Zannis Vassilis I, Chroni Angeliki, Krieger Monty
Molecular Genetics, Whitaker Cardiovascular Institute and Department of Biochemistry, Boston University School of Medicine, MA 02118, USA.
J Mol Med (Berl). 2006 Apr;84(4):276-94. doi: 10.1007/s00109-005-0030-4. Epub 2006 Feb 25.
The concentration, composition, shape, and size of plasma high-density lipoprotein (HDL) are determined by numerous proteins that influence its biogenesis, remodeling, and catabolism. The discoveries of the HDL receptor (scavenger receptor class B type I, SR-BI) and the ABCA1 (ATP-binding cassette transporter A1) lipid transporter provided two missing links that were necessary to understand the biogenesis and some of the functions of HDL. Existing data indicate that functional interactions between apoA-I and ABCA1 are necessary for the initial lipidation of apoA-I. Through a series of intermediate steps, lipidated apoA-I proceeds to form discoidal HDL particles that can be converted to spherical particles by the action of lecithin:cholesterol acyltransferase (LCAT). Discoidal and spherical HDL can interact functionally with SR-BI and these interactions lead to selective lipid uptake and net efflux of cholesterol and thus remodel HDL. Defective apoA-I/ABCA1 interactions prevent lipidation of apoA-I that is necessary for the formation of HDL particles. In the same way, specific mutations in apoA-I or LCAT prevent the conversion of discoidal to spherical HDL particles. The interactions of lipid-bound apoA-I with SR-BI are affected in vitro by specific mutations in apoA-I or SR-BI. Furthermore, deficiency of SR-BI affects the lipid and apolipoprotein composition of HDL and is associated with increased susceptibility to atherosclerosis. Here we review the current status of the pathway of HDL biogenesis and mutations in apoA-I, ABCA1, and SR-BI that disrupt different steps of the pathway and may lead to dyslipidemia and atherosclerosis in mouse models. The phenotypes generated in experimental mouse models for apoA-I, ABCA1, LCAT, SR-BI, and other proteins of the HDL pathway may facilitate early diagnosis of similar phenotypes in the human population and provide guidance for proper treatment.
血浆高密度脂蛋白（HDL）的浓度、组成、形状和大小由众多影响其生物合成、重塑和分解代谢的蛋白质所决定。HDL受体（B类清道夫受体I型，SR-BI）和ABCA1（ATP结合盒转运体A1）脂质转运体的发现提供了理解HDL生物合成及其部分功能所需的两个缺失环节。现有数据表明，载脂蛋白A-I（apoA-I）与ABCA1之间的功能相互作用对于apoA-I的初始脂质化是必需的。通过一系列中间步骤，脂质化的apoA-I进而形成盘状HDL颗粒，这些颗粒可通过卵磷脂胆固醇酰基转移酶（LCAT）的作用转化为球状颗粒。盘状和球状HDL可与SR-BI发生功能相互作用，这些相互作用导致胆固醇的选择性摄取和净流出，从而重塑HDL。有缺陷的apoA-I/ABCA1相互作用会阻止apoA-I的脂质化，而这是HDL颗粒形成所必需的。同样，apoA-I或LCAT中的特定突变会阻止盘状HDL颗粒向球状颗粒的转化。脂质结合的apoA-I与SR-BI之间的相互作用在体外会受到apoA-I或SR-BI中特定突变的影响。此外，SR-BI的缺乏会影响HDL的脂质和载脂蛋白组成，并与动脉粥样硬化易感性增加有关。在此，我们综述HDL生物合成途径的现状以及apoA-I、ABCA1和SR-BI中的突变，这些突变会破坏该途径的不同步骤，并可能在小鼠模型中导致血脂异常和动脉粥样硬化。针对apoA-I、ABCA1、LCAT、SR-BI以及HDL途径中其他蛋白质的实验小鼠模型所产生的表型，可能有助于早期诊断人群中类似的表型，并为适当治疗提供指导。
