PCSK9降解低密度脂蛋白受体分子机制研究进展

血清低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)水平的升高是导致心血管疾病发生的主要危险因素。低密度脂蛋白受体(LDL receptor, LDLR)介导的低密度脂蛋白(low density lipoprotein, LDL)清除是决定循环中LDL-C水平的主要因素。LDL与细胞表面的LDLR结合后通过经典的网格蛋白小窝(clathrin-coated vesicles)内化进入细胞。在酸性核内体中,LDLR与LDL解离并循环回到细胞表面,释放的LDL将被运送到溶酶体中降解。前蛋白转化酶枯草溶菌素9 (proprotein convertase subtilisin kexin type 9, PCSK9)编码一种肝脏分泌型蛋白,其突变与LDL-C水平密切相关。前期研究已经证明,PCSK9直接与细胞表面的LDLR相互作用,二者一起通过网格蛋白小窝内化进入细胞。然而,在酸性核内体中,PCSK9和LDLR形成紧密的复合物,并进入溶酶体中进行降解,从而减少肝细胞表面LDLR的水平,降低肝脏对LDL-C的清除,该过程对于维持血浆中LDL在相对恒定的水平具有重要作用。因此,阻断PCSK9功能已成为治疗高胆固醇血症的新策略。本文综述了PCSK9的功能和机制研究的最新进展,并着重介绍了PCSK9抑制剂的研究进展,旨在为PCSK9-LDLR通路的研究和胆固醇代谢的调控提供参考。     

细胞内吞的研究进展

细胞内吞(endocytosis)是细胞从周围环境中摄取各种物质的过程,是细胞生理代谢的一个极为重要的现象。几乎所有的真核细胞都通过内吞作用摄取细胞外基质中的大分子。70年代中期,Steinman等人发现了细胞膜系就再循环现象,Goldstein等人第一次较为完整地描述了由受体介导的低密度脂蛋白(Low densitylipoprotein,简称LDL)内吞过程,这两项成果使细胞内吞成为细胞生物学研究领域中的     

中国人群家族性高胆固醇血症LDLR基因突变研究进展

家族性高胆固醇血症(Familial hypercholesterolemia,FH)主要是由于低密度脂蛋白受体(Low-density lipoprotein receptor,LDLR)基因突变导致的单基因显性遗传性疾病。FH患者LDLR基因突变导致细胞膜表面LDLR减少或缺如,机体代谢胆固醇能力降低,血浆胆固醇增高并沉积在不同的组织和器官,常伴有全身黄色瘤和早发冠心病,因此FH也是最常见的严重代谢性疾病。世界范围内对LDLR基因突变的报道总共有1741种,经整理我国目前报道的140例FH指示病例,包括108种LDLR基因突变类型。文章对已报道的中国FH患者LDLR基因突变特点进行系统分析和综述,旨在为FH诊断治疗提供参考依据。     

oxLDL对血管内皮细胞的损伤机制

天然的低密度脂蛋白(LDL)经氧化修饰形成氧化低密度脂蛋白(oxLDL).天然LDL核心的脂肪酸中含有大量不饱和脂肪酸,约占LDL总脂肪酸含量的35-70%,所以容易发生自身氧化.oxLDL具有一系列生物学毒性作用,氧化修饰后的LDL不能经LDL受体代谢,由清道夫受体识别、结合、内吞饮入细胞并逃逸正常的胆固醇代谢途径,引起细胞内脂质沉积,泡沫样变.oxLDL引发动脉粥样硬化的机制之一就是损伤血管内皮细胞,因此细胞损伤机制的进一步阐明将为改善内皮细胞功能和治疗动脉粥样硬化提供新的思路.     

