Miller Michael, Rhyne Jeffrey, Hamlette Steven, Birnbaum Josh, Rodriguez Anabelle
Departments of Medicine and Epidemiology, Veterans Affairs and University of Maryland Medical Center, Baltimore, MD 21201, USA.
Curr Opin Lipidol. 2003 Jun;14(3):273-9. doi: 10.1097/00041433-200306000-00007.
To review gene regulation of HDL-cholesterol and discuss molecular abnormalities in HDL candidate genes that may lead to human pathologic states.
The inverse association between HDL-cholesterol and vascular disease, especially coronary heart disease, has long been recognized, but understanding gene regulation of HDL in humans gained considerable momentum following the identification of ABCA1 as playing a pivotal role in reverse cholesterol transport. Recent data suggest that potentially important targets for upregulating HDL in humans include upregulators of ABCA1 and APOA1 (e.g. peroxisome proliferator activated receptor and liver X receptor agonists) and downregulators of CETP (e.g. JTT-705). A host of other nuclear receptors under investigation in animal models may advance to human testing in the near future.
Disorders affecting HDL metabolism are complex because monogenic disorders causing low HDL do not necessarily correlate with premature vascular disease. To date, pathologic phenotypes have only been deduced among several HDL candidate genes. Understanding the genetic underpinnings associated with variant HDL and reverse cholesterol transport provides an exceptional opportunity to identify novel agents that may optimize this process and reduce vascular event rates beyond currently available LDL lowering therapies.
综述高密度脂蛋白胆固醇（HDL-胆固醇）的基因调控，并讨论HDL候选基因中可能导致人类病理状态的分子异常。
HDL-胆固醇与血管疾病，尤其是冠心病之间的负相关关系早已为人所知，但在确定ATP结合盒转运体A1（ABCA1）在胆固醇逆向转运中起关键作用后，对人类HDL基因调控的理解有了很大进展。最近的数据表明，在人类中上调HDL的潜在重要靶点包括ABCA1和载脂蛋白A1（APOA1）的上调剂（如过氧化物酶体增殖物激活受体和肝X受体激动剂）以及胆固醇酯转运蛋白（CETP）的下调剂（如JTT-705）。在动物模型中正在研究的许多其他核受体可能在不久的将来进入人体试验阶段。
影响HDL代谢的疾病很复杂，因为导致HDL水平低的单基因疾病不一定与血管疾病早发相关。迄今为止，仅在几个HDL候选基因中推断出病理表型。了解与变异HDL和胆固醇逆向转运相关的遗传基础，为识别可能优化这一过程并降低血管事件发生率的新型药物提供了一个绝佳机会，其效果优于目前可用的降低低密度脂蛋白（LDL）的疗法。
