Niesor Eric J
F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
Biology (Basel). 2015 Jan 6;4(1):17-38. doi: 10.3390/biology4010017.
The relationship between levels of high-density lipoprotein cholesterol (HDL-C) and cardiovascular (CV) risk is well recognized; however, in recent years, large-scale phase III studies with HDL-C-raising or -mimicking agents have failed to demonstrate a clinical benefit on CV outcomes associated with raising HDL-C, casting doubt on the "HDL hypothesis." This article reviews potential reasons for the observed negative findings with these pharmaceutical compounds, focusing on the paucity of translational models and relevant biomarkers related to HDL metabolism that may have confounded understanding of in vivo mechanisms. A unique function of HDL is its ability to interact with the ATP-binding cassette transporter (ABC) A1 via apolipoprotein (Apo) A1. Only recently, studies have shown that this process may be involved in the intestinal uptake of dietary sterols and antioxidants (vitamin E, lutein and zeaxanthin) at the basolateral surface of enterocytes. This parameter should be assessed for HDL-raising drugs in addition to the more documented reverse cholesterol transport (RCT) from peripheral tissues to the liver. Indeed, a single mechanism involving the same interaction between ApoA1 and ABCA1 may encompass two HDL functions previously considered as separate: antioxidant through the intestinal uptake of antioxidants and RCT through cholesterol efflux from loaded cells such as macrophages.
高密度脂蛋白胆固醇（HDL-C）水平与心血管（CV）风险之间的关系已得到充分认识；然而，近年来，使用升高HDL-C或模拟HDL-C的药物进行的大规模III期研究未能证明升高HDL-C对CV结局有临床益处，这使人们对“HDL假说”产生怀疑。本文回顾了这些药物化合物出现阴性结果的潜在原因，重点关注可能混淆了对体内机制理解的翻译模型和与HDL代谢相关的生物标志物的匮乏。HDL的一个独特功能是它能够通过载脂蛋白（Apo）A1与ATP结合盒转运蛋白（ABC）A1相互作用。直到最近，研究表明这个过程可能参与了肠细胞基底外侧表面对膳食固醇和抗氧化剂（维生素E、叶黄素和玉米黄质）的肠道摄取。除了记录更多的从外周组织到肝脏的逆向胆固醇转运（RCT）外，还应评估升高HDL的药物的这一参数。事实上，涉及ApoA1和ABCA1之间相同相互作用的单一机制可能涵盖了以前被认为是分开的两种HDL功能：通过肠道摄取抗氧化剂实现抗氧化作用，以及通过从负载细胞（如巨噬细胞）中排出胆固醇实现逆向胆固醇转运。
