糖尿病大鼠载脂蛋白A5水平和PPAR基因表达及罗格列酮的影响
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摘要
背景
载脂蛋白A5(ApoA5)是2001年在对人与小鼠的ApoA1/C3/A4基因簇序列进行比较时发现的一个新的载脂蛋白家族成员,是目前发现的第一个过度表达引起甘油三酯(TG)水平下降的载脂蛋白。动物和人类实验研究表明,ApoA5不仅影响血脂代谢,而且与胰岛素水平有一定关联,说明ApoA5与糖、脂代谢密切相关。2型糖尿病常常合并高血糖、高胰岛素血症、高TG血症等糖、脂代谢紊乱,其中心血管并发症是糖尿病患者的主要并发症和致死原因,糖尿病作为冠心病的等危症已为全球所共识。罗格列酮(RSG)是目前临床上用于糖尿病和代谢综合征治疗的有效药物。然而,目前人们对于ApoA5在血清中的水平、调控因素及其临床意义知之甚少,因此研究血清中ApoA5水平,了解其在糖脂代谢中的作用及可能的调节机制有重要意义。
目的
研究糖尿病大鼠血清ApoA5水平及RSG的影响,糖尿病大鼠肝脏过氧化物酶体增殖激活受体(PPAR)αmRNA和PPAR7 mRNA的表达及RSG的影响;分析血清ApoA5水平与糖脂代谢指标及肝脏PPAR表达的相关性,探讨ApoA5在糖脂代谢中的作用及调控的可能机制。
方法
采用40只雄性SD大鼠进行动物实验,建立对照组、高脂组、糖尿病组和糖尿病RSG干预组4组动物模型。实验模型建立前采血检测各组大鼠空腹血糖(FBG)、空腹胰岛素(FINS)、稳态模型评价的胰岛素抵抗指数(HOMA-IR)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白一胆固醇(HDL-C)、低密度脂蛋白一胆固醇(LDL-C)、游离脂肪酸(FFA)。糖尿病大鼠模型的建立参照周氏等方法,给予高脂高糖饲料喂养、腹腔注射链脲佐菌素。应用RSG对糖尿病大鼠干预治疗8周。全部动物实验于第14周结束时集中处死动物,搜集血标本和肝脏组织标本。检测各组大鼠的血FBG、FINS、HOMA-IR、TG、TC、HDL-C、LDL-C、FFA浓度。用双抗体酶联免疫吸附法(ELISA)检测各组大鼠血清ApoA5水平;并与血清FBG、FINS、HOMA-IR、TG、TC、HDL-C、LDL-C、FFA水平进行相关分析。逆转录多聚酶链式反应(RT-PCR)测定各组大鼠肝脏组织PPARa mRNA和PPARqt mRNA的表达;并与血清ApoA5水平进行相关性分析。
结果
1、与对照组比较,高脂组、糖尿病组和RSG干预组大鼠血清ApoA5明显降低,以糖尿病组降低为甚(P均＜0.05);而RSG干预组大鼠较糖尿病组血清ApoA5水平有明显升高,差异有统计学意义(P＜0.05)。
2、大鼠血清ApoA5水平与TG(r=-0.781,P=0.000),TC(r=-0.643,P=0.000),FBG(r=-0.758,P=0.000),FINS(r=-0.578,P=0.001),HOMA-IR(r=-0.798,P=0.000)均呈显著负相关;而与HDL-C(r=0.469,P=0.010)呈显著正相关;与LDL-C(r=-0.323,P=0.088)和FFA(r=-0.329,P=0.082)无明显相关性。
3、PPARαmRNA和PPARγmRNA在各组大鼠的肝脏均有表达(灰度值比值)。四组大鼠中,以糖尿病组PPARαmRNA表达为最低,PPARγmRNA表达为最高(P均＜0.05);与糖尿病组比较,RSG干预组PPARαmRNA的表达有升高(P＜0.05),PPARγmRNA的表达有减低(p＜0.05)。
4、大鼠血清ApoA5水平与肝组织PPARαmRNA表达呈显著正相关(r=0.577,P=0.001);而与肝组织PPARγmRNA表达呈显著负相关(r=-0.593,P=0.001)。
结论
1、糖尿病大鼠血清ApoA5水平明显下降,罗格列酮可上调血清ApoA5水平;大鼠血清ApoA5水平与TG、TC、FBG、FINS、HOMA-IR水平呈显著负相关,与HDL-C水平呈显著正相关,提示ApoA5参与糖、脂代谢并受罗格列酮的影响。
2、PPARαmRNA和PPARγmRNA在大鼠肝脏组织均有表达;以糖尿病组大鼠PPARαmRNA的表达为最低,PPARγmRNA的表达为最高;RSG可调节糖尿病大鼠肝脏PPARαmRNA和PPARγmRNA的表达;血清ApoA5水平与肝脏组织PPARαmRNA呈显著正相关,与肝脏组织PPARγmRNA显著负相关,提示血清ApoA5水平可能与PPAR的调控有关。
Background
Apolipoprotein A5(ApoA5),a new member of lipoprotein family,has been identified by comparative sequencing of human and mouse DNA in the ApoA1/C3/A4 gene cluster in 2001.ApoA5 is the first discovered lipoprotein which lowers serum triglyceride levels when overexpressing.Now it was observed in the animal and human study that ApoA5 not only effected the metabolism of lipid,but also correlated with the level of insulin.It was indicated that ApoA5 had close correlation with the glycose and lipid metabolism.Type 2 diabetes mellitus(DM)always complicates with the metabolic disorder of hyperglycemia,hypersinsulineima,hypertriglycerideemia and so on;And cardiovascular diseases continue to be a major cause of morbidity and mortality in diabetic patients.It is the global consensus that DM has been regarded as the equal danger disease of coronary heart disease. Rosiglitazone(RSG)is the effective drug to treat DM and metabolic syndrome now.However,until now there is few reports about the expression of serum ApoA5,its regulatory factors and its clinical significances.So it is great important to study the level of serum ApoA5 and to realize its effect in glycose and lipid metabolism and its possible regulatory mechanism.
