As macrophages indulge, atherosclerotic lesions bulge.
As macrophages indulge, atherosclerotic lesions bulge.
复制标题
当巨噬细胞沉迷时，动脉粥样硬化病变就会膨胀。
DOI：
10.1161/circresaha.108.178947
复制
发表时间：
2008
影响因子：
20.1
通讯作者：
Lu,Hong
中科院分区：
文献类型：
--
作者：
Daugherty,Alan;Rateri,DebraL;Lu,Hong
在大多数动物模型和人类中，载脂巨噬细胞是动脉粥样硬化形成阶段的主要细胞类型。1-3在高倍镜下观察石蜡包埋组织切片时，脂肪沉积表现为大量具有泡沫外观的细胞内液滴。因此，泡沫细胞的描述性名称适用于这些富含脂质的巨噬细胞。泡沫细胞起源于重新招募的单核细胞，它被假设为去除了被保留和修饰在内皮下间隙中的脂蛋白。4为了使这一功能发挥作用，富含脂质的巨噬细胞随后会从形成病变的区域中排出。然而，该系统经常出错。被招募到动脉壁的巨噬细胞会被大量的脂肪充斥，这可能是因为脂质代谢失衡。在这种极度肥大的状态下，巨噬细胞无法通过内皮细胞并被转移回血腔。因此，这些细胞不会离开动脉，而是会被保留和积累。除了这些细胞构成不断演变的病变的团块外，还有可能分泌许多生物活性分子，这些分子可能使动脉粥样硬化的形成过程永久化和修改。已经有许多方法通过操纵细胞内运输、细胞内存储或脂类的外流来改变泡沫细胞的发育。细胞外脂质的运输形成细胞内液滴被认为是通过内吞作用通过脂蛋白受体发生的，而脂蛋白受体不会因胆固醇含量的增加而下调。有许多种类的清道夫受体将修饰的脂蛋白转运到巨噬细胞，其中研究最多的是A类清道夫受体(SR-A)和CD36。然而，SR-A和CD36的基因操作对动脉粥样硬化的影响产生了不一致的结果。6-8一旦进入细胞，脂蛋白衍生的胆固醇酯在溶酶体中被酸性胆固醇酯水解酶分解。未酯化的胆固醇被酰基辅酶A：胆固醇酰基转移酶(ACAT)转运到细胞质中进行再酯化，生成包裹着蛋白质的脂滴。一旦储存在脂滴中，中性胆固醇水解酶可以将核心内容转化回未酯化的胆固醇。未酯化的胆固醇也可以分配到质膜，并转移到细胞外受体。已经提出了几种胆固醇外流的途径，包括ABC转运体和SR-B1。因此，巨噬细胞中的胆固醇稳态在其转化为泡沫细胞的过程中涉及多个水平的调节(图)。在本期《循环研究》中，Paul等人研究了脂肪分化相关蛋白(也称为脂肪蛋白、ADRP或ADFP)在巨噬细胞泡沫细胞形成和动脉粥样硬化中的作用。ADFP是PAT结构域蛋白家族中的一员，由该家族的3个创始成员命名：Perilipin、adiophlin和47 kDa的TRAIL相互作用蛋白。ADFP可能在大多数细胞类型中都有表达，尽管与其他一些PAT结构域家族成员不同，它在成熟脂肪细胞中的表达相对较少。10只ADFP缺乏的小鼠有适度的表型，包括肝脏甘油三酯含量降低和对饮食诱导的脂肪肝的抵抗力。然而，他们在体重、血浆甘油三酯和胆固醇浓度、脂肪质量或脂肪细胞分化方面没有差异。11.
Lipid-laden macrophages are the predominant cell type in the formative stages of atherosclerosis in most animal models and humans. 1–3 Lipid deposition appears as large numbers of intracellular droplets that have a foam-like appearance when paraffin-embedded tissue sections are viewed at high magnification. Consequently, the descriptive name of foam cells is applied to these lipid-laden macrophages. Originating from recruited monocytes, it has been hypothesized that foam cells remove lipoproteins that have been retained and modified in the subendothelial space. 4 For this function to be beneficial, lipid-laden macrophages would subsequently egress from the area of the forming lesion. However, the system frequently goes awry. Macrophages recruited to the arterial wall become grossly engorged with lipid, presumably because of an imbalance in lipid metabolism. In this greatly hypertrophied state, macrophages are unable to transit through the endothelium and be transferred back to the blood compartment. Therefore, instead of exiting the artery, these cells are retained and accumulate. In addition to these cells forming the mass of the evolving lesions, there is also the potential for secretion of many bioactive molecules that may perpetuate and modify the atherogenic process. There have been many approaches to modify the development of foam cells by manipulating intracellular transport, intracellular storage, or efflux of lipids. The transport of extracellular lipid to form intracellular droplets is presumed to occur via endocytosis through lipoprotein receptors that are not downregulated by increased cholesterol content. There are many classes of scavenger receptors that transport modified lipoproteins into macrophages, of which the most intensely studied has been class A scavenger receptor (SR-A) and CD36. 5 However, genetic manipulation of SR-A and CD36 has generated inconsistent findings for effects on atherosclerosis. 6–8 Once inside the cell, lipoprotein-derived cholesterol ester is cleaved in lysosomes by an acidic cholesterol ester hydrolase. Unesterified cholesterol is transported to the cytosol for reesterification by acyl-coenzyme A: cholesterol acyltransferase (ACAT) to generate lipid droplets that are protein-coated. Once stored in lipid droplets, neutral cholesterol hydrolase can convert the core content back to unesterified cholesterol. Unesterified cholesterol may also partition to the plasma membrane and transfer to extracellular acceptors. Several pathways have been proposed for cholesterol efflux, including the ABC transporters and SR-B1. Therefore, cholesterol homeostasis in macrophages has many levels of regulation involved in their conversion to foam cells (Figure).In this issue of Circulation Research, Paul et al9 have studied the role of adipose differentiation–related protein (also known as adipophilin, ADRP, or ADFP) on macrophage foam cell formation and atherosclerosis. ADFP, as it is referred to in this article, is a member of the PAT domain family of proteins that are named from the founding 3 members of this group: perilipin, adipophilin, and tailinteracting protein of 47 kDa. ADFP is probably expressed in the majority of cell types, although, unlike some other PAT domain family members, it is relatively sparsely expressed in mature adipocytes. 10 Mice that are deficient in ADFP have a modest phenotype that includes reductions in liver triglyceride content and resistance to diet-induced fatty liver. However, they have no difference in body weight, plasma triglyceride and cholesterol concentrations, fat mass, or adipocyte differentiation. 11