醛糖还原酶通过调控肝代谢性核受体PPARα的磷酸化及活性影响脂质稳态
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摘要
醛糖还原酶(aldose reductase，AR)在糖尿病并发症的发生发展过程中扮演了重要的角色，但其机制尚未完全阐明。在本项研究中，我们利用细胞模型和动物模型，就AR对肝脏过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptorα，PPARα)转录活性和脂质代谢的影响进行了一系列的体内体外研究。
我们首先构建了AR表达载体pFLAG-mAR，将此质粒和含过氧化物酶体增殖物反应元件(peroxisome proliferator response element，PPRE)的荧光素酶报告质粒PPRE-tk-Luc共转染进AML12小鼠肝细胞中，并在反应体系中用PPARγ的拮抗剂G3335抑制PPARγ的转录活性。我们利用这样一个系统研究了AR过量表达对PPARα／δ的转录活性的影响。我们的结果显示，AR在AML12小鼠肝细胞的过量表达强烈地抑制了PPARα／δ的转录活性(74％，P＜0.001)，而在培养基中加入AR抑制剂zopolrestat可以使AR过量表达诱导的PPARα／δ转录活性的下降得到显著的改善。与此同时，RT-PCR半定量分析结果显示，AR诱导的PPARα／δ转录活性的下降伴随着酰基辅酶A氧化酶(acyl-CoA oxidase，ACO)和肉碱棕榈酰转运酶-1(carnitine palmitoyl transferase-1，CPT-1)的mRNA表达水平的下降(ACO下降34.3％，P＜0.01；CPT-1下降23.3％，P＜0.05)。ACO和CPT-1是PPARα的两个靶标基因，与脂肪酸氧化密切相关。这些结果提示，AR参与了对PPARα转录活性的调控，进而影响了脂质代谢。更进一步地，利用Western blot，我们证明了AR的过量表达显著地增加了PPARα的磷酸化水平，其中第12位丝氨酸残基磷酸化增加了2.2倍(P＜0.001)，第21位丝氨酸残基磷酸化增加了2.1倍(P＜0.05)，而磷酸化的增加伴随着转录活性的下降。与PPARα磷酸化水平的提高相对应，细胞外信号调节激酶ERK1和ERK2的磷酸化也分别增加了14倍(P＜0.001)和4.1倍(P＜0.01)，提示ERK-MAPK信号转导通路可能介导了PPARα的磷酸化。与此相呼应，ERK1／2抑制剂的处理使得AR诱导的PPARα转录活性的抑制被显著改善(达到对照的78％，P＜0.001)，而P13K、p38、JNK及PKC抑制剂处理则没有此作用。特别重要的是，用25 mM浓度的葡萄糖处理AML12细胞也获得了与上述效应相似的结果。与在5 mM葡萄糖浓度下培养相比，25 mM葡萄糖的处理使得AML12细胞的AR的表达显著上调，同时引起PPARα／δ转录活性下降和ERK1／2及PPARα的磷酸化程度显著增加。用AR siRNA抑制AR表达后，25 mM葡萄糖浓度处理下的AML12中PPARα的磷酸化程度显著降低。
我们采用腹腔注射链脲佐菌素(streptozotoxin，STZ)在C57BL／6小鼠中诱导Ⅰ型糖尿病。在STZ—糖尿病小鼠中，AR抑制剂处理或敲除AR基因，导致肝组织ERK1／2和PPARα的去磷酸化，而且AR抑制剂处理使ACO的mRNA水平显著上升(44％，P＜0.01)，载脂蛋白ApoC3的mRNA水平显著下降(34.8％，P＜0.01)。与此同时，血甘油三酯(TG)和游离脂肪酸水平也显著下降。另一方面，在Ⅱ型糖尿病小鼠模型db／db小鼠中，AR抑制剂的处理也导致肝组织ERK1／2和PPARα显著的去磷酸化，同时伴随着ACO和载脂蛋白ApoA5的mRNA水平的显著上升(ACO上升92％，P＜0.05；ApoA5上升73％，P＜0.05)。与此相对应，肝TG和血TG水平显著下降，同时肝组织的油红染色结果也说明了AR抑制剂处理显著降低了db／db小鼠肝脏中性脂肪含量。
综上所述，AR在肝脏中可对PPARα的磷酸化及转录活性进行调控，进而影响动物体脂质代谢。AR对PPARα的调控作用在很大程度上是由ERK1／2信号转导通路介导的。
Aldose reductase (AR) is implicated in the development of a number of diabeticcomplications but the underlying mechanisms remain to be fully elucidated. Weperformed this study to determine whether and how AR might influence hepaticperoxisome proliferator-activated receptorα(PPARα) activity and lipid metabolism.
We first constructed an AR over-expressing vector, pFLAG-mAR, andco-transfected it with a reporter plasmid PPRE-tk-Luc containing peroxisomeproliferator response element (PPRE) into mouse hepatocyte AML12 cells in thepresence of a PPARγantagonist G3335. These transfection studies showed that ARover-expression caused strong suppression of PPARα/δactivity (74%, P＜0.001).These suppressive effects were attenuated by selective AR inhibitor (ARI) zopolrestat.The AR-induced reduction in PPARα/δactivities, on the other hand, was associatedwith down-regulated mRNA expression of acyl-CoA oxidase (ACO) (34.3%, P＜0.01)and carnitine palmitoyl transferase-1 (CPT-1) (23.3%, P＜0.05), two PPARαtargetgenes critical for fatty acid oxidation, suggesting AR is involved in the modulation ofhepatic PPARαactivity to affect lipid metabolism. It was further demonstrated byWestern blot that AR over-expression greatly increased phosphorylated PPARαlevels(2.2 folds for phospho-Serine-12 PPARα, P＜0.001 and 2.1 folds forphospho-Serine-21 PPARα, P＜0.05), which is consistent with down-regulatedPPARαactivity. Paralleling this increase, there was a greatly increasedphosphorylation of both ERK1 (14 folds, P＜0.001) and ERK2 (4.1 folds, P＜0.01),suggesting that the ERK-MAPK signaling pathway contributed to the increasedPPARαphosphorylation. In accordance with this, AR-induced suppression of PPARαwas attenuated (78% of the control level, P＜0.001) by treatment with inhibitor forERK1/2 but not that for PI3K, p38, JNK and PKC. Importantly, similar effects wereobserved for cells exposed to 25 mM glucose. AR was up-regulated in AML 12 cellsafter treated with 25 mM glucose, while PPARαtranscriptional activity wassignificantly suppressed, and that was associated with increased phosphorylation ofPPARαand ERK1/2. Knock down of AR by siRNA dephosphorylated PPARαand ERK1/2.
We investigated effects of AR on PPARαin streptozotoxin (STZ)-induceddiabetic C57BL/6 mice. Our results showed that ARI treatment or genetic deficiencyof AR resulted in significant dephosphorylation of both hepatic PPARαand ERK1/2.With the dephosphorylation of PPARα, ARI treatment caused a 44% up-regulation ofhepatic ACO mRNA expression (P＜0.01) and a 34.8% down-regulation ofapolipoprotein ApoC3 mRNA expression (P＜0.01) in wild type STZ-diabetic mice,and that was associated with substantial reductions in blood triglyceride (TG) andnon-esterified fatty acid (NEFA) levels. We further investigated effects of AR onPPARαin Type 2 diabetes mellitus models. In db/db mice, ARI treatment alsoresulted in significant dephosphorylation of both PPARαand ERK1/2. And hepaticACO and apolipoprotein ApoA5 mRNA expression increased 92% (P＜0.01) and73% (P＜0.01) respectively. Liver TG levels decreased significantly and serum TGlevels also decreased significantly after ARI treatment. Oil red O staining of liversection also showed that neutral lipid contents were reduced after ARI treatment indb/db mice.
