Hill S A, McQueen M J
Department of Laboratory Medicine, Hamilton Health Sciences Corporation, Canada.
Clin Biochem. 1997 Oct;30(7):517-25. doi: 10.1016/s0009-9120(97)00098-2.
This review article will summarize the current knowledge surrounding the reverse cholesterol transport system; the process, the effect of mutations in genes coding for proteins which function in the system, and the possible clinical implications of these alterations.
High-density lipoprotein-cholesterol (HDL-C) concentration is a marker for the reverse cholesterol transport (RCT) system, whereby cholesterol is returned from peripheral cells to the liver for reuse or excretion in the bile. Increased HDL-C concentrations are generally accepted to be protective against the future development of atherosclerosis and coronary artery disease (CAD), but recent evidence has indicated that the underlying cause of the increased HDL-C may affect whether it is protective or detrimental. The major steps in the RCT pathway are the efflux of free cholesterol from cells and binding by pre-beta HDL, esterification of HDL-bound cholesterol by lecithin cholesterol acyl transferase (LCAT), cholesteryl ester transfer protein (CETP) mediated exchange of cholesteryl ester and triglycerides between HDL and apo B-containing particles, and hepatic lipase (HL) mediated uptake of cholesterol and triglycerides by the liver. Mutations in proteins active in the RCT pathway can shed light on the functions and control of the various steps in the system. LCAT deficiency, leading to greatly reduced HDL and fish eye disease, is not usually associated with increased risk of CAD. Several new mutations in LCAT have recently been reported, however, which do result in CAD. Mutations leading to reduced CETP activity result in less CE being directed into apo-B containing particles and more remaining in the HDL. This has been associated with increased HDL-C concentrations. The generally accepted hypothesis that reduced CETP activity leads to reduced CAD risk has been challenged by a number of recent publications, and has become an area of active investigation. Mutations leading to reduced HL activity are rare occurrences. To date, all have been associated with increased HDL-C concentrations and CAD.
The development of techniques to identify and characterize the functional significance of mutations in proteins involved in RCT will aid in the understanding of the mechanisms and control of this pathway.
这篇综述文章将总结目前关于逆向胆固醇转运系统的知识；该过程、在该系统中发挥作用的蛋白质编码基因中的突变影响，以及这些改变可能的临床意义。
高密度脂蛋白胆固醇（HDL-C）浓度是逆向胆固醇转运（RCT）系统的一个标志物，通过该系统胆固醇从外周细胞返回肝脏以供再利用或经胆汁排泄。HDL-C浓度升高通常被认为可预防动脉粥样硬化和冠状动脉疾病（CAD）的未来发展，但最近的证据表明，HDL-C升高的潜在原因可能会影响其是具有保护作用还是有害作用。RCT途径的主要步骤包括游离胆固醇从细胞中流出并与前β-HDL结合、卵磷脂胆固醇酰基转移酶（LCAT）将HDL结合的胆固醇酯化、胆固醇酯转运蛋白（CETP）介导HDL与含载脂蛋白B颗粒之间胆固醇酯和甘油三酯的交换，以及肝脂肪酶（HL）介导肝脏对胆固醇和甘油三酯的摄取。RCT途径中活性蛋白的突变可以揭示该系统各个步骤的功能和调控。LCAT缺乏导致HDL大幅降低并引发鱼眼病，通常与CAD风险增加无关。然而，最近报道了一些新的LCAT突变，这些突变确实会导致CAD。导致CETP活性降低的突变会使较少的胆固醇酯进入含载脂蛋白B的颗粒，而更多的胆固醇酯留在HDL中。这与HDL-C浓度升高有关。降低CETP活性会降低CAD风险这一普遍接受的假说受到了一些近期出版物的挑战，并且已成为一个活跃的研究领域。导致HL活性降低的突变很少见。迄今为止，所有这些突变都与HDL-C浓度升高和CAD有关。
开发用于鉴定和表征参与RCT的蛋白质中突变的功能意义的技术将有助于理解该途径的机制和调控。
