期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 107, 期 11, 页码 1423-1432出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI10852
关键词
-
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据