Together our data indicate that AR plays an important role in the regulation ofhepatic PPARαphosphorylation and activity and lipid homeostasis. A significantportion of the AR-induced modulation is achieved through ERK1/2 signaling.
我们首先构建了AR表达载体pFLAG-mAR，将此质粒和含过氧化物酶体增殖物反应元件(peroxisome proliferator response element，PPRE)的荧光素酶报告质粒PPRE-tk-Luc共转染进AML12小鼠肝细胞中，并在反应体系中用PPARγ的拮抗剂G3335抑制PPARγ的转录活性。我们利用这样一个系统研究了AR过量表达对PPARα／δ的转录活性的影响。我们的结果显示，AR在AML12小鼠肝细胞的过量表达强烈地抑制了PPARα／δ的转录活性(74％，P＜0.001)，而在培养基中加入AR抑制剂zopolrestat可以使AR过量表达诱导的PPARα／δ转录活性的下降得到显著的改善。与此同时，RT-PCR半定量分析结果显示，AR诱导的PPARα／δ转录活性的下降伴随着酰基辅酶A氧化酶(acyl-CoA oxidase，ACO)和肉碱棕榈酰转运酶-1(carnitine palmitoyl transferase-1，CPT-1)的mRNA表达水平的下降(ACO下降34.3％，P＜0.01；CPT-1下降23.3％，P＜0.05)。ACO和CPT-1是PPARα的两个靶标基因，与脂肪酸氧化密切相关。这些结果提示，AR参与了对PPARα转录活性的调控，进而影响了脂质代谢。更进一步地，利用Western blot，我们证明了AR的过量表达显著地增加了PPARα的磷酸化水平，其中第12位丝氨酸残基磷酸化增加了2.2倍(P＜0.001)，第21位丝氨酸残基磷酸化增加了2.1倍(P＜0.05)，而磷酸化的增加伴随着转录活性的下降。与PPARα磷酸化水平的提高相对应，细胞外信号调节激酶ERK1和ERK2的磷酸化也分别增加了14倍(P＜0.001)和4.1倍(P＜0.01)，提示ERK-MAPK信号转导通路可能介导了PPARα的磷酸化。与此相呼应，ERK1／2抑制剂的处理使得AR诱导的PPARα转录活性的抑制被显著改善(达到对照的78％，P＜0.001)，而P13K、p38、JNK及PKC抑制剂处理则没有此作用。特别重要的是，用25 mM浓度的葡萄糖处理AML12细胞也获得了与上述效应相似的结果。与在5 mM葡萄糖浓度下培养相比，25 mM葡萄糖的处理使得AML12细胞的AR的表达显著上调，同时引起PPARα／δ转录活性下降和ERK1／2及PPARα的磷酸化程度显著增加。用AR siRNA抑制AR表达后，25 mM葡萄糖浓度处理下的AML12中PPARα的磷酸化程度显著降低。
我们采用腹腔注射链脲佐菌素(streptozotoxin，STZ)在C57BL／6小鼠中诱导Ⅰ型糖尿病。在STZ—糖尿病小鼠中，AR抑制剂处理或敲除AR基因，导致肝组织ERK1／2和PPARα的去磷酸化，而且AR抑制剂处理使ACO的mRNA水平显著上升(44％，P＜0.01)，载脂蛋白ApoC3的mRNA水平显著下降(34.8％，P＜0.01)。与此同时，血甘油三酯(TG)和游离脂肪酸水平也显著下降。另一方面，在Ⅱ型糖尿病小鼠模型db／db小鼠中，AR抑制剂的处理也导致肝组织ERK1／2和PPARα显著的去磷酸化，同时伴随着ACO和载脂蛋白ApoA5的mRNA水平的显著上升(ACO上升92％，P＜0.05；ApoA5上升73％，P＜0.05)。与此相对应，肝TG和血TG水平显著下降，同时肝组织的油红染色结果也说明了AR抑制剂处理显著降低了db／db小鼠肝脏中性脂肪含量。
综上所述，AR在肝脏中可对PPARα的磷酸化及转录活性进行调控，进而影响动物体脂质代谢。AR对PPARα的调控作用在很大程度上是由ERK1／2信号转导通路介导的。
Aldose reductase (AR) is implicated in the development of a number of diabeticcomplications but the underlying mechanisms remain to be fully elucidated. Weperformed this study to determine whether and how AR might influence hepaticperoxisome proliferator-activated receptorα(PPARα) activity and lipid metabolism.