Objective
The aim of this study was to investigate the level of serum ApoA5 and the expression of the PPARαmRNA and PPARγmRNA in the liver by the intervention of RSG in the type 2 diabetic rats;and to investigate the correlations of serum ApoA5 level and the expression of the PPARαmRNA and PPARγmRNA in rats;and to explore the effect of ApoA5 on the glycose and lipid metabolism and its possible regulatory mechanisms.
Methods
Forty male healthy Sprague-Dawley(SD)rats were chosen as study objects.And establish the animal model of four groups which are control group,high fat chow group(HF group),diabetes mellitus group(DM group) and diabetes mellitus with rosiglitazone intervention group(RSG group). Fasting blood glucose(FBG),fasting insulin(FINS),Homeostasis model assessment of insulin resistance(HOMA-IR),triglyceride(TG),total cholesterol(TC),high density lipoprotein-cholestero(HDL-C),low density lipoprotein-cholestero(LDL-C)and free fat acid(FFA)were measured at the beginning of the study.The diabetic rats' model was established in accordance with the method of Zhou etc,which was feeding high fat chow and intraperitoneal injection of streprozotocin.And then the diabetic rats were randomly treated with rosiglitazone by daily gavage for 8 weeks.All the rats were killed at the end of the fourteenth week,and collect the blood preparation and tissue preparations of the liver.Then examine the level of FBG、FINS、HOMA-IR、TG、TC、HDL-C、LDL-C and FFA;and measure the level of ApoA5 in serum by enzyme linked immunosorbent assay(ELISA) and analyze the correlations of serum apoA5 level and FBG、FINS、HOMA-IR、TG、TC、HDL-C、LDL-C and FFA.Reverse transacription polymerase chain reaction(RT-PCR)was used to PPARαmRNAand PPARγmRNA expressions in the liver in rats;And analyze the correlations of serum apoA5 level and PPARαmRNAand PPARγmRNA expressions.
Results
1、Compared to control group,serum ApoA5 concentrations in HF group, DM group and RSG group were decreased significantly,serum ApoA5 concentrations in DM group were the lowest;and compared to DM group, the concentrations in RSG group were increased.All the differences have statistical significance(all the P＜0.05).
2、The level of serum ApoA5 negative correlated with TG(r= - 0.781,P =0.000),TC(r=-0.643,P=0.000),FBG(r=- 0.758,P = 0.000),FINS (r=-0.578,P=0.001),HOMA-IR(r=-0.798,P=0.000)significantly; and the level positive correlated with HDL-C(r=0.469,P=0.010) significantly;while the level had no correlation with LDL-C(r=-0.323,P= 0.088)and FFA(r=-0.329,P=0.082).
3、PPARαmRNA and PPARγ,mRNA were both detected in the liver;the expression of PPARαmRNA in DM group were the lowest and the expression of PPARγmRNA in DM group were the highest(all the P＜0.05); and compared to DM group,PPARαmRNA in RSG group were increased markedly(P＜0.05),and PPARγmRNA in RSG group were decreased markedly(P＜0.05).
4、The level of serum ApoA5 positive correlated with the expression of PPARαmRNA(r=0.577,P=0.001)and negtive correlated with the expression of PPARγmRNA(r=-0.593,P = 0.001)in liver.
Conclusion
1、The level of serum ApoA5 decreased significantly in diabetic rats,and RSG up-regulated the level;And the level of serum apoM negtive correlated with TG、TC、FBG、FINS、HOMA-IR and positive correlated with HDL-C significantly.It was indicated that ApoA5 may participate the glycose and lipid metabolism and may be regulated by rosiglitazone.
2、PPARαmRNA and PPARγmRNA were both expressed in the liver of the rats;The expression of PPARαmRNA in DM group were the lowest and the expression of PPARγmRNA in DM group were the highest;PPARγ,agonist could regulate the expressions of PPARαmRNA and PPARγmRNA in diabetic rats;And the level of serum ApoA5 positive correlated with the expression of PPARαmRNA and negtive correlated with the expression of PPARγmRNA in liver of the rats.It was indicated that the level of ApoA5 may be regulated by PPAR.