家族性高胆固醇血症患者低密度脂蛋白受体基因新突变位点的鉴定

家族性高胆固醇血症(hypercholesterolemia familial,FH)是由于低密度脂蛋白受体(low density lipoprotein receptor,LDLR)基因突变导致的常染色体显性遗传性疾病,临床上表现为多发黄色瘤、高水平血浆LDL、早发性冠心病及有阳性家族史。本研究通过临床症状结合血脂测定诊断出一个FH家系,其纯合子FH患者的血浆总胆固醇水平高达19．05mmol／L,LDL达17．06mmol／L,并有黄色瘤;而杂合子FH患者的血浆总胆固醇水平为7．96mmol／L,LDL为5．55mmol/L,并有心绞痛症状和黄色瘤。我们对该FH家系患者LDLR基因的PCR扩增DNA片段进行测序,发现纯合子FH患者LDLR基因Exon4区域内发生了GAG683GCG突变,即编码LDLR第683位的谷氨酸被丙氨酸替换,而杂合子FH患者该位点呈现杂合突变。此基因型与临床诊断遗传谱完全一致。同时,利用获得Epstein-Barr(EB)病毒转化型人永生淋巴细胞株(EBV-Ls)与荧光探针DiI标记的LDL结合反应,再通过流式细胞仪检测结果显示,具有功能性LDLR的EBV-Ls细胞比例,在纯合子FH患者(7．02％)和杂合子FH患者(62．64％)均比健康对照者(84．69％)低,纯合子FH患者LDLR活性仅为健康对照者的8．29％、而杂合子FH患者LDLR活性约为健康对照者的73．96％,前者呈现非常显著的降低。这些EBV-Ls细胞LDLR的功能变化分析,有力地支持了该FH家系的临床诊断和DNA测序结果。经查阅最新的UMD-LDLR完全版证实,本研究发现鉴定的GAG683GCG突变是人LDLR基因的新突变位点。     

铬与胰岛素敏感性

铬可以提高动物机体组织对胰岛素的敏感性,但对其具体作用机制直到最近才有了较深入的认识.铬在吸收后主要由转铁蛋白运输.血液胰岛素水平升高可以促进转铁蛋白受体从细胞内的小泡中移位到细胞膜上.携带铬的转铁蛋白与细胞膜表面的转铁蛋白受体发生结合,通过内吞作用将铬转运到细胞内.在细胞内,内吞小泡中的酸性环境可使铬从转铁蛋白中释放,4个三价铬离子与apochromodulin形成有活性的holochromodulin. Holochromodulin 除了可与胰岛素和/或胰岛素受体直接结合起作用外,还可以通过激活AMPK激酶来降低细胞膜胆固醇含量,改善细胞骨架功能,促进GLUT4移位,然后又通过激活p38MAPK激酶增强GLUT4的内在活性,从而促进葡萄糖吸收.但其具体分子机制仍不完全清楚.本文就铬在提高动物机体组织对胰岛素的敏感性的作用机制问题进行综述.     

死亡受体6的胞内结构域对其亚细胞定位的调节

死亡受体6(death receptor 6,DR6)是死亡受体家族的一员,在免疫系统和神经系统中发挥着重要功能,然而,其亚细胞定位和调节机制尚不清楚。作者研究发现DR6不仅能够定位在细胞质膜表面,同时也存在于细胞内体系统。膜表面的DR6可以发生内吞,功能性单克隆抗体能够加速其内吞。通过构建一系列胞内结构域的缺失突变体,结果显示单独缺失丝氨酸/脯氨酸富集结构域,DR6在细胞膜表面定位显著增加,在内体定位显著减少。而分别缺失另外三个胞内结构域,DR6主要定位在细胞内体。以上结果提示DR6的胞内不同结构域在调控DR6的亚细胞定位和功能中发挥着重要作用。     

PCSK9结构与功能

前蛋白转化酶枯草溶菌素9（PCSK9）基因属于前蛋白转化酶（PC）家族,由信号肽、前结构域、催化结构域和羧基末端结构域组成.大量研究发现,PCSK9能介导低密度脂蛋白受体（LDLR）降解,调节血浆LDL胆固醇（LDL-C）水平;而PCSK9的两类主要突变,功能获得型、功能缺失型可分别导致高胆固醇血症和低胆固醇血症. 因而研究PCSK9对相关心血管疾病的防治有重要意义. PCSK9结构特性与其生化功能密切相关,突变致使其调节胆固醇代谢的机制更为复杂.本文旨在总结PCSK9结构与功能的分子生物学特性,并指出目前研究中存在的问题,以利对PCSK9的进一步探索.     

