PPARδ激动剂GW501516在oxLDL诱导THP-1源性巨噬细胞凋亡及脂质蓄积中的作用
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摘要
研究背景：过氧化物酶体增殖物激活型受体δ(peroxisome Proliferator- activated receptorδ, PPARδ)是过氧化物酶体增殖物激活型受体家族中的一员,广泛表达于多种器官和组织,主要控制脂肪组织和肌肉中脂肪酸氧化和能量解偶联,抑制巨噬细胞诱导的炎症,改善动脉粥样硬化,并参与许多疾病的发生和发展过程。PPARδ的配体分为天然配体和合成配体。GW501516是PPARδ的合成配体,属于苯氧乙酸衍生物,PPARδ与GW501516结合后,活化的PPARδ与9-顺视黄酸类受体(9-cisretinoid X receptor, RXR)形成异二聚体,然后识别并于靶基因启动子上游的过氧化物酶体增殖物反应元件(peroxisome proliferator response element, PPRE)结合,调节靶基因下游的基因转录、翻译及生物学效应。本课题观察oxLDL对THP-1源性巨噬细胞PPARδ表达的影响。同时以PPARδ激动剂GW501516来探讨PPARδ对巨噬细胞增殖、凋亡的影响及在巨噬细胞荷脂过程的作用。
第一部分oxLDL对THP-1源性巨噬细胞PPARδ表达的影响
目的：观察oxLDL对THP-1源性巨噬细胞PPAR 8表达的影响。
方法：1.用不同浓度(0mg/L、25mg/L、50mg/L、100mg/L)的oxLDL与THP-1源性巨噬细胞共孵育24小时；用RT-PCR及Western blotting检测细胞PPARδmRNA和蛋白的表达。2.50mg/L oxLDL与THP-1源性巨噬细胞共孵育0h、12h、24h、48h等不同时间,用RT-PCR及Western blotting检测细胞PPAR 8 mRNA和蛋白的表达。
结果：不同浓度oxLDL可诱导THP-1源性巨噬细胞PPAR 8的表达。随着oxLDL浓度的增加,细胞PPAR8的mRNA水平及蛋白表达逐渐增加,差别有显著性,且在浓度为50mg/L时PPAR 8 mRNA的表达达峰值(P<0.05)。而时效试验结果显示50mg/L oxLDL与THP-1源性巨噬细胞孵育孵育24h时,PPARδmRNA水平及蛋白表达增加明显,且差别有统计学意义(P<0.05)。而在孵育48h后,表达较24h时有所减少,但与24h相比差别无统计学意义。
结论：oxLDL可上调THP-1源性巨噬细胞PPARδ的表达
第二部分PPARδ对THP-1源性巨噬细胞增殖、凋亡的影响
目的：通过PPARδ激动剂GW501516活化PPARδ来观察PPARδ在oxLDL诱导THP-1源性巨噬细胞增殖、凋亡中的作用。
方法：THP-1单核细胞经PMA诱导分化成为巨噬细胞后,以50mg/L oxLDL孵育THP-1源性巨噬细胞24h为阳性对照组,50mg/L oxLDL与不同浓度的PPARδ激动剂GW501516 (1、10、100nmol及1μmol)共同孵育THP-1源性巨噬细胞24h,MTT法检测THP-1源性巨噬细胞增殖活性,Hoechst33258染色、Annexin V/PI双染后细胞流式仪检测空白组、oxLDL组及1μmol GW501516组细胞凋亡情况,分光光度法测定细胞内caspase 3活性变化。
结果：PPARδ激动剂GW501516可阻抑oxLDL对THP-1源性巨噬细胞增殖的抑制作用,且能减少oxLDL诱导THP-1源性巨噬细胞的凋亡。MTT及Hoechst33258染色结果显示在GW501516浓度达100nmol时作用显著,且1μmol浓度时作用更明显(P<0.05)。流式分析结果也同样表明1μmol GW501516能显著抑制oxLDL诱导THP-1源性巨噬细胞的凋亡(P<0.05)。分光光度法检测细胞内Caspase 3活性显示GW501516能呈浓度依赖性下调caspase 3的活性(P<0.05)
结论：PPARδ激动剂GW501516可下调caspase 3活性,抑制oxLDL诱导的THP-1源性巨噬细胞凋亡。
第三部分PPARδ对THP-1源性巨噬细胞脂质蓄积的影响
目的：通过PPARδ激动剂GW501516活化PPARδ来观察PPARδ对THP-1源性巨噬细胞脂质蓄积的影响的影响。
方法：THP-1单核细胞经PMA诱导分化成为巨噬细胞后,以50mg/L oxLDL孵育THP-1源性巨噬细胞24h为阳性对照组,50mg/L oxLDL与不同浓度的PPARδ激动剂GW501516 (1、10、100nmol及1μmol)共同孵育THP-1源性巨噬细胞24h,油红O染色观察细胞内脂质蓄积情况,高效液相色谱检测细胞内总胆固醇、和胆固醇酯含量。
结果：PPARδ激动剂GW501516可增加THP-1源性巨噬细胞内脂质蓄积,油红0染色显示100nmol GW501516处理后可见细胞内脂滴颗粒体积明显增大且脂滴数增多,当GW501516浓度达1μmol时作用更为明显(P<0.05)。高效液相色谱检测结果显示阳性对照组总胆固醇含量为483.10±12.70,胆固醇酯/总胆固醇(%)为49.60%。1、10、100nmol和1μmolGW501516处理组总胆固醇含量分别为501.53±15.73,497.69±14.25,647.42±18.62和696.55±20.35；胆固醇酯/总胆固醇(%)分别为56.7%,53.90%,64.48%和66.26%,100nmol和1μmol GW501516组与阳性对照组比较差别有显著性(P<0.05)。
结论：PPARδ激动剂GW501516可增加THP-1源性巨噬细胞内脂质蓄积。
总结：
(1) oxLDL可上调THP-1源性巨噬细胞PPARδ的表达。
(2) PPARδ激动剂GW501516可下调caspase 3活性,抑制oxLDL诱导的THP-1源性巨噬细胞凋亡。
(3) PPARδ激动剂GW501516可增加THP-1源性巨噬细胞内脂质蓄积。
BACKGROUND:PPARδis one of the three isoforms of peroxisome proliferator-activated receptors (PPARs) which is expressed ubiquitously. PPARδcan enhance fatty acid catabolism and energy uncoupling in adipose tissue and muscles, suppress macrophage-induced inflammation, decrease atherosclerosis and is involved in the progression of many diseases. PPARδligands are divided into two kinds, natural ligands and synthetic ligands. GW501516 is a synthetic ligand which belongs to the phenoxy acetic acid derivative. When it binds to PPARδ, PPARδis activated and heterodimers will be formed together with retinoid X receptors (RXRs). The heterodimer binds to peroxisome proliferator response element (PPRE) to modulate transcription and translation of the target genes downstream and regulate biological functions such as controlling weight gain, enhancing physical endurance, and improving insulin sensitivity. We investigated the effect of oxLDL on the PPARδexpression in THP-1 derived macrophage and observed the effect of PPARδagonist GW501516 on macrophage proliferation, apoptosis and foam cells formation.
