,10(12):1344-1351.
10.王庆斌,高芳,岳桂华等.黄连素治疗高脂血症39例[J].滨州医学院学报,2001,24(2):157.
11.钟岚,范建高,王国良,等.肥胖、高脂血症性脂肪性肝炎模型的建立[J].实验动物科学与管理,2000,17(2):16-20.
12. Ronti T,Lupattelli G,Mannarino E.The endocrine function of adipose tissue:an update[J].Clin Endocrinol(Oxf),2006,64 (4):355-365.
13.赵宝珍,武艳丽,郗光霞,等.罗格列酮对糖耐量受损大鼠血清脂联素和肝脏脂联素受体表达的影响[J].中国药物与临床,2008,8(5):351-354.
14. Oh D K,Ciaraldi T,Henry R R.Adiponectin in health and disease[J].Diabetes Obes Metab 2007,9(3):282-289.
15. Hui JM,Hodge A.Farrell GC,et a1.Beyond insulin resistance in NASH: TNF- alpha or adiponectin? [J].Hepatology,2004.40(1):46-54.
16. Yoon D,Lee SH.Park HS,et a1.Hypoadiponectinemia and insulin resistance are associated with nonalcoholic fatty liver disease[J].Korean Med Sci,2005,20(3):421-426.
17. Zhang BJ,Xu D,Guo Y,et al.Protection by and anti-oxidant mechanism of berberine against rat liver fibrosis induced by multiple hepatotoxic factors[J]. Clinical and Experimental Pharmacology and Physiology.2008, 35(3):303-309.
18. Schulze MB,Rimm EB,Shai I,et al.Relationship between adiponectin and glycemic control,blood lipids,and inflamma-tory markers in men with type 2 diabetes[J].Diabetes Care,2004,7(27):1680-1687.
19. Beylot M ,Pinteur C,Peroni O. Expression of the adiponectin receptors AdipoR1 and AdipoR2 in lean rats and in obese Zucker rats[J].Metabolism,2006,55(3):396-401.
20.魏文青.脂联素的研究现状与展望[J].标记免疫分析与临床.2007,14(2):122-125.
21. Aygun C ,Sent urk O,Hulagu S,et al.Serum levels of hepato-protective peptide adiponectin in non-alcoholic fatty liver disease[J].Eur J Gast roenterol Hepatol ,2006 ,18 (2):175-180.
22. Wolf A M,Wolf D,Avila M A,et al.Up-regulation of the Anti-inflammatory adipokine adiponectin in acute liver failure in mice[J].Hepatol ,2006 ,44 (3):537-543.
23.中国成人血脂异常防治指南制订联合委员会.中国成人血脂异常防治指南.中华心血管病杂志,2007,35(5)390-419.
24.谢兴辉.中西药结合治疗混合性高脂血症的研究[J].现代中西药结合杂志,2009,18,(17):1971-1974.
25.中华人民共和国卫生部.中药新药临床研究指导原则:第2辑[S].1995:171.
26.祁哲,陈纪林,刘雪梅,等.辛伐他汀20mg治疗冠心病合并中度原发性高胆固醇血症疗效分析[J].中国实用内科,2002, 22(4):229-230.
27. Endo A. The discovery development of HMG-COA reuctase inhibitor.[J] Lipid Res,1991,33(1):569.
28. Zhang BJ,Xu D,Guo Y,et al.Protection by and anti-oxidant mechanism of berberine against rat liver fibrosis induced by multiple hepatotoxic factors[J].Clinical and Experimental Pharmacology and Physiology ,2008, 35 (3):303-309.
29.罗根艳,宫剑滨,汗俊军,等.急性冠状动脉综合征患者血浆低密度脂蛋白免疫复合物的变化及意义[J].医学研究生学报,2007,20(7):723-726.
30.罗根艳,官剑滨,汪俊军,等.复杂冠状动脉病变患者血清低密度脂蛋白免疫复合物的变化及意义[J].医学研究生学报2007,20(9):934-937.
