Statin-induced inhibition of the Rho-signaling pathway activates PPARα and induces HDL apoA-I
Statin-induced inhibition of the Rho-signaling pathway activates PPARα and induces HDL apoA-I
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DOI：
10.1172/jci10852
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发表时间：
2001-06-01
影响因子：
15.9
通讯作者：
Staels, B
中科院分区：
文献类型：
--
作者：
Martin, G;Duez, H;Staels, B
他汀类药物是胆固醇合成限速酶3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的抑制剂，除了降低低密度脂蛋白胆固醇外，他汀类药物治疗还增加抗动脉粥样硬化高密度脂蛋白及其主要载脂蛋白apoA-I的水平。在这里，我们研究了apoA-I调节他汀类药物的分子机制。用他汀类药物治疗增加人HepG 2肝癌细胞中apoA-I mRNA水平，并且这种作用通过加入甲羟戊酸逆转，暗示HMG-CoA还原酶是这些药物的相关靶点。预处理-与放线菌素D取消apoA-I mRNA的增加，表明他汀类药物在转录水平上的作用。事实上，他汀类药物增加了转染细胞中的人apoA-I启动子活性，我们已经确定了一个他汀类反应元件，该元件与已知赋予贝特类药物对该基因的反应性的PPAR α反应元件一致。他汀类药物的作用不仅可以通过甲羟戊酸，而且可以通过香叶基香叶基焦磷酸来消除，而香叶基香叶基转移酶活性的抑制或用Rho GTP结合蛋白家族的抑制剂治疗增加了PPARa活性。使用这些蛋白质的显性负性形式，我们发现Rho A本身介导这种反应。由于他汀类药物和贝特类药物联合治疗以协同方式激活PPARa，这些观察结果为他汀类药物和贝特类药物联合治疗冠心病提供了分子基础。
Statins are inhibitors of the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, In addition to reducing LDL cholesterol, statin treatment increases the levels of the antiatherogenic HDL and its major apolipoprotein apoA-I. Here, we investigated the molecular mechanisms of apoA-I regulation by statins. Treatment with statins increased apoA-I mRNA levels in human HepG2 hepatoma cells, and this effect was reversed by the addition of mevalonate, implicating HMG-CoA reductase as the relevant target of these drugs. Pretreatment- with Actinomycin D abolished the increase of apoA-I mRNA, indicating that statins act at the transcriptional level. Indeed, statins increased the human apoA-I promoter activity in transfected cells, and we have identified a statin response element that coincides with a PPAR alpha response element known to confer fibrate responsiveness to this gene. The statin effect could be abolished not only by mevalonate, but also by geranylgeranyl pyrophosphate, whereas inhibition of geranylgeranyl transferase activity or treatment with an inhibitor of the Rho GTP-binding protein family increased PPARa activity. Using dominant negative forms of these proteins, we found that Rho A itself mediates this response. Because cotreatment with statins and fibrates activated PPARa in a synergistic manner, these observations provide a molecular basis for combination treatment with statins and fibrates in coronary heart disease.