PartⅠ. Effect of oxLDL on PPARδExpression Induced by oxLDL in THP-1 Derived Macrophages
Objective:To identify the effect of oxLDL on PPARδexpression in THP-1-derived macrophages.
Method:1. THP-1 derived macrophages were incubated with different concentrations (0 mg/L,25 mg/L,50 mg/L,100 mg/L) of oxLDL for 24 hours. RT-PCR and Western blotting were applied to detect PPAR 8 mRNA and protein expression, respectively.2. THP-1 derived macrophages were treated with 50mg/L oxLDL in different time (Ohour, 12 hours,24 hours h,48 hours). RT-PCR and Western blotting were used to detect PPARδmRNA and protein expression in cells
Results:Different concentrations of oxLDL increased the mRNA and protein expression of PPARδgene in THP-1 derived macrophage. With increasing in the concentration of oxLDL the mRNA and protein expression of PPARδwas gradually increased with statistical significance At the concentration of 50mg/L oxLDL the expression level of PPARδmRNA was peaked (P<0.05). The time-course experiments showed that after 50mg/L oxLDL incubation with THP-1 derived macrophages for 24 hours, the expression levels of PPARδboth mRNA and protein significantluy increased, (P<0.05). In the time duration of 48 hours incubation, the expression of PPARδdecreased, but there was no significant difference compared to that in 24 hours.
Conclusions:oxLDL may increase THP-1 derived macrophages PPARδexpression.
PartⅡ. Effect of PPARδAgonist GW501516 on Oxidized LDL-induced Cell Proliferation and Apoptosis of THP-1 Derived Macrophages
Objective:To explore the effect of PPARδagonist GW501516 on proliferation and apoptosis induced by oxLDL in THP-1 derived macrophages.
Methods:THP-1 monocytes were stimulated with PMA to differentiate into macrophage. Then the cells were incubated with 50mg/L oxLDL for 24 hours, also designed as the positive control group. Other groups were co-incubated 50mg/L of oxLDL and different concentrations of PPARδagonists GW501516 (1,10, 100nmol and 1μmol, respectively) for 24h. MTT assay was used to determine THP-1 derived macrophage proliferation activity. The dye Hoechst33258 staining, Annexin V/PI double staining and flow cytometer were applied to detect cell apoptosis in control group, oxLDL group and lumol GW501516 group of cells, Spectrophotometry determined caspase 3 activity in cells.
Results:PPARδagonist GW501516 down-regulated oxLDL inhibition effect on proliferation of THP-1 derived macrophage, and reduced the oxLDL-induced THP-1 derived macrophage apoptosis. MTT and Hoechst33258 staining results showed that 100nmol GW501516 was effective and in 1μmol such effect was more significantly (P <0.05). Flow cytometry analysis results also showed that 1μmol GW501516 significantly inhibited oxLDL-induced THP-1 derived macrophage apoptosis (P<0.05). Spectrophotometry results showed GW501516 reduced the activity of apoptotic executive enzyme, caspase 3, in a concentration-dependent manner (P<0.05).
Conclusion:PPAR 8 activation may reduce the activity of caspase 3 and inhibit oxLDL induced apoptosis of THP-1 derived macrophage.
PartⅢ. Effect of PPARδAgonist GW501516 on lipid accumulation in THP-1 Derived Macrophages
Objective:To observe the effect of PPARδagonist GW501516 on the lipid accumulation in THP-1 derived macrophage induced by treatment of oxidized LDL.
Methods:THP-1 derived macrophages were from monocytes pretreated with PMA. Then, THP-1-derived macrophages were incubated with 50mg/L of oxLDL for 24 hours, that was assigned as the positive control. In other experiments, the cells were co-incubated with 50mg/L of oxLDL and different concentrations of PPARδagonists GW501516 (1,10,100 nmol and 1μmol, respectively) for same time as in control. The harvested cells were stained with oil red to show the lipid droplets under microscope. High performancel iquid chromatography (HPLC) was applied to analyze and evaluate the contents of intracellular cholesterol and cholestryl ester.
Results:Oil red O staining showed that PPARδagonist GW501516 increased lipid accumulation in THP-1 derived macrophages. 100nmol of GW501516 significantly increased intracellular lipid droplets both in size and in number (P<0.05). HPLC data demonstrated that the contents of cholesterol and cholesteryl ester in cells were also significantly increased. the data showed in positive group, total cholesterol was 483.10±12.70, cholesterol ester/total cholesterol(%) was 49.60%, and in 1,10,100 nmol and 1μmol GW501516 treatment groups, the total cholesterol levels were 501.53±15.73, 497.69±14.25,647.42±18.62 and 696.55±20.35 respectively; cholesterol ester/total cholesterol(%)respectively,56.7%,53.90%,64.48% and 66.26%. The cholesterol ester/total cholesterol(%) in 100nmol and 1μmol GW501516 group were both significantly increased compared with the positive control group (P<0.05)
Conclusion:PPARδagonist GW501516 increases the THP-1 derived macrophage lipid accumulation.
Summary
(1) oxLDL may up-regulate both mRNA and protein expression in THP-1 derived macrophages.
(2) PPARδagonist GW501516 may inhibit oxLDL-induced cell apoptosis of THP-1 derived macrophages, and reduce the activity of caspase 3.
(3) PPARδagonist GW501516 may increase the lipid accumulation of THP-1 derived macrophages.
第一部分oxLDL对THP-1源性巨噬细胞PPARδ表达的影响
目的：观察oxLDL对THP-1源性巨噬细胞PPAR 8表达的影响。
方法：1.用不同浓度(0mg/L、25mg/L、50mg/L、100mg/L)的oxLDL与THP-1源性巨噬细胞共孵育24小时；用RT-PCR及Western blotting检测细胞PPARδmRNA和蛋白的表达。2.50mg/L oxLDL与THP-1源性巨噬细胞共孵育0h、12h、24h、48h等不同时间,用RT-PCR及Western blotting检测细胞PPAR 8 mRNA和蛋白的表达。
结果：不同浓度oxLDL可诱导THP-1源性巨噬细胞PPAR 8的表达。随着oxLDL浓度的增加,细胞PPAR8的mRNA水平及蛋白表达逐渐增加,差别有显著性,且在浓度为50mg/L时PPAR 8 mRNA的表达达峰值(P<0.05)。而时效试验结果显示50mg/L oxLDL与THP-1源性巨噬细胞孵育孵育24h时,PPARδmRNA水平及蛋白表达增加明显,且差别有统计学意义(P<0.05)。而在孵育48h后,表达较24h时有所减少,但与24h相比差别无统计学意义。
结论：oxLDL可上调THP-1源性巨噬细胞PPARδ的表达
第二部分PPARδ对THP-1源性巨噬细胞增殖、凋亡的影响
目的：通过PPARδ激动剂GW501516活化PPARδ来观察PPARδ在oxLDL诱导THP-1源性巨噬细胞增殖、凋亡中的作用。
方法：THP-1单核细胞经PMA诱导分化成为巨噬细胞后,以50mg/L oxLDL孵育THP-1源性巨噬细胞24h为阳性对照组,50mg/L oxLDL与不同浓度的PPARδ激动剂GW501516 (1、10、100nmol及1μmol)共同孵育THP-1源性巨噬细胞24h,MTT法检测THP-1源性巨噬细胞增殖活性,Hoechst33258染色、Annexin V/PI双染后细胞流式仪检测空白组、oxLDL组及1μmol GW501516组细胞凋亡情况,分光光度法测定细胞内caspase 3活性变化。
结果：PPARδ激动剂GW501516可阻抑oxLDL对THP-1源性巨噬细胞增殖的抑制作用,且能减少oxLDL诱导THP-1源性巨噬细胞的凋亡。MTT及Hoechst33258染色结果显示在GW501516浓度达100nmol时作用显著,且1μmol浓度时作用更明显(P<0.05)。流式分析结果也同样表明1μmol GW501516能显著抑制oxLDL诱导THP-1源性巨噬细胞的凋亡(P<0.05)。分光光度法检测细胞内Caspase 3活性显示GW501516能呈浓度依赖性下调caspase 3的活性(P<0.05)
结论：PPARδ激动剂GW501516可下调caspase 3活性,抑制oxLDL诱导的THP-1源性巨噬细胞凋亡。
第三部分PPARδ对THP-1源性巨噬细胞脂质蓄积的影响
目的：通过PPARδ激动剂GW501516活化PPARδ来观察PPARδ对THP-1源性巨噬细胞脂质蓄积的影响的影响。
方法：THP-1单核细胞经PMA诱导分化成为巨噬细胞后,以50mg/L oxLDL孵育THP-1源性巨噬细胞24h为阳性对照组,50mg/L oxLDL与不同浓度的PPARδ激动剂GW501516 (1、10、100nmol及1μmol)共同孵育THP-1源性巨噬细胞24h,油红O染色观察细胞内脂质蓄积情况,高效液相色谱检测细胞内总胆固醇、和胆固醇酯含量。
结果：PPARδ激动剂GW501516可增加THP-1源性巨噬细胞内脂质蓄积,油红0染色显示100nmol GW501516处理后可见细胞内脂滴颗粒体积明显增大且脂滴数增多,当GW501516浓度达1μmol时作用更为明显(P<0.05)。高效液相色谱检测结果显示阳性对照组总胆固醇含量为483.10±12.70,胆固醇酯/总胆固醇(%)为49.60%。1、10、100nmol和1μmolGW501516处理组总胆固醇含量分别为501.53±15.73,497.69±14.25,647.42±18.62和696.55±20.35；胆固醇酯/总胆固醇(%)分别为56.7%,53.90%,64.48%和66.26%,100nmol和1μmol GW501516组与阳性对照组比较差别有显著性(P<0.05)。
结论：PPARδ激动剂GW501516可增加THP-1源性巨噬细胞内脂质蓄积。
总结：
(1) oxLDL可上调THP-1源性巨噬细胞PPARδ的表达。
(2) PPARδ激动剂GW501516可下调caspase 3活性,抑制oxLDL诱导的THP-1源性巨噬细胞凋亡。
(3) PPARδ激动剂GW501516可增加THP-1源性巨噬细胞内脂质蓄积。
BACKGROUND:PPARδis one of the three isoforms of peroxisome proliferator-activated receptors (PPARs) which is expressed ubiquitously. PPARδcan enhance fatty acid catabolism and energy uncoupling in adipose tissue and muscles, suppress macrophage-induced inflammation, decrease atherosclerosis and is involved in the progression of many diseases. PPARδligands are divided into two kinds, natural ligands and synthetic ligands. GW501516 is a synthetic ligand which belongs to the phenoxy acetic acid derivative. When it binds to PPARδ, PPARδis activated and heterodimers will be formed together with retinoid X receptors (RXRs). The heterodimer binds to peroxisome proliferator response element (PPRE) to modulate transcription and translation of the target genes downstream and regulate biological functions such as controlling weight gain, enhancing physical endurance, and improving insulin sensitivity. We investigated the effect of oxLDL on the PPARδexpression in THP-1 derived macrophage and observed the effect of PPARδagonist GW501516 on macrophage proliferation, apoptosis and foam cells formation.
PartⅠ. Effect of oxLDL on PPARδExpression Induced by oxLDL in THP-1 Derived Macrophages
Objective:To identify the effect of oxLDL on PPARδexpression in THP-1-derived macrophages.
Method:1. THP-1 derived macrophages were incubated with different concentrations (0 mg/L,25 mg/L,50 mg/L,100 mg/L) of oxLDL for 24 hours. RT-PCR and Western blotting were applied to detect PPAR 8 mRNA and protein expression, respectively.2. THP-1 derived macrophages were treated with 50mg/L oxLDL in different time (Ohour, 12 hours,24 hours h,48 hours). RT-PCR and Western blotting were used to detect PPARδmRNA and protein expression in cells
Results:Different concentrations of oxLDL increased the mRNA and protein expression of PPARδgene in THP-1 derived macrophage. With increasing in the concentration of oxLDL the mRNA and protein expression of PPARδwas gradually increased with statistical significance At the concentration of 50mg/L oxLDL the expression level of PPARδmRNA was peaked (P<0.05). The time-course experiments showed that after 50mg/L oxLDL incubation with THP-1 derived macrophages for 24 hours, the expression levels of PPARδboth mRNA and protein significantluy increased, (P<0.05). In the time duration of 48 hours incubation, the expression of PPARδdecreased, but there was no significant difference compared to that in 24 hours.
Conclusions:oxLDL may increase THP-1 derived macrophages PPARδexpression.
PartⅡ. Effect of PPARδAgonist GW501516 on Oxidized LDL-induced Cell Proliferation and Apoptosis of THP-1 Derived Macrophages
Objective:To explore the effect of PPARδagonist GW501516 on proliferation and apoptosis induced by oxLDL in THP-1 derived macrophages.
Methods:THP-1 monocytes were stimulated with PMA to differentiate into macrophage. Then the cells were incubated with 50mg/L oxLDL for 24 hours, also designed as the positive control group. Other groups were co-incubated 50mg/L of oxLDL and different concentrations of PPARδagonists GW501516 (1,10, 100nmol and 1μmol, respectively) for 24h. MTT assay was used to determine THP-1 derived macrophage proliferation activity. The dye Hoechst33258 staining, Annexin V/PI double staining and flow cytometer were applied to detect cell apoptosis in control group, oxLDL group and lumol GW501516 group of cells, Spectrophotometry determined caspase 3 activity in cells.
Results:PPARδagonist GW501516 down-regulated oxLDL inhibition effect on proliferation of THP-1 derived macrophage, and reduced the oxLDL-induced THP-1 derived macrophage apoptosis. MTT and Hoechst33258 staining results showed that 100nmol GW501516 was effective and in 1μmol such effect was more significantly (P <0.05). Flow cytometry analysis results also showed that 1μmol GW501516 significantly inhibited oxLDL-induced THP-1 derived macrophage apoptosis (P<0.05). Spectrophotometry results showed GW501516 reduced the activity of apoptotic executive enzyme, caspase 3, in a concentration-dependent manner (P<0.05).
Conclusion:PPAR 8 activation may reduce the activity of caspase 3 and inhibit oxLDL induced apoptosis of THP-1 derived macrophage.
PartⅢ. Effect of PPARδAgonist GW501516 on lipid accumulation in THP-1 Derived Macrophages
Objective:To observe the effect of PPARδagonist GW501516 on the lipid accumulation in THP-1 derived macrophage induced by treatment of oxidized LDL.
Methods:THP-1 derived macrophages were from monocytes pretreated with PMA. Then, THP-1-derived macrophages were incubated with 50mg/L of oxLDL for 24 hours, that was assigned as the positive control. In other experiments, the cells were co-incubated with 50mg/L of oxLDL and different concentrations of PPARδagonists GW501516 (1,10,100 nmol and 1μmol, respectively) for same time as in control. The harvested cells were stained with oil red to show the lipid droplets under microscope. High performancel iquid chromatography (HPLC) was applied to analyze and evaluate the contents of intracellular cholesterol and cholestryl ester.
Results:Oil red O staining showed that PPARδagonist GW501516 increased lipid accumulation in THP-1 derived macrophages. 100nmol of GW501516 significantly increased intracellular lipid droplets both in size and in number (P<0.05). HPLC data demonstrated that the contents of cholesterol and cholesteryl ester in cells were also significantly increased. the data showed in positive group, total cholesterol was 483.10±12.70, cholesterol ester/total cholesterol(%) was 49.60%, and in 1,10,100 nmol and 1μmol GW501516 treatment groups, the total cholesterol levels were 501.53±15.73, 497.69±14.25,647.42±18.62 and 696.55±20.35 respectively; cholesterol ester/total cholesterol(%)respectively,56.7%,53.90%,64.48% and 66.26%. The cholesterol ester/total cholesterol(%) in 100nmol and 1μmol GW501516 group were both significantly increased compared with the positive control group (P<0.05)
Conclusion:PPARδagonist GW501516 increases the THP-1 derived macrophage lipid accumulation.
Summary
(1) oxLDL may up-regulate both mRNA and protein expression in THP-1 derived macrophages.
(2) PPARδagonist GW501516 may inhibit oxLDL-induced cell apoptosis of THP-1 derived macrophages, and reduce the activity of caspase 3.
(3) PPARδagonist GW501516 may increase the lipid accumulation of THP-1 derived macrophages.
引文
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[5]Yoshikawa T, Brkanac Z, Barbara R, Xing GQ, Leach RJ, Detera-Wadleigh SD. Assignment of the Human Nuclear Hormone Receptor, NUC1 (PPARD), to Chromosome 6p21.1-p21.2. Genomics,1996; 35:637-638.
[6]Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators[J]. Nature,1990,347(6294):645-650.
[7]Xu HE, LambertMH, Valerie G, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA, Milburn MV. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell,1999; 3 (3):397-403.
[8]Krey G, Braissant O, L'Horset F, Kalkhoven E, Perroud M, Parker MG, Wahli W. Fatty acid, eicosanoids, and hypolip idemic agents identified as ligands of peroxisome proliferator activated receptors by coactivator dependent receptor ligand assay. Mol Endocrinol,1997; 11(6):779-791.
[9]SznaidmanML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, Lambert MH, Willson TM, Oliver WR Jr, Sternbach DD. Novel selective small molecule agonists for peroxisome proliferator -activated receptor8 (PPAR8) synthesis and biological activity. Bioorg Med Chem Lett,2003; 13 (9):1517-1521.
[10]常永生,方福德.PPARγ----节俭基因的主控基因[J].中国医学科学院学报.2002(3)：315-32
[11]Sprecher DL, Massien C, Pearce G, Billin AN, Perlstein I, Willson TM, Hassall DG, Patterson SD, Lobe DC, Johnson TG. Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor δ Agonist. Arterioscler Thromb Vasc Biol,2007; 27:359-365.
[12]Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Keio J Med.2004,53(2):53-58
[13]Muoio DM, MacLean PS, Lang DB, et al. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. Biol.Chem 2002,277(29):26089-26097.
[14]Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM. Peroxisome proliferator-activated receptor 8 activates fat metabolism to prevent obesity. Cell, 2003;113:159-170.
[15]Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, Muscat GE. The peroxisome proliferator-activated receptor β/δ agonist,GW501516, regulates the expression of genes involved in lipid Catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol,2003; 2477-2493.
[16]Holst D, Luquet S, Nogueira V, Kristiansen K, Leverve X, Grimaldi PA. Nutritional regulation and role of peroxisome proliferator-activated receptor δ in fatty acid catabolism in skeletal muscle[J]. Biochim Biophys Acta 2003;1633(1):43-50.
[17]Tanaka T, Yamamoto J, Iwasaki S et al.Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome[J]. Proc Natl Acad Sci USA,2003,100(26):15924-15929
[18]Wang YX, Zhang CL, Yu RT et al. Regulation of muscle fiber type and running endurance by PPARδ[J]. PLOS Biol.2004;2(10):e294
[19]Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM, Gonzalez FJ, Ham J, Kang H, Peters JM, Evans RM. PPARδ regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci,2006; 103:3444-3449.
[20]Hu C, Jia W, Fang Q, Zhang R, Wang C, Lu J and Xiang K. Peroxisome proliferator-activated receptor (PPAR)delta genetic polymorphism and its association with insulin resistance index and fasting plasma glucose concentrations in Chinese subjects Diabet. Med,2006; 23:1307-1312.
[21]Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM, Curtiss LK. Transcriptional repression of atherogenic inflammation:modulation by PPARdelta. Science.2003; 302 (5644):453-457
[22]Han J, Hajjar DP, Febbraio M, et al. Native and modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor, CD36. J Biol Chem.1997; 272:21654-21659.
[23]董军,陈文祥,李健斋.高效液相色谱测定微量胆固醇氧化产物.生物化学与生物物理进展.1996；23：179-182.
[24]王娜,张志文.PPARγ调节与糖脂代谢。BMBOReports,2004,5:142-147
[25]张芳芳.RXR,CAR,和PRAR对UGT基因转录的调节.国外医学分册.2005.2：99-103
[26]姜鹏,王建春,钱桂生.过氧化物酶增殖物激活受体与炎症及免疫反应.生命的化学.学2005.3：232-236
[27]Han J, Zhou X, Yokoyama T, et al. Pitavastatin downregulates expression of the macrophage type B scavenger receptor, CD36. Circulation.2004.17:790-796.
[28]Umetani N, Kanayama Y, Okamura M, et al.Lovastatin inhibits gene expression of type-Ⅰ scavenger receptor in THP-1 human macrophages. Biochim Biophys Acta. 1996;1303:199-206.
[29]Hrboticky N, Draude G, Hapfelmeier G,et al. Oxidized LDLs in human blood monocytes during the early stage of differentiation into macrophages. Arterioscler Thromb Vasc Biol.19:1267-1275.
[30]Chinetti G, Lestavel S, Bocher V, et al. PPAR-alpha and PPARgamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med.2001;7:53-58.
[31]柴欣楼,王伟,张永生.血清药漏芦对ox2LDL诱导U937细胞形成泡沫细胞过程中PPARγ表达的影响.北京中医药大学学报.2005,28(5)：41-43.
[32]Gupta RA, Sarraf P,Mueller E, et al. Peroxisome proliferator-activated receptorymediated differentiation [J]. J Biol Chem,2003,278 (25):22669-22677
[33]Fuhrman B, Koren L, Volkova N, et al. Atorvastatin therapy in hypercholesterolomic patients suppresses cellular uptake of oxidized-LDL by differentiating monocytes. Atherosclerosis.2002; 164:179-185.
[34]Nieholson AC, Hajjar DP. CD36, oxidized LDL and PAPR gamma:Pathological interactions in macrophages and atheroselerosis. Vasc Pharmacol.2004;41:139-146.
[35]Colles SM, Maxson JM, Carlson SG, Chisolm GM. Oxidized LDL indueed injury and apoptosis in atheroselerosis. Potential roles for oxysterols. Trends Cardiovasc Med.2001;11:131-138.
[36]Martinet W, Koekx MM. Apoptosis in atherosclerosis:focus on oxidized lipids and inflammation. Curr Opin Lipidol.2001:12:535-541.
[37]Panini SR, Sinensky MS. Mechanisms of oxysteorl-induced apoptosis. Curr Opin Lipidol.2001;12:529-533.
[38]Salvayre R, Auge N, Benoist H, Negre-Salvayre A. Oxidized low-density lipoprotein-indueed apoptosis. Biochim Biophys Aeta.2002;1585:213-221.
[39]杨永宗,阮长耿,唐朝枢等.动脉粥样硬化性心血管病基础与临床[M].北京科学出版社,第一版,609.
[40]Akiyama T E,Lambert G,Nicol C J,et al.Proliferator-activated receptor β/δ regulates very low density lipoprotein production and catabolism in mice on a western diet[J].J Biol Chem,2004,179(20):20874-20881.
[41]Oliver WR, Shenk JL, Snaith MR et al. A selective peroxisome proliferator- acti-veted receptor 8 agonist promotes reverse cholesterol transport[J]. Proc Natl Acad Sci USA.2001;98(9):5306-5311
[42]Wallace JM, Schwarz M, Coward P et al. Effects of peroxisome proliferator-activated receptor a/8 agonists on HDLcholesterol in monkeys[J]. J Lipid Res 2005;46(5):1009-1016.
[43]Vosper H, Patel L,Graham TL, et al.The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages[J]. J. Biol. Chem.2001; 276(47):44258-44265.
[1]Steiner G. A new perspective in the treatment of dyslipidemia:can fenofibrate offer unique benefits in the treatment of type 2 diabetes mellitus? Treat Endocrinol 2005; 4:311-7.
[2]DRUGDEX evaluations. Gemfibrozil. Greenwood Village, CO:Thomson Micromedex Healthcare Series (accessed 2007 Mar 16).
[3]DRUGDEX evaluations. Fenofibrate. Greenwood Village, CO:Thomson Micromedex Healthcare Series (accessed 2007 Mar 16).
[4]Irons BK, Greene RS, Mazzolini TA, Edwards KL, Sleeper RB. Implications of rosiglitazone and pioglitazone on cardiovascular risk in patients with type 2 diabetes mellitus. Pharmacotherapy 2006;26:168-81.
[5]Steiner G. Fibrates and coronary risk reduction. Atherosclerosis 2005; 182:199-207.
[6]Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-8.
[7]Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.
[8]Waugh J, Keating GM, Plosker GL, Easthope S, Robinson DM. Pioglitazone:a review of its use in type 2 diabetes mellitus. Drugs 2006;66:85-109.
[9]Patel C, Wyne KL, McGuire DK. Thiazolidinediones, peripheral oedema and congestive heart failure:what is the evidence? Diab Vasc Dis Res 2005;2:61-6.
[10]Chiquette E, Ramirez G, Defronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med 2004; 164: 2097-104.
[11]Kendall DM. Thiazolidinediones:the case for early use. Diabetes Care 2006;29: 154-7.
[12]Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796-803.
[13]Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose:a randomised controlled trial. Lancet 2006;368:1096-105.
[14]Savkur RS, Miller AR. Investigational PPAR-gamma agonists for the treatment of type 2 diabetes. Expert Opin Investig Drugs 2006; 15:763-78.
[15]National Institutes of Health. Safety and efficacy study of metaglidasen in type 2 diabetes in patients suboptimally controlled on insulin. www.clinicaltrials.gov/ct/show/NCT00353587;jsessionid B776AE684FD8C21A0CA8D1655CFEF19D?order=1(accessed 2007 Mar 16).
[16]Rosenstock J, Flores-Lozano F, Schwartz S, Gonzalex-Galves G, Karpf DB. MBX-102:a novel non-TZD insulin sensitizer that improves glycemic control without causing edema or weight gain in patients with type 2 diabetes (T2DM) on concomitant insulin therapy (abstract 44-OR). Diabetes 2005;54(suppl 1):A11.
[17]National Institutes of Health. GW501516 in subjects who have low level of high-density lipoprotein cholesterol. www.clinicaltrials.gov/ct/gui/ show/NCT00158899.(accessed 2007 Mar 16).
[18]Endocrinologic and Metabolic Drugs Advisory Committee FAC. September 9,2005, briefing information—pargluva (muraglitazar) briefing information. www.fda.gov/ohrms/dockets/ac/cder05. html#Endocrinologic Metabolic (accessed 2007 Mar 16).
[19]Saad MF, Greco S, Osei K, et al. Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects:a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care 2004;27:1324-9.
[20]Goldstein BJ, Rosenstock J, Anzalone D, Tou C, Ohman KP. Effect of tesaglitazar, a dual PPAR alpha/gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes:a 12-week dose-ranging trial. Curr Med Res Opin 2006;22:2575-90.
[21]Fagerberg B, Edwards S, Halmos T, et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 2005;48:1716-25.
[22]Artis R, Bollag G, Ibrahim P, et al. A novel PPAR pan-modulator improves lipid and glucose homeostasis in insulin resistant and diabetic mouse models (abstract 2074-PO). Diabetes 2006;55(suppl 1):A480.
[23]Ortmeyer HK, Collins CA, Minnick DT, et al. A novel PPAR pan-modulator improves lipid and glucose homeostasis in insulin resistant and diabetic mouse models (abstract 666-P). Diabetes 2004;52(suppl 2):A159.
[24]Upton R, Widdowson PS, Ishii S, Tanaka H, Williams G. Improved metabolic status and insulin sensitivity in obese fatty (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats treated with the thiazolidinedione, MCC-555. Br J Pharmacol 1998;125:1708-14.
[25]Pickavance LC, Widdowson PS, Foster JR, Williams G, Wilding JP. Chronic treatment with the thiazolidinedione, MCC-555, is associated with reductions in nitric oxide synthase activity and beta-cell apoptosis in the pancreas of the Zucker Diabetic Fatty rat. Int J Exp Pathol 2003; 84:83-9.
[2]Anderson JL, Muhlestein JB, Carlquist J. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for chlamydia pneumoniae infection. Circulation,1999; 99:1540-1547.
[3]Libby P, Geng Y J, Aikawa M, et al. Macrophage and atherosclerotic plaque stability. Curr Opin Lipidol,1996,7(5):330～335
[4]Boyle J J. Macrophage activation in atherosclerosis:pathogenesis and pharmacology of plaque rupture. Curr Vasc Pharmacol,2005,3(1):63-68。
[5]Yoshikawa T, Brkanac Z, Barbara R, Xing GQ, Leach RJ, Detera-Wadleigh SD. Assignment of the Human Nuclear Hormone Receptor, NUC1 (PPARD), to Chromosome 6p21.1-p21.2. Genomics,1996; 35:637-638.
[6]Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators[J]. Nature,1990,347(6294):645-650.
[7]Xu HE, LambertMH, Valerie G, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA, Milburn MV. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell,1999; 3 (3):397-403.
[8]Krey G, Braissant O, L'Horset F, Kalkhoven E, Perroud M, Parker MG, Wahli W. Fatty acid, eicosanoids, and hypolip idemic agents identified as ligands of peroxisome proliferator activated receptors by coactivator dependent receptor ligand assay. Mol Endocrinol,1997; 11(6):779-791.
[9]SznaidmanML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, Lambert MH, Willson TM, Oliver WR Jr, Sternbach DD. Novel selective small molecule agonists for peroxisome proliferator -activated receptor8 (PPAR8) synthesis and biological activity. Bioorg Med Chem Lett,2003; 13 (9):1517-1521.
[10]常永生,方福德.PPARγ----节俭基因的主控基因[J].中国医学科学院学报.2002(3)：315-32
[11]Sprecher DL, Massien C, Pearce G, Billin AN, Perlstein I, Willson TM, Hassall DG, Patterson SD, Lobe DC, Johnson TG. Triglyceride:High-Density Lipoprotein Cholesterol Effects in Healthy Subjects Administered a Peroxisome Proliferator Activated Receptor δ Agonist. Arterioscler Thromb Vasc Biol,2007; 27:359-365.
[12]Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Keio J Med.2004,53(2):53-58
[13]Muoio DM, MacLean PS, Lang DB, et al. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. Biol.Chem 2002,277(29):26089-26097.
[14]Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM. Peroxisome proliferator-activated receptor 8 activates fat metabolism to prevent obesity. Cell, 2003;113:159-170.
[15]Dressel U, Allen TL, Pippal JB, Rohde PR, Lau P, Muscat GE. The peroxisome proliferator-activated receptor β/δ agonist,GW501516, regulates the expression of genes involved in lipid Catabolism and energy uncoupling in skeletal muscle cells. Mol Endocrinol,2003; 2477-2493.
[16]Holst D, Luquet S, Nogueira V, Kristiansen K, Leverve X, Grimaldi PA. Nutritional regulation and role of peroxisome proliferator-activated receptor δ in fatty acid catabolism in skeletal muscle[J]. Biochim Biophys Acta 2003;1633(1):43-50.
[17]Tanaka T, Yamamoto J, Iwasaki S et al.Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome[J]. Proc Natl Acad Sci USA,2003,100(26):15924-15929
[18]Wang YX, Zhang CL, Yu RT et al. Regulation of muscle fiber type and running endurance by PPARδ[J]. PLOS Biol.2004;2(10):e294
[19]Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM, Gonzalez FJ, Ham J, Kang H, Peters JM, Evans RM. PPARδ regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci,2006; 103:3444-3449.
[20]Hu C, Jia W, Fang Q, Zhang R, Wang C, Lu J and Xiang K. Peroxisome proliferator-activated receptor (PPAR)delta genetic polymorphism and its association with insulin resistance index and fasting plasma glucose concentrations in Chinese subjects Diabet. Med,2006; 23:1307-1312.
[21]Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM, Curtiss LK. Transcriptional repression of atherogenic inflammation:modulation by PPARdelta. Science.2003; 302 (5644):453-457
[22]Han J, Hajjar DP, Febbraio M, et al. Native and modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor, CD36. J Biol Chem.1997; 272:21654-21659.
[23]董军,陈文祥,李健斋.高效液相色谱测定微量胆固醇氧化产物.生物化学与生物物理进展.1996；23：179-182.
[24]王娜,张志文.PPARγ调节与糖脂代谢。BMBOReports,2004,5:142-147
[25]张芳芳.RXR,CAR,和PRAR对UGT基因转录的调节.国外医学分册.2005.2：99-103
[26]姜鹏,王建春,钱桂生.过氧化物酶增殖物激活受体与炎症及免疫反应.生命的化学.学2005.3：232-236
[27]Han J, Zhou X, Yokoyama T, et al. Pitavastatin downregulates expression of the macrophage type B scavenger receptor, CD36. Circulation.2004.17:790-796.
[28]Umetani N, Kanayama Y, Okamura M, et al.Lovastatin inhibits gene expression of type-Ⅰ scavenger receptor in THP-1 human macrophages. Biochim Biophys Acta. 1996;1303:199-206.
[29]Hrboticky N, Draude G, Hapfelmeier G,et al. Oxidized LDLs in human blood monocytes during the early stage of differentiation into macrophages. Arterioscler Thromb Vasc Biol.19:1267-1275.
[30]Chinetti G, Lestavel S, Bocher V, et al. PPAR-alpha and PPARgamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med.2001;7:53-58.
[31]柴欣楼,王伟,张永生.血清药漏芦对ox2LDL诱导U937细胞形成泡沫细胞过程中PPARγ表达的影响.北京中医药大学学报.2005,28(5)：41-43.
[32]Gupta RA, Sarraf P,Mueller E, et al. Peroxisome proliferator-activated receptorymediated differentiation [J]. J Biol Chem,2003,278 (25):22669-22677
[33]Fuhrman B, Koren L, Volkova N, et al. Atorvastatin therapy in hypercholesterolomic patients suppresses cellular uptake of oxidized-LDL by differentiating monocytes. Atherosclerosis.2002; 164:179-185.
[34]Nieholson AC, Hajjar DP. CD36, oxidized LDL and PAPR gamma:Pathological interactions in macrophages and atheroselerosis. Vasc Pharmacol.2004;41:139-146.
[35]Colles SM, Maxson JM, Carlson SG, Chisolm GM. Oxidized LDL indueed injury and apoptosis in atheroselerosis. Potential roles for oxysterols. Trends Cardiovasc Med.2001;11:131-138.
[36]Martinet W, Koekx MM. Apoptosis in atherosclerosis:focus on oxidized lipids and inflammation. Curr Opin Lipidol.2001:12:535-541.
[37]Panini SR, Sinensky MS. Mechanisms of oxysteorl-induced apoptosis. Curr Opin Lipidol.2001;12:529-533.
[38]Salvayre R, Auge N, Benoist H, Negre-Salvayre A. Oxidized low-density lipoprotein-indueed apoptosis. Biochim Biophys Aeta.2002;1585:213-221.
[39]杨永宗,阮长耿,唐朝枢等.动脉粥样硬化性心血管病基础与临床[M].北京科学出版社,第一版,609.
[40]Akiyama T E,Lambert G,Nicol C J,et al.Proliferator-activated receptor β/δ regulates very low density lipoprotein production and catabolism in mice on a western diet[J].J Biol Chem,2004,179(20):20874-20881.
[41]Oliver WR, Shenk JL, Snaith MR et al. A selective peroxisome proliferator- acti-veted receptor 8 agonist promotes reverse cholesterol transport[J]. Proc Natl Acad Sci USA.2001;98(9):5306-5311
[42]Wallace JM, Schwarz M, Coward P et al. Effects of peroxisome proliferator-activated receptor a/8 agonists on HDLcholesterol in monkeys[J]. J Lipid Res 2005;46(5):1009-1016.
[43]Vosper H, Patel L,Graham TL, et al.The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages[J]. J. Biol. Chem.2001; 276(47):44258-44265.
[1]Steiner G. A new perspective in the treatment of dyslipidemia:can fenofibrate offer unique benefits in the treatment of type 2 diabetes mellitus? Treat Endocrinol 2005; 4:311-7.
[2]DRUGDEX evaluations. Gemfibrozil. Greenwood Village, CO:Thomson Micromedex Healthcare Series (accessed 2007 Mar 16).
[3]DRUGDEX evaluations. Fenofibrate. Greenwood Village, CO:Thomson Micromedex Healthcare Series (accessed 2007 Mar 16).
[4]Irons BK, Greene RS, Mazzolini TA, Edwards KL, Sleeper RB. Implications of rosiglitazone and pioglitazone on cardiovascular risk in patients with type 2 diabetes mellitus. Pharmacotherapy 2006;26:168-81.
[5]Steiner G. Fibrates and coronary risk reduction. Atherosclerosis 2005; 182:199-207.
[6]Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-8.
[7]Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.
[8]Waugh J, Keating GM, Plosker GL, Easthope S, Robinson DM. Pioglitazone:a review of its use in type 2 diabetes mellitus. Drugs 2006;66:85-109.
[9]Patel C, Wyne KL, McGuire DK. Thiazolidinediones, peripheral oedema and congestive heart failure:what is the evidence? Diab Vasc Dis Res 2005;2:61-6.
[10]Chiquette E, Ramirez G, Defronzo R. A meta-analysis comparing the effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med 2004; 164: 2097-104.
[11]Kendall DM. Thiazolidinediones:the case for early use. Diabetes Care 2006;29: 154-7.
[12]Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796-803.
[13]Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose:a randomised controlled trial. Lancet 2006;368:1096-105.
[14]Savkur RS, Miller AR. Investigational PPAR-gamma agonists for the treatment of type 2 diabetes. Expert Opin Investig Drugs 2006; 15:763-78.
[15]National Institutes of Health. Safety and efficacy study of metaglidasen in type 2 diabetes in patients suboptimally controlled on insulin. www.clinicaltrials.gov/ct/show/NCT00353587;jsessionid B776AE684FD8C21A0CA8D1655CFEF19D?order=1(accessed 2007 Mar 16).
[16]Rosenstock J, Flores-Lozano F, Schwartz S, Gonzalex-Galves G, Karpf DB. MBX-102:a novel non-TZD insulin sensitizer that improves glycemic control without causing edema or weight gain in patients with type 2 diabetes (T2DM) on concomitant insulin therapy (abstract 44-OR). Diabetes 2005;54(suppl 1):A11.
[17]National Institutes of Health. GW501516 in subjects who have low level of high-density lipoprotein cholesterol. www.clinicaltrials.gov/ct/gui/ show/NCT00158899.(accessed 2007 Mar 16).
[18]Endocrinologic and Metabolic Drugs Advisory Committee FAC. September 9,2005, briefing information—pargluva (muraglitazar) briefing information. www.fda.gov/ohrms/dockets/ac/cder05. html#Endocrinologic Metabolic (accessed 2007 Mar 16).
[19]Saad MF, Greco S, Osei K, et al. Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects:a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care 2004;27:1324-9.
[20]Goldstein BJ, Rosenstock J, Anzalone D, Tou C, Ohman KP. Effect of tesaglitazar, a dual PPAR alpha/gamma agonist, on glucose and lipid abnormalities in patients with type 2 diabetes:a 12-week dose-ranging trial. Curr Med Res Opin 2006;22:2575-90.
[21]Fagerberg B, Edwards S, Halmos T, et al. Tesaglitazar, a novel dual peroxisome proliferator-activated receptor alpha/gamma agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population. Diabetologia 2005;48:1716-25.
[22]Artis R, Bollag G, Ibrahim P, et al. A novel PPAR pan-modulator improves lipid and glucose homeostasis in insulin resistant and diabetic mouse models (abstract 2074-PO). Diabetes 2006;55(suppl 1):A480.
[23]Ortmeyer HK, Collins CA, Minnick DT, et al. A novel PPAR pan-modulator improves lipid and glucose homeostasis in insulin resistant and diabetic mouse models (abstract 666-P). Diabetes 2004;52(suppl 2):A159.
[24]Upton R, Widdowson PS, Ishii S, Tanaka H, Williams G. Improved metabolic status and insulin sensitivity in obese fatty (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats treated with the thiazolidinedione, MCC-555. Br J Pharmacol 1998;125:1708-14.
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