大米蛋白调控成熟期大鼠LDLR基因及蛋白表达

为了探讨大米蛋白对成熟期大鼠胆固醇代谢调控因子一低密度脂蛋白受体（low—densitv lipoprotein receptor．LDLR）的调控作用,以18周龄雄性Wistar成熟期大鼠为研究对象,应用大米蛋白及酪蛋白为食物蛋白源,饲喂无胆固醇及富含胆固醇饲料,经18日自由摄食后,测定实验鼠血浆总胆固醇、血浆高密度胆固醇水平及肝脏LDLR基因及蛋白表达水平。对照酪蛋白,大米蛋白均能显著降低大鼠血浆总胆固醇、血浆非高密度胆固醇水平及动脉粥样硬化指数,并且,显著刺激肝脏LDL基因及蛋白表达水平。实验结果表明,大米蛋白降低成熟期大鼠血浆胆固醇水平的作用功效与膳食胆固醇添加与否无关,大米蛋白降胆固醇的作用机制之一是能够有效刺激LDLR的表达,从而抑制LDL—C的转运入血。     

RAGE 与阿尔茨海默病关系的研究进展

阿尔茨海默病属于神经系统退行性疾病,该类疾病给社会和家庭带来了沉重的负担,且目前尚无一疗效突破性药物,已经 成为一个严重的社会问题和经济问题。A茁是阿尔茨海默病的重要发病机制之一,通过多种途径介导神经损伤,其中与细胞表面 的结合位点结合而引发的病理损害成为当今的前沿认识。一方面,它们可以使A茁聚集,造成细胞膜的直接损伤;另一方面,它们 可以以受体的形式,参与细胞内的信号传导;另外,还可以激活细胞内吞作用,通过溶酶体途径造成细胞损伤。关于与A茁结合的 细胞表面结合位点,晚期糖基化终末产物受体备受瞩目。它是一种多功能受体,属于细胞表面免疫球蛋白家族成员, 在神经元、小 胶质细胞以及血管内皮细胞上都有表达,A茁是它的配体之一。研究已证实,它与A茁相互作用,通过激活细胞内不同的信号通路, 对阿尔茨海默病的发生发展发挥重要作用。随着对它的不断深入研究,有望在防治退行性疾病方面产生新的治疗策略与措施。     

LDL receptor binds newly synthesized apoE in macrophages. A precursor pool for apoe secretion.

There appear to be multiple post-translational sites for regulation of macrophage apolipoprotein (apo)E secretion, including the presence of a distinct cell surface pool of apoE. Cell surface proteoglycans have been shown to be involved in forming this pool. The current studies were designed to investigate the role of an additional cell surface site, i.e., the low density lipoprotein (LDL) receptor. Antiserum to the LDL receptor displaced apoE from the macrophage cell surface and into the medium during a 4 degrees C incubation from apoE-expressing J774 cells, from proteoglycan-depleted apoE-expressing J774 cells, and from human monocyte-derived macrophages. Similar results were obtained when purified monoclonal antibody to the LDL receptor was added to human monocyte-derived macrophages. J774 cells transfected to express an LDL receptor binding-defective mutant of apoE did not show a similar response to addition of LDL receptor antibody. Studies were conducted in which cells were pulse labeled for 30 min, followed by various periods of chase at 4 degrees C or 37 degrees C in the presence or absence of LDL receptor antibody. The results of these studies indicated that nascent macrophage-derived apoE binds to the LDL receptor, and that this apoE served as a precursor pool for apoE released into the medium.These studies establish a role for the LDL receptor in forming the cell surface pool of apoE and, along with data regarding the importance of proteoglycans, indicate that cell surface binding sites for nascent macrophage-derived apoE are heterogeneous. The heterogeneity of such sites could have implication for the size and turnover of this cell surface pool.     

Inhibition of low density lipoprotein uptake in confluent endothelial cell monolayers correlates with a restricted surface receptor redistribution.

Binding of either low density lipoprotein (LDL) or Concanavalin A (ConA) to actively growing vascular endothelial cells is associated with a redistrubution of the appropriate cell surface receptor sites which form patches and caps. This receptor lateral mobility is greatly restricted when endothelial cells reach confluence and adopt the configuration of a cell monolayer composed of closely apposed and non-overlapping cells. In this case, although the cells still exhibit specific LDL binding to the appropriate cell surface receptor sites, neither the binding of LDL nor of ConA induces a receptor redistribution. The lack of LDL receptor redistribution correlates with a marked decrease in the rate of LDL internalization. In contrast, no such density-dependent changes are observed in cell types which grow on top of each other and form multiple cell layers at confluence. Thus, neither LDL nor ConA induced cap formation in either sparse or confluent smooth muscle cell cultures and the same rate of LDL internalization is observed at both cell densities. Similarly, adsorptive endocytosis of cationized LDL (which enters the cells independently of the LDL receptor sites) was not correlