A Century of Milestones and Breakthroughs Related to Low- and High-Density Lipoproteins.
A Century of Milestones and Breakthroughs Related to Low- and High-Density Lipoproteins.
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与低密度和高密度脂蛋白相关的一个世纪的里程碑和突破。
DOI：
10.1161/atvbaha.123.319482
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Remaley,AlanT
中科院分区：
文献类型：
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作者：
Sorci-Thomas,MaryG;Hegele,RobertA;Remaley,AlanT
高夫曼的同事弗兰克·林格伦（Frank Lindgren）和亚历山大·尼科尔斯（Alexander Nicholls）进一步描述了脂蛋白的结构、功能和代谢作用，而理查德·哈维尔（Richard Havel）在研究中使用制备型超离心法测定脂蛋白。[2]随后，Donald Fredrickson、Robert Levy和Robert Lees在1967年提出了人类血脂异常的临床分类系统，并期望生化表型最终能被证明具有分子遗传学基础。我们现在认识到，6种Frederickson表型中只有2种，即1型高脂蛋白血症或家族性乳糜微粒血症综合征，以及2A型单基因家族性高胆固醇血症（FH）患者的子集，是离散的单基因疾病，而其余的包括3型（异常β脂蛋白血症）在本质上主要是多基因的。自20世纪70年代以来，无数的研究人员已经将LDL与动脉粥样硬化发生联系起来的机制拼凑在一起，包括其在以下方面的作用：（1）通过吞噬聚集的LDL颗粒形成巨噬细胞来源的泡沫细胞，其中组分已经被修饰（2）释放具有局部和全身作用的生物活性促炎脂质;（3）细胞外脂质沉积物的形成（如胆固醇结晶）;（4）诱导先天性和适应性免疫反应;（5）诱导血栓形成前基因的表达;（6）损害动脉斑块中的细胞吞噬作用;以及（7）促成动脉斑块侵蚀和破裂等。4发表在美国心脏协会期刊上的数千篇评估这些途径的手稿，包括Circulation，Circulation Research和Arteriopathy，Thrombosis and Vascular Biology，已经建立了LDL是ASCVD因果关系的实验案例。4 LDL是其他血浆脂蛋白重塑的最终产物，从肝脏分泌的VLDL（极低密度脂蛋白）开始。为了扩大低密度脂蛋白胆固醇（LDL-C）的诊断应用，有必要绕过超离心方法
Gofman’s associates Frank Lindgren and Alexander Nicholls further characterized the structure, function, and metabolic roles of lipoproteins, while Richard Havel used the preparative ultracentrifuge for the implementation of lipoprotein determinations in research. 2 Subsequently, a clinical classification system for human dyslipidemias was proposed by Donald Fredrickson, Robert Levy, and Robert Lees in 1967 with the expectation that the biochemical phenotypes would eventually be shown to have a molecular genetic basis. 3 We now appreciate that only 2 of the 6 Frederickson phenotypes, namely type 1 hyperlipoproteinemia or familial chylomicronemia syndrome, and the subset of type 2A patients with monogenic familial hypercholesterolemia (FH), are discrete single-gene disorders, while the remainder including type 3 (dysbetalipoproteinemia) are largely polygenic in nature. Since the 1970s, countless researchers have pieced together the mechanisms linking LDL to atherogenesis including its roles in (1) formation of macrophage-derived foam cells through phagocytic uptake of aggregated LDL particles in which components have been modified (eg, by oxidation);(2) release of bioactive proinflammatory lipids with local and systemic effects;(3) formation of extracellular lipid deposits (eg, cholesterol crystals);(4) inducing both innate and adaptive immune responses;(5) inducing expression of prothrombotic genes;(6) impairing cellular efferocytosis in arterial plaques; and (7) contributing to arterial plaque erosion and rupture, among others. 4 Thousands of manuscripts evaluating these pathways, published in American Heart Association journals including Circulation, Circulation Research, and Arteriosclerosis, Thrombosis and Vascular Biology, have built the experimental case that LDL is causal for ASCVD. 4 LDL is the terminal product of remodeling of other plasma lipoproteins, beginning with hepatically secreted VLDL (very low-density lipoprotein). To scale-up the diagnostic application of LDL cholesterol (LDL-C), it was necessary to bypass ultracentrifugation methodology