载脂蛋白A5(ApoA5)是2001年在对人与小鼠的ApoA1/C3/A4基因簇序列进行比较时发现的一个新的载脂蛋白家族成员,是目前发现的第一个过度表达引起甘油三酯(TG)水平下降的载脂蛋白。动物和人类实验研究表明,ApoA5不仅影响血脂代谢,而且与胰岛素水平有一定关联,说明ApoA5与糖、脂代谢密切相关。2型糖尿病常常合并高血糖、高胰岛素血症、高TG血症等糖、脂代谢紊乱,其中心血管并发症是糖尿病患者的主要并发症和致死原因,糖尿病作为冠心病的等危症已为全球所共识。罗格列酮(RSG)是目前临床上用于糖尿病和代谢综合征治疗的有效药物。然而,目前人们对于ApoA5在血清中的水平、调控因素及其临床意义知之甚少,因此研究血清中ApoA5水平,了解其在糖脂代谢中的作用及可能的调节机制有重要意义。
目的
研究糖尿病大鼠血清ApoA5水平及RSG的影响,糖尿病大鼠肝脏过氧化物酶体增殖激活受体(PPAR)αmRNA和PPAR7 mRNA的表达及RSG的影响;分析血清ApoA5水平与糖脂代谢指标及肝脏PPAR表达的相关性,探讨ApoA5在糖脂代谢中的作用及调控的可能机制。
方法
采用40只雄性SD大鼠进行动物实验,建立对照组、高脂组、糖尿病组和糖尿病RSG干预组4组动物模型。实验模型建立前采血检测各组大鼠空腹血糖(FBG)、空腹胰岛素(FINS)、稳态模型评价的胰岛素抵抗指数(HOMA-IR)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白一胆固醇(HDL-C)、低密度脂蛋白一胆固醇(LDL-C)、游离脂肪酸(FFA)。糖尿病大鼠模型的建立参照周氏等方法,给予高脂高糖饲料喂养、腹腔注射链脲佐菌素。应用RSG对糖尿病大鼠干预治疗8周。全部动物实验于第14周结束时集中处死动物,搜集血标本和肝脏组织标本。检测各组大鼠的血FBG、FINS、HOMA-IR、TG、TC、HDL-C、LDL-C、FFA浓度。用双抗体酶联免疫吸附法(ELISA)检测各组大鼠血清ApoA5水平;并与血清FBG、FINS、HOMA-IR、TG、TC、HDL-C、LDL-C、FFA水平进行相关分析。逆转录多聚酶链式反应(RT-PCR)测定各组大鼠肝脏组织PPARa mRNA和PPARqt mRNA的表达;并与血清ApoA5水平进行相关性分析。
结果
1、与对照组比较,高脂组、糖尿病组和RSG干预组大鼠血清ApoA5明显降低,以糖尿病组降低为甚(P均＜0.05);而RSG干预组大鼠较糖尿病组血清ApoA5水平有明显升高,差异有统计学意义(P＜0.05)。
2、大鼠血清ApoA5水平与TG(r=-0.781,P=0.000),TC(r=-0.643,P=0.000),FBG(r=-0.758,P=0.000),FINS(r=-0.578,P=0.001),HOMA-IR(r=-0.798,P=0.000)均呈显著负相关;而与HDL-C(r=0.469,P=0.010)呈显著正相关;与LDL-C(r=-0.323,P=0.088)和FFA(r=-0.329,P=0.082)无明显相关性。
3、PPARαmRNA和PPARγmRNA在各组大鼠的肝脏均有表达(灰度值比值)。四组大鼠中,以糖尿病组PPARαmRNA表达为最低,PPARγmRNA表达为最高(P均＜0.05);与糖尿病组比较,RSG干预组PPARαmRNA的表达有升高(P＜0.05),PPARγmRNA的表达有减低(p＜0.05)。
4、大鼠血清ApoA5水平与肝组织PPARαmRNA表达呈显著正相关(r=0.577,P=0.001);而与肝组织PPARγmRNA表达呈显著负相关(r=-0.593,P=0.001)。
结论
1、糖尿病大鼠血清ApoA5水平明显下降,罗格列酮可上调血清ApoA5水平;大鼠血清ApoA5水平与TG、TC、FBG、FINS、HOMA-IR水平呈显著负相关,与HDL-C水平呈显著正相关,提示ApoA5参与糖、脂代谢并受罗格列酮的影响。
2、PPARαmRNA和PPARγmRNA在大鼠肝脏组织均有表达;以糖尿病组大鼠PPARαmRNA的表达为最低,PPARγmRNA的表达为最高;RSG可调节糖尿病大鼠肝脏PPARαmRNA和PPARγmRNA的表达;血清ApoA5水平与肝脏组织PPARαmRNA呈显著正相关,与肝脏组织PPARγmRNA显著负相关,提示血清ApoA5水平可能与PPAR的调控有关。
Background
Apolipoprotein A5(ApoA5),a new member of lipoprotein family,has been identified by comparative sequencing of human and mouse DNA in the ApoA1/C3/A4 gene cluster in 2001.ApoA5 is the first discovered lipoprotein which lowers serum triglyceride levels when overexpressing.Now it was observed in the animal and human study that ApoA5 not only effected the metabolism of lipid,but also correlated with the level of insulin.It was indicated that ApoA5 had close correlation with the glycose and lipid metabolism.Type 2 diabetes mellitus(DM)always complicates with the metabolic disorder of hyperglycemia,hypersinsulineima,hypertriglycerideemia and so on;And cardiovascular diseases continue to be a major cause of morbidity and mortality in diabetic patients.It is the global consensus that DM has been regarded as the equal danger disease of coronary heart disease. Rosiglitazone(RSG)is the effective drug to treat DM and metabolic syndrome now.However,until now there is few reports about the expression of serum ApoA5,its regulatory factors and its clinical significances.So it is great important to study the level of serum ApoA5 and to realize its effect in glycose and lipid metabolism and its possible regulatory mechanism.
Objective
The aim of this study was to investigate the level of serum ApoA5 and the expression of the PPARαmRNA and PPARγmRNA in the liver by the intervention of RSG in the type 2 diabetic rats;and to investigate the correlations of serum ApoA5 level and the expression of the PPARαmRNA and PPARγmRNA in rats;and to explore the effect of ApoA5 on the glycose and lipid metabolism and its possible regulatory mechanisms.
Methods
Forty male healthy Sprague-Dawley(SD)rats were chosen as study objects.And establish the animal model of four groups which are control group,high fat chow group(HF group),diabetes mellitus group(DM group) and diabetes mellitus with rosiglitazone intervention group(RSG group). Fasting blood glucose(FBG),fasting insulin(FINS),Homeostasis model assessment of insulin resistance(HOMA-IR),triglyceride(TG),total cholesterol(TC),high density lipoprotein-cholestero(HDL-C),low density lipoprotein-cholestero(LDL-C)and free fat acid(FFA)were measured at the beginning of the study.The diabetic rats' model was established in accordance with the method of Zhou etc,which was feeding high fat chow and intraperitoneal injection of streprozotocin.And then the diabetic rats were randomly treated with rosiglitazone by daily gavage for 8 weeks.All the rats were killed at the end of the fourteenth week,and collect the blood preparation and tissue preparations of the liver.Then examine the level of FBG、FINS、HOMA-IR、TG、TC、HDL-C、LDL-C and FFA;and measure the level of ApoA5 in serum by enzyme linked immunosorbent assay(ELISA) and analyze the correlations of serum apoA5 level and FBG、FINS、HOMA-IR、TG、TC、HDL-C、LDL-C and FFA.Reverse transacription polymerase chain reaction(RT-PCR)was used to PPARαmRNAand PPARγmRNA expressions in the liver in rats;And analyze the correlations of serum apoA5 level and PPARαmRNAand PPARγmRNA expressions.
Results
1、Compared to control group,serum ApoA5 concentrations in HF group, DM group and RSG group were decreased significantly,serum ApoA5 concentrations in DM group were the lowest;and compared to DM group, the concentrations in RSG group were increased.All the differences have statistical significance(all the P＜0.05).
2、The level of serum ApoA5 negative correlated with TG(r= - 0.781,P =0.000),TC(r=-0.643,P=0.000),FBG(r=- 0.758,P = 0.000),FINS (r=-0.578,P=0.001),HOMA-IR(r=-0.798,P=0.000)significantly; and the level positive correlated with HDL-C(r=0.469,P=0.010) significantly;while the level had no correlation with LDL-C(r=-0.323,P= 0.088)and FFA(r=-0.329,P=0.082).
3、PPARαmRNA and PPARγ,mRNA were both detected in the liver;the expression of PPARαmRNA in DM group were the lowest and the expression of PPARγmRNA in DM group were the highest(all the P＜0.05); and compared to DM group,PPARαmRNA in RSG group were increased markedly(P＜0.05),and PPARγmRNA in RSG group were decreased markedly(P＜0.05).
4、The level of serum ApoA5 positive correlated with the expression of PPARαmRNA(r=0.577,P=0.001)and negtive correlated with the expression of PPARγmRNA(r=-0.593,P = 0.001)in liver.
Conclusion
1、The level of serum ApoA5 decreased significantly in diabetic rats,and RSG up-regulated the level;And the level of serum apoM negtive correlated with TG、TC、FBG、FINS、HOMA-IR and positive correlated with HDL-C significantly.It was indicated that ApoA5 may participate the glycose and lipid metabolism and may be regulated by rosiglitazone.
2、PPARαmRNA and PPARγmRNA were both expressed in the liver of the rats;The expression of PPARαmRNA in DM group were the lowest and the expression of PPARγmRNA in DM group were the highest;PPARγ,agonist could regulate the expressions of PPARαmRNA and PPARγmRNA in diabetic rats;And the level of serum ApoA5 positive correlated with the expression of PPARαmRNA and negtive correlated with the expression of PPARγmRNA in liver of the rats.It was indicated that the level of ApoA5 may be regulated by PPAR.
引文
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[17]Buse JB,Polonsky KS,Burant CF.Type 2 diabetes mellitus in:Reed-larsen P,Kronenberg HM,Melmed S,et al.Willams Text book of Endocrimology[M]10~(th)ed.Philadelphia:WB Saunders Co,2003:1427-1484.