31. Goldstein JL,Brown MS.Regulation of the mevalonate pathway [J]. Nature,1990 343,(6257):425-430.
32. Sholtz CL,Peeters AV,Hoogendijk CF,d a1.Mutation 59。C tin repeat 2 of the LDL receptor promoter:regulation in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia [J]. Hum Mol Genet,1999,8(1):2025-2030.
33. Hoogendijk CF.Scholtz CL,Pimstone SM,et.al.Allelic variation in the promoter region of the LDL receptor gene:analysis of an African-specific variant in the FP2 cis-acting regulatory element[J].Mol Cell Probes,2003,17(4):175-178.
34. Hobbs HH,Brown MS,Goldenstein JL.Molecular genetics of the LDL receptor gene in familial hypereholest erolemia[J].Hum Mutat,1992,1(6):445-466.
35. Cheng Huang,Yuebo Zhang,Zhenwei Gong,et.al.Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARγpathway[J].Biochemical and Biophysical Research Communications,2006,348(2):571-578.
36. Wei-Jia Kong, Jin Wei, Zeng-Yan Zuo, Yue-Ming Wang, et al.Combination of simvastatin with berberine improves the lipid-lowering efficacy[J]. Metabolism Clinical and Experimental,2008,57(8):1029-1037.
1. Choudhury J.Sanyal AJ.Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease[J].Clin liver Dis,2004,14(8):575- 594.
2. Zigman JM,Elmquist JK.Minireview:From anorexia to obesity-the yin and yang of body weight control[J].Endocrinology,2003,144(9):3749-3756.
3. Barouch LA,Berkowitz DE,Harrison RW,et al.Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice[J].Circulation,2003,108(6):754-759.
4. Kazuyuki T,Ryo S,Masashi A.et a1.Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) a) mouse liver[J].Biol Chem,2001,276:3837-3840.
5. Kim KO.Park SH,Hen TH,et al.Relationship between the severity of Iiver damage and the serum leptin level for normleo holic fatty liver disease[J].Korean Hepatol,2005,11:51-58.
6. Angulo P,Alba LM,Petrovic LM,et al.Leptint ,insulin resistance,and liver fibrosis in human nonalcoholic fatty liver disease[J].Hepatol,2004,41:943-949.
7. Berg AH,Combs TP,Scherer PE.Acrp30/adipnectin:an adipocutokine regulating glucose and lipid metabolism[J].Trends Endocrinol Metbolism,2002,13(1):84-89.
8. Wang Y,Xu A,kNIGHTc,Xu LY,Cooper GJ.Hydruxyltion nd glycosylation of the four conserved lysine residues in the collgenous domain of adiponectin: potential role in the modulation of its insulin-sensitizing activity[J].Biol,2002,227(22):521-529.
9. Yoda-Murakami M,Taniguchi M,Takahashi K,et al.Change in expression of GBP28/adiponectin in cabon tetrachloride administrated mouse liver[J].Biochm Biopgus Res Commun,2001,285(2):372-377.
10. Pajvani UB,Du X,Combs TP,et al.Complex distribution,not absolute amount ofadiponectin,correlates with thizolidinedione mediated improvement in insulin sensitivity[J].BiolChem,2004,279(13):152-162.
11. Pajvani UB,Du X,Combs TP,et al.Structure-Function Studies of the Adiponectin secreted Hormone Acrp30/Adiponectin[J].Biol Chem,2003,178(11):73-85.
12. Tsao TS,Tomas E,Murrey HE,Hug C,et al.Role of Disulfide bonds in Acrp30/ Adiponectin Structure and Signaling Specificity[J].Biol Chem,2003, 278(50): 810-817.
13. Yamamchi T,Kamon T,Minokoshi Y,et al.Adiponectin stimulates glucose utilize- tion and fatty-cid oxidation by activating AMP-acivated protein kinase[J].Nature Medicine,2002,8(11):288-295.
14. Wu X,Motoshima H,Mahadev K,Stalker TJ,et al.Involvement of AMP-activted protetin kinase in glucose uptake stimulated by the globular domain of adiponectin in primry rat adipocytes[J].Dibetes,2003,52(2):355-363.