We first constructed an AR over-expressing vector, pFLAG-mAR, andco-transfected it with a reporter plasmid PPRE-tk-Luc containing peroxisomeproliferator response element (PPRE) into mouse hepatocyte AML12 cells in thepresence of a PPARγantagonist G3335. These transfection studies showed that ARover-expression caused strong suppression of PPARα/δactivity (74%, P＜0.001).These suppressive effects were attenuated by selective AR inhibitor (ARI) zopolrestat.The AR-induced reduction in PPARα/δactivities, on the other hand, was associatedwith down-regulated mRNA expression of acyl-CoA oxidase (ACO) (34.3%, P＜0.01)and carnitine palmitoyl transferase-1 (CPT-1) (23.3%, P＜0.05), two PPARαtargetgenes critical for fatty acid oxidation, suggesting AR is involved in the modulation ofhepatic PPARαactivity to affect lipid metabolism. It was further demonstrated byWestern blot that AR over-expression greatly increased phosphorylated PPARαlevels(2.2 folds for phospho-Serine-12 PPARα, P＜0.001 and 2.1 folds forphospho-Serine-21 PPARα, P＜0.05), which is consistent with down-regulatedPPARαactivity. Paralleling this increase, there was a greatly increasedphosphorylation of both ERK1 (14 folds, P＜0.001) and ERK2 (4.1 folds, P＜0.01),suggesting that the ERK-MAPK signaling pathway contributed to the increasedPPARαphosphorylation. In accordance with this, AR-induced suppression of PPARαwas attenuated (78% of the control level, P＜0.001) by treatment with inhibitor forERK1/2 but not that for PI3K, p38, JNK and PKC. Importantly, similar effects wereobserved for cells exposed to 25 mM glucose. AR was up-regulated in AML 12 cellsafter treated with 25 mM glucose, while PPARαtranscriptional activity wassignificantly suppressed, and that was associated with increased phosphorylation ofPPARαand ERK1/2. Knock down of AR by siRNA dephosphorylated PPARαand ERK1/2.
We investigated effects of AR on PPARαin streptozotoxin (STZ)-induceddiabetic C57BL/6 mice. Our results showed that ARI treatment or genetic deficiencyof AR resulted in significant dephosphorylation of both hepatic PPARαand ERK1/2.With the dephosphorylation of PPARα, ARI treatment caused a 44% up-regulation ofhepatic ACO mRNA expression (P＜0.01) and a 34.8% down-regulation ofapolipoprotein ApoC3 mRNA expression (P＜0.01) in wild type STZ-diabetic mice,and that was associated with substantial reductions in blood triglyceride (TG) andnon-esterified fatty acid (NEFA) levels. We further investigated effects of AR onPPARαin Type 2 diabetes mellitus models. In db/db mice, ARI treatment alsoresulted in significant dephosphorylation of both PPARαand ERK1/2. And hepaticACO and apolipoprotein ApoA5 mRNA expression increased 92% (P＜0.01) and73% (P＜0.01) respectively. Liver TG levels decreased significantly and serum TGlevels also decreased significantly after ARI treatment. Oil red O staining of liversection also showed that neutral lipid contents were reduced after ARI treatment indb/db mice.
Together our data indicate that AR plays an important role in the regulation ofhepatic PPARαphosphorylation and activity and lipid homeostasis. A significantportion of the AR-induced modulation is achieved through ERK1/2 signaling.
引文
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