Faculty of Pharmacy A15, University of Sydney, NSW 2006, Australia.
Curr Pharm Biotechnol. 2012 Feb;13(2):352-64. doi: 10.2174/138920112799095356.
Binding of High Density Lipoprotein (HDL) and its major apolipoprotein A-I (apoA-I) to cell surface receptors is believed to initiate a plethora of signaling cascades that promote atheroprotective cell behavior, including the removal of excess cholesterol from lipid-loaded macrophages. More specifically, HDL and apoA-I binding to scavenger receptor BI (SR-BI) and ATP-binding cassette (ABC) transporter A1 has been shown to activate protein kinase A and C (PKA, PKC), Rac/Rho GTPases, Janus Kinase 2 (JAK2), calmodulin as well as mitogen-activated protein kinases (MAPK). Some of these signaling events upregulate mobilization of cholesterol from cellular pools, while others promote efflux pathways through increased expression, stability, and cell surface localization of SR-BI and ABCA1. This review aims to summarize the current knowledge of HDL- and apoA-I -induced signal transduction pathways that are linked to cholesterol efflux and discusses the underlying mechanisms that could couple ligand binding to SR-BI and ABCA1 with signaling and cholesterol export. Additional focus is given on the potential of pharmacological intervention to modulate the activity of signaling cascades for the inhibition or regression of cholesterol accumulation in atherosclerotic lesions.
高密度脂蛋白（HDL）及其主要载脂蛋白 A-I（apoA-I）与细胞表面受体的结合被认为是启动多种信号级联反应的起始步骤，这些级联反应可促进动脉粥样保护细胞行为，包括从富含脂质的巨噬细胞中清除多余的胆固醇。更具体地说，已经表明 HDL 和 apoA-I 与清道夫受体 BI（SR-BI）和 ATP 结合盒（ABC）转运蛋白 A1 的结合可激活蛋白激酶 A 和 C（PKA、PKC）、Rac/Rho GTPases、Janus 激酶 2（JAK2）、钙调蛋白以及丝裂原激活蛋白激酶（MAPK）。这些信号事件中的一些上调了胆固醇从细胞库中的动员，而另一些则通过增加 SR-BI 和 ABCA1 的表达、稳定性和细胞表面定位来促进流出途径。本综述旨在总结与胆固醇流出相关的 HDL 和 apoA-I 诱导的信号转导途径的最新知识，并讨论将配体结合与 SR-BI 和 ABCA1 与信号转导和胆固醇外排偶联的潜在机制。此外，还重点关注了通过药理学干预来调节信号级联反应活性以抑制或逆转动脉粥样硬化病变中胆固醇积累的潜力。