15. Kern PA,Di Gregorio GB,Lu T,et al.Adiponectin expression from human adipose tissue relation to obesity,insulin resistance,and tumor necrosis factor-expression[J].Diadtes,2003,52(7):779-785.
16. Tsou PL,Jiang YD,Chang CC,et al.Sex related differences between adiponectin and insulin resistance in shoolchidldern[J].Diabetes Care,2004,27(2):308-313.
17. Zietz B,Herfarth H,Panl G,et al.Adiponectin represents an independent cardiovascular risk factor prediceing serum HDL-cholesterol levels in type 2 diabetes[J].FBES Lett,2003,545(23):102-104.
18. Krakoff J,Funahashi T,Stehoumer CD,et al.Inflammtory markers,adiponectin,and risk of type 2 diabetes in the Pima Indian[J].Diabetes Care,2003,26(6):745-751.
19. Viengchareun S,Christina M,Laurent P,et a1. Brown adipocyes are novel sites of expression and regulation of adiponectin and resistin[J].FEBS Letters,2002,532(3):345-350.
20. Yang G,Li L,Tang Y,et a1.Short-term pioglitazone treatment prevents free fatty acid-induced hepatic insulin resistance in normal rats:possible role of the resistin and adiponectin[J].Biochem Biophys Res Commun,2006,339(4):1190-1196.
21. Maeda N,Takahaslhi M,Funahashi T,et a1.PPAR gamma ligands increase expression and plasma concentrations of adiponectin , an adipose-derived protein[J].Diabetes,2001,50(9):2094-2099.
22. Combs TP , Wagner JA , Berger J , et al . Induction of adipocyte complement-reIated protein of 30kDa by PPAR gamma agonists:a potential mechanism of insuIin sensitization[J].Endocrinology,2002,143(3):998-1007.
23. Fasshauer M,KralIsch S,Klier M,et a1.Adiponectin gene expression and secretion is inhibited by interleukin-6 in 3T3-L1 adipocytes[J].Biochem Biophys Res Commun,2003,301(4):1045-1050.
24. Nishizawa H,Shimomura I,Kishida K,et a1.Androgens decrease plasma adiponectin,an insulin-sensitizing adipocyte-derived protein[J].Diabetes,2002,51(9):2734-2741.
25. Zeng Q,Isobe K,Fu L,et al.Effects of exercise on adiponectin and adiponectin receptor levels in rats[J].Life Sci,2007,80(5):454-459.
26. Lin E,Phillips LS,Ziegler TR,et a1.Increases in adiponectin predict improved liver,but not peripheral,insulin sensitivity in severely obese women during weight loss[J].Diabetes,2007,56(3):735-742.
27. Wolf AM,Wolf D,Avila MA,et a1.Up-regulation of the anti-infiammatory adipokine adiponectin in acute liver failure in mice[J].J Hepatol,2006,44(3):537-543.
28. Yoda Murakami M,Taniguchi M,Takahashi K,et a1.Change in expression of GBP28/adiponectin in carbon tetrachloride-administrated mouse liver[J]. Bioch- a) em Biophys Res Commun,2001,285(2):372-377.
29. Steppan CM,Bailey ST,Bhats,et a1.The hormone resistin kinks obesity to diabetes[J].Nature,2001,409(6818):307-12.
30. Banerjee RR.Lazar MA.Dimerization of resistin and resistin-like molecules is determined by a single cysteine[J]Biol Chem,2001,276(28):25970-25973.
31. Chosh S,Singh AK,arunn B,Mukhopadhyay S,at a1.The genotic organization of mouse resistin reveals major differences from the human resistin:functional implications[J].Gene,2003.305(1):27.
32. Kleiner DE,Brunt EM,Van Natta M,et a1.Design and validation of a histological scoring system for nonalcoholic fatty liver disease.Hepatology,2005,4 l(6):1313-1321.
33. McTernan CL,McTernan PG,Harte AL,et a1.Resistin,central obesity,and type 2 Diabetes.Lancet,2002,359(9300):46-47.
34. Bajaj M,Suraamornkul S,Hardies LJ,et a1.Plasma resistin concentration,hepatic fat content , and hepatic and peripheral insulin resistance in pioglitazone-treated type II diabetic patients.Int J Obes Relat Metab Disord,2004,28(6):783-789.
35. Banerjee RR,Rangwala SM,Shapiro JS,et a1.Regulation of fasted blood glucose by resistin.Science,2004,303(5661):l195-1198.
36. Pagano C,Soardo G,Pilon C,et a1.Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance.J Clin Endocrinol Metab,2006,9 l(3):1081-1086.
37. Gaillard I,ClauserE,Corvol P.Structure of the human angiotensinogen gene [J]. DNA,1989,8(2):87-99.
38.竹井谦之等.脂肪因子同肝脏的相关性.日本医学介绍,2007,28(4):152-153.
1. Wei-Jia Kong,Jin Wei,Parveen Abidi,et al .Berberine is a novel cholesterol- lowering drug working through a unique mechanism distinct from statins.[J].Nature Medicine, 2004,10(2):1344-1351.
2.魏敬、蒋建东、吴锦丹等.盐酸小檗碱调脂的研究[J].中华糖尿病杂志,2005,13(1):49-51.
3.谢兴辉.中西药结合治疗混合性高脂血症的研究[J].现代中西药结合杂志,2009,18,(17):1971-1974.
4.中华人民共和国卫生部.中药新药临床研究指导原则:第2辑[S].1995:171.
5.祁哲,陈纪林,刘雪梅,等.辛伐他汀20mg治疗冠心病合并中度原发性高胆固醇血症疗效分析[J].中国实用内科,2002, 22(4):229–230.
6.叶任高、陆再英等.人民卫生出版社内科学,2005(6):821-831.
7. Endo A. The discovery development of HMG-COA reuctase inhibitor.[J] Lipid Res,1991,33(1):569.
8. Zhang BJ,Xu D,Guo Y,et al.Protection by and anti-oxidant mechanism of berberine against rat liver fibrosis induced by multiple hepatotoxic factors[J].Clinical and Experimental Pharmacology and Physiology , 2008,35(3): 303-309.
9.罗根艳,宫剑滨,汗俊军,等.急性冠状动脉综合征患者血浆低密度脂蛋白免疫复合物的变化及意义[J].医学研究生学报,2007,20(7):723-726.
10.罗根,,官剑滨,汪俊军,等.复杂冠状动脉病变患者血清低密度脂蛋白免疫复合物的变化及意义[J].医学研究生学报2007,20(9):934-937.
11. Goldstein JL,Brown MS.Regulation of the mevalonate pathway [J].Nature,1990, 343,(6257):425-430.
12. Sholtz CL,Peeters AV,Hoogendijk CF,d a1.Mutation-59C-t in repeat 2 of the LDL receptor promoter:regulation in transcriptional activity and possible allelic interaction in a South African family with familial hypercholesterolaemia[J].Hum Mol Genet,1999,8(1):2025-2030.
13. Hoogendijk CF.Scholtz CL,Pimstone SM,et.al.Allelic variation in the promoter region of the LDL receptor gene:analysis of an African-specific variant in the FP2 cis-acting regulatory element[J].Mol Cell Probes,2003,17(4):175-18.
14. Hobbs HH,Brown MS,Goldenstein JL.Molecular genetics of the LDL receptor gene in familial hypereholest erolemia[J].Hum Mutat,1992,1(6):445-466.
15. Cheng Huang,Yuebo Zhang,Zhenwei Gong,et.al.Berberine inhibits 3T3-L1 adipocyte differentiation through the PPARγpathway [J].Biochemical and Biophysical Research Communications,2006,348(2):571-578.
16. Wei-Jia Kong, Jin Wei, Zeng-Yan Zuo, Yue-Ming Wang, et al.Combination of simvastatin with berberine improves the lipid-lowering efficacy[J]. Metabolism Clinical and Experimental,2008,57(8):1029-1037.