[18]Hanley AI,Wagenknecht IF,D'A gostino RB,et al.Identification of su bjects with insulin resistance and beta-cell dysfunction using alternative definitions of the metabolic syndrome[J].Diabetes,2003,52(11):2740-2747.
[19]Vander Vliet HN,Schaap FG,Levels JH,et al.Adenoviral over-expression of apolipoprotein AV reduces serum levels of triglycerides and cholesterol in mice[J].Biochem Biophys Res Common,2002,295(5):1156-1159.
[20]Pennacchio LA,Olivier M,Hubacek JA,et al.Two independent apolipoprotein A5 influence human plasma triglyceride levels.Hum Mol Genet,2002,11(24):3031-3038.
[21]Lai CQ,Demissie S,Cupples LA,et al.Influence of APOA5 locus on plasma triglyceride,lipoprotein subclasses,and CVD risk in the Framingham Heart Study.J Lipid Res,2004,45(11):2096-2105.
[22]Baum L,Tomlinson B,Thomas GN.APOA5-1131T＞C polymorphism is associated with triglyceride levels in Chinese men.Clin Genet,2003,63(5):377-379.
[23]Li GP,Wang JY,Yan SK,et al.Genetic effect of two polymorphisms in the apolipoprotein A5 gene and apolipoprotein gene on serum lipids and lipoproteins levels in a Chinese population[J].J Clin Genet,2004,65(6):470-476.
[24]Schaap FG,Rensen PC,Voshol PJ,et al.ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotem-triglyceride(VLDL-TG)production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis[J].J Biol Chem.2004,279(27):27941-27947.
[25]Marcais C,Verges B,Charriere S.ApoA5 Q139X truncation predisposes to late-onset hyperchylomicronemisa due to lipoprotein lipase impairment[J].Clin Invest,2005,115(10):2862-2869.
[26]Jamila FN,Eric B,Loredan-Stefan N,et al.Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5[J].Biochem Biophys Res Common,2004,319(2):397-404.
[27]Henneman P,Schaap FG,Havekes LM,et al.Plasma apoAV levels are markedly elevated in severe hypertriglyceridemia and positive correlated with APOA5 S19W polymorphism[J].Atherosclerosis,2007,193(1):129-134.
[28]Ichiro Takada,Ruth T,Yu H,et al.Alteration of a single amino acid in peroxisome proliferatior-activated receptor-α(PPARα)generates a PPAR phenotype [J].Molecular Endocrinology,2000,14(5):733-740.
[29]Glass C.Going nuclear in metabolic and cardiovascular disease[J].J Clin Invest,2006,116(3):556-560.
[30]Willson TM,Brown PJ,Stembach DD,et al.The PPARs:from orphan recepters to drug discovery[J].J Med Chem.2000,43(4):527-550.
[31]Rangwalla SM,Rhoades B,Shapiro JS,et al.Genetic modulation of PPAR gammar phosphorylation regulates insulin sensitivity.Dev Cell.2003,5(4):657-663.
[32]Zingarelli B,Cook JA.Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation[J].Shock,2005,23(5):393-399.
[33]Braissant O,Foufelle F,Scotto C,et al.Differential expression of peroxisome proliferators activated receptors(PPARs):Tissue distribution of PPARα,β and γ in the adult rat[J].Endocrinology,1996,137(1):345-349.
[34]袁成良,金小岚。过氧化物酶体增殖体活化受体的生物学基础与病理生理研究进展。国际检验医学杂志,2007,28(4):366-368。
[35]Vu-Dac N,Gervois P,Jakel H,et al.Apolipoportein A5,a crucial determinant of plasma triglyceride levels,is highly responsive to peroxisome proliferatoractivated receptor α activators[J].J Biol Chem,2003,278(20):17982-17985.
[36]Prieur X,Coste H,Rodriguez JC.The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element[J].J Biol Chem,2003,278(28):25468-25480.
[1] Seda O, Sedova L. New apolipoprotein A-V: comparative genomics meets metabolism [J]. Physiol Res, 2003, 52 (2): 141-146.
[2] Groenendijk M, Cantor RM, de Bruin TW, et al. The apoAI- CIII-AIV gene cluster [J]. Atherosclerosis, 2001,157 (1): 1-11.
[3] Pennaacchio IA, Oliver M , Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing [J]. Science, 2001,294(5540): 169-173.
[4] van der Vliet HN, Sammels MG, Leegwater AC, et al. Apolipoprotein A-V, A novel apolipoprotein associated with an early phase of liver regeneration [J]. J Biol Chem, 2001, 276 (48): 44512-44520.
[5] Weinberg RB, Cook VR, Beckstead JA, et al. Structure and interfacial properties of human apolipoprotein A-V [J]. J Biol Chem, 2003, 278 (36): 34438-34444.
[6] Beckstead JA, Oda MN, Martin DD, et al. Structure-function study of human apolipoprotein A-V: a regulator of plasma lipid homeostasis [J]. Biochemistry, 2003, 42 (31): 9416-9423.
[7] Peter J.O'Brier, Willianm E. Alborn, et al. The novel apolipoprotein A5 is present in human serum, is associated with VLDI, HDL and CM, and circulates at very low concentrations compared with other apolipoproteins [J]. Clin Chem, 2005, 51 (2): 351-359.
[8] Grundy SM, Hansen B, Smith SC, et al. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management [J]. Circulation, 2004,109 (4):551-556.
[9] Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus in: Reed-larsen P, Kronenberg HM, Melmed S, et al. Willams Text book of Endocrimology [M] 10~(th) ed. Philadelphia: WB Saunders Co, 2003: 1427-1484.
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[11] Hanley AJ, Karter AJ, Festa A, et al. Factor analysis of metabolic syndrome using directly measured insulin sensitivity: The Insulin Resistance Atherosclerosis Study [J]. Diabetes, 2002, 51 (8):2642-2647.
[12] Lawlor DA, Ebrahim S, Timpeson N, et al. Avoiding milk is associated with a reduced risk of insulin resistance and the metabolic syndrome: findings from the British Women's Heart and Health Study [J]. Diabet Med, 2005,22 (6):808-811.
[13] Taha DA, Umpaiehitra V, Banerji MA, et al. Type 2 diabetes meliltusin African-American adolescents: impaired beta-cell function in the face of severe insulinre sistance [J]. J Pediatr Endocrinol Metab, 2006, 19 (2): 135-142.
[14] Forst T, Lubben G, Hohberg C, et al. Influence of glucose control and improvement of insulin resistance on microvascular blood flow and endothelial functionin patients with diabetes mellitus type2 [J]. Microcirculation, 2005, 12 (7): 543-550.
[15] Despres JP. Is visceral obesity the cause of the metabolic syndrome [J]. Ann Med, 2006, 38 (1): 56-63.
[16] Saad MF, Rewers M, Selby J, et al. Insulin resistance and hypertension: the Insulin Resistance Atherosclerosis study [J]. Hypertension. 2004, 43 (6): 1324-1331.
[17] Simons LA, Simons J, Friendlander Y, et al. Dose a diagnosis of the metabolic syndrome provide an additional prediction of cardiovascular disease and total mortality in the elderly? The Dubbo Study [J]. Med J Aust, 2007, 186 (8): 400-403.
[18] Onat A, Sari I, Hergenc G, Yazici M, et al. Predictions of abdominal obesity and high susceptibility of cardiometabolic risk to its increments among Turkish women: a prospective population-basal study [J]. Metabolism, 2007, 56 (3): 348-56.
[19] St-pierce J, Lenienx I, Penon P, et al. Relaiton of the "hypertriglyceridemic Waist" phenotype to earlier manifestation of coronary artery disease in patients with glucose intolerance and type 2 diabetes mellitus [J]. Am J Cardiol. 2007, 99 (3): 369 -373.
[20] Lao XQ, Thomas G N, Jiang CQ, et al. Association of the metabolic syndrome with vascular disease in an older Chinese populaiton: Guangzhou Biobank Cohort Study [J]. J Endocrinol Invest, 2006, 29 (11): 989-996.
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[26] Vu-Dac N, Gervois P, Jakel H, et al. Apolipoportein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor a activators [J]. J Biol Chem, 2003, 278 (20): 17982-17985.
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[31] Vander Vliet HN, Schaap FG, Levels JH, et al. Adenoviral over-expression of apolipoprotein AV reduces serum levels of triglycerides and cholesterol in mice [J]. Biochem Biophys Res Common, 2002,295 (5): 1156-1159.
[32] Fruchart-Najib Jamila, Bauge Eric, Niculescu IS, et al. Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5 [J]. Biochem Biophys Res Common, 2004, 319 (2): 397-404.
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[36] Zhao SP, Hu S, Li J, et al. Association of human serum apolipoprotein A5 with lipid profiles affected by gender [J]. Clin Chim Acta, 2007, 376 (1-2): 68-71.
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[39] Schaap FG, Rensen PC, Voshol PJ, et al. ApoAV reduces plasma tri-glycerides by inhibiting very low density lipoprotem-triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis [J]. J Biol Chem. 2004, 279 (27): 27941-27947.
[40] Marcais C, Verges B, Charriere S. ApoA5 Q139X truncation predisposes to late-onset hyperchylomicronemisa due to lipoprotein lipase impairment [J]. Clin Invest, 2005,115 (10): 2862-2869.
[41] Jamila FN, Eric B, Loredan-Stefan N, et al. Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5 [J]. Biochem Biophys Res Commun, 2004, 319 (2): 397-404.
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[47]毕楠,邵盛恺,李国平等.冠心病患者载脂蛋白A5和载脂蛋白C3基因多态性的研究[J].中华心血管病杂志,2005,33(2):116-121.
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[3]Nowak M,Heleboid-Chapman A,Jakel H,et al.Insulin-mediated down regulation of apolipoprotein A5 gene expression through the phosphatidyhnositol 3-kinase pathway:role of upstream stimulatory factor[J].Molecular and Cellular Biology.2005,25(4):1537-1548.
[4]Chin KC,Chiu YF,Boyadjian AA,et al.Impact of apolipoprotein A5polymorphisms on insulin sensitivity and beta-cell function[J].J Pancreas,2005,30(4):328-332.
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[6]Peter J.O'Brier,Willianm E.Alborn,et al.The novel apolipoprotein A5 is present in human serum,is associated with VLDI,HDL and CM,and circulates at very low concentrations compared with other apolipoproteins[J].Clin Chem,2005,51(2):351-359.
[7]刘琼,赵水平。ApoA5单克隆抗体的制备及其临床初步应用[J]。医学临床研究,2006,23(2):153-156。
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[9]Zhao SP,Hu S,Li J,et al.Association of human serum apolipoprotein A5with lipid profiles affected by gender[J].Clin Chim Acta,2007,376(1-2):68-71.
[10]Ishihara M,Kujinaoka T,Tuasaki T,et al.A sandwich enzyme-linked immunosorbent assay for human plasma apolipoprotein A-V concentration[J].J lipid Res,2005,46(9):2015-2022.
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[13]Lawlor DA,Ebrahim S,Timpeson N,et al.Avoiding milk is associated with a reduced risk of insulin resistance and the metabolic syndrome:findings from the British Women's Heart and Health Study[J].Diabet Med,2005,22(6):808-811.
[14]Taha DA,Umpaiehitra V,Banerji MA,et al.Type 2 diabetes meliltusin African-American adolescents:impaired beta-cell function in the face of severe insulinre sistance[J].J Pediatr Endocrinol Metab,2006,19(2):135-142.
[15]Forst T,Lubben G,Hohberg C,et al.Influence of glucose control and improvement of insulin resistance on microvascular blood flow and endothelial functionin patients with diabetes mellitus type2[J].Microcirculation,2005,12(7):543-550.
[16]Hanley A J,Karter AJ,Festa A,et al.Factor analysis of metabolic syndrome using directly measured insulin sensitivity:The Insulin Resistance Atherosclerosis Study[J].Diabetes,2002,51(8):2642-2647.
[17]Buse JB,Polonsky KS,Burant CF.Type 2 diabetes mellitus in:Reed-larsen P,Kronenberg HM,Melmed S,et al.Willams Text book of Endocrimology[M]10~(th)ed.Philadelphia:WB Saunders Co,2003:1427-1484.
[18]Hanley AI,Wagenknecht IF,D'A gostino RB,et al.Identification of su bjects with insulin resistance and beta-cell dysfunction using alternative definitions of the metabolic syndrome[J].Diabetes,2003,52(11):2740-2747.
[19]Vander Vliet HN,Schaap FG,Levels JH,et al.Adenoviral over-expression of apolipoprotein AV reduces serum levels of triglycerides and cholesterol in mice[J].Biochem Biophys Res Common,2002,295(5):1156-1159.
[20]Pennacchio LA,Olivier M,Hubacek JA,et al.Two independent apolipoprotein A5 influence human plasma triglyceride levels.Hum Mol Genet,2002,11(24):3031-3038.
[21]Lai CQ,Demissie S,Cupples LA,et al.Influence of APOA5 locus on plasma triglyceride,lipoprotein subclasses,and CVD risk in the Framingham Heart Study.J Lipid Res,2004,45(11):2096-2105.
[22]Baum L,Tomlinson B,Thomas GN.APOA5-1131T＞C polymorphism is associated with triglyceride levels in Chinese men.Clin Genet,2003,63(5):377-379.
[23]Li GP,Wang JY,Yan SK,et al.Genetic effect of two polymorphisms in the apolipoprotein A5 gene and apolipoprotein gene on serum lipids and lipoproteins levels in a Chinese population[J].J Clin Genet,2004,65(6):470-476.
[24]Schaap FG,Rensen PC,Voshol PJ,et al.ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotem-triglyceride(VLDL-TG)production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis[J].J Biol Chem.2004,279(27):27941-27947.
[25]Marcais C,Verges B,Charriere S.ApoA5 Q139X truncation predisposes to late-onset hyperchylomicronemisa due to lipoprotein lipase impairment[J].Clin Invest,2005,115(10):2862-2869.
[26]Jamila FN,Eric B,Loredan-Stefan N,et al.Mechanism of triglyceride lowering in mice expressing human apolipoprotein A5[J].Biochem Biophys Res Common,2004,319(2):397-404.
[27]Henneman P,Schaap FG,Havekes LM,et al.Plasma apoAV levels are markedly elevated in severe hypertriglyceridemia and positive correlated with APOA5 S19W polymorphism[J].Atherosclerosis,2007,193(1):129-134.
[28]Ichiro Takada,Ruth T,Yu H,et al.Alteration of a single amino acid in peroxisome proliferatior-activated receptor-α(PPARα)generates a PPAR phenotype [J].Molecular Endocrinology,2000,14(5):733-740.
[29]Glass C.Going nuclear in metabolic and cardiovascular disease[J].J Clin Invest,2006,116(3):556-560.
[30]Willson TM,Brown PJ,Stembach DD,et al.The PPARs:from orphan recepters to drug discovery[J].J Med Chem.2000,43(4):527-550.
[31]Rangwalla SM,Rhoades B,Shapiro JS,et al.Genetic modulation of PPAR gammar phosphorylation regulates insulin sensitivity.Dev Cell.2003,5(4):657-663.
[32]Zingarelli B,Cook JA.Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation[J].Shock,2005,23(5):393-399.
[33]Braissant O,Foufelle F,Scotto C,et al.Differential expression of peroxisome proliferators activated receptors(PPARs):Tissue distribution of PPARα,β and γ in the adult rat[J].Endocrinology,1996,137(1):345-349.
[34]袁成良,金小岚。过氧化物酶体增殖体活化受体的生物学基础与病理生理研究进展。国际检验医学杂志,2007,28(4):366-368。
[35]Vu-Dac N,Gervois P,Jakel H,et al.Apolipoportein A5,a crucial determinant of plasma triglyceride levels,is highly responsive to peroxisome proliferatoractivated receptor α activators[J].J Biol Chem,2003,278(20):17982-17985.
[36]Prieur X,Coste H,Rodriguez JC.The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element[J].J Biol Chem,2003,278(28):25468-25480.
[1] Seda O, Sedova L. New apolipoprotein A-V: comparative genomics meets metabolism [J]. Physiol Res, 2003, 52 (2): 141-146.
[2] Groenendijk M, Cantor RM, de Bruin TW, et al. The apoAI- CIII-AIV gene cluster [J]. Atherosclerosis, 2001,157 (1): 1-11.
[3] Pennaacchio IA, Oliver M , Hubacek JA, et al. An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing [J]. Science, 2001,294(5540): 169-173.
[4] van der Vliet HN, Sammels MG, Leegwater AC, et al. Apolipoprotein A-V, A novel apolipoprotein associated with an early phase of liver regeneration [J]. J Biol Chem, 2001, 276 (48): 44512-44520.
[5] Weinberg RB, Cook VR, Beckstead JA, et al. Structure and interfacial properties of human apolipoprotein A-V [J]. J Biol Chem, 2003, 278 (36): 34438-34444.
[6] Beckstead JA, Oda MN, Martin DD, et al. Structure-function study of human apolipoprotein A-V: a regulator of plasma lipid homeostasis [J]. Biochemistry, 2003, 42 (31): 9416-9423.
[7] Peter J.O'Brier, Willianm E. Alborn, et al. The novel apolipoprotein A5 is present in human serum, is associated with VLDI, HDL and CM, and circulates at very low concentrations compared with other apolipoproteins [J]. Clin Chem, 2005, 51 (2): 351-359.
[8] Grundy SM, Hansen B, Smith SC, et al. Clinical management of metabolic syndrome: report of the American Heart Association/National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management [J]. Circulation, 2004,109 (4):551-556.
[9] Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus in: Reed-larsen P, Kronenberg HM, Melmed S, et al. Willams Text book of Endocrimology [M] 10~(th) ed. Philadelphia: WB Saunders Co, 2003: 1427-1484.
[10] Hanley AI, Wagenknecht IF, D'A gostino RB, et al. Identification of su bjects with insulin resistance and beta-cell dysfunction using alternative definitions of the metabolic syndrome [J]. Diabetes, 2003, 52 (11): 2740-2747.
[11] Hanley AJ, Karter AJ, Festa A, et al. Factor analysis of metabolic syndrome using directly measured insulin sensitivity: The Insulin Resistance Atherosclerosis Study [J]. Diabetes, 2002, 51 (8):2642-2647.
[12] Lawlor DA, Ebrahim S, Timpeson N, et al. Avoiding milk is associated with a reduced risk of insulin resistance and the metabolic syndrome: findings from the British Women's Heart and Health Study [J]. Diabet Med, 2005,22 (6):808-811.
[13] Taha DA, Umpaiehitra V, Banerji MA, et al. Type 2 diabetes meliltusin African-American adolescents: impaired beta-cell function in the face of severe insulinre sistance [J]. J Pediatr Endocrinol Metab, 2006, 19 (2): 135-142.
[14] Forst T, Lubben G, Hohberg C, et al. Influence of glucose control and improvement of insulin resistance on microvascular blood flow and endothelial functionin patients with diabetes mellitus type2 [J]. Microcirculation, 2005, 12 (7): 543-550.
[15] Despres JP. Is visceral obesity the cause of the metabolic syndrome [J]. Ann Med, 2006, 38 (1): 56-63.
[16] Saad MF, Rewers M, Selby J, et al. Insulin resistance and hypertension: the Insulin Resistance Atherosclerosis study [J]. Hypertension. 2004, 43 (6): 1324-1331.
[17] Simons LA, Simons J, Friendlander Y, et al. Dose a diagnosis of the metabolic syndrome provide an additional prediction of cardiovascular disease and total mortality in the elderly? The Dubbo Study [J]. Med J Aust, 2007, 186 (8): 400-403.
[18] Onat A, Sari I, Hergenc G, Yazici M, et al. Predictions of abdominal obesity and high susceptibility of cardiometabolic risk to its increments among Turkish women: a prospective population-basal study [J]. Metabolism, 2007, 56 (3): 348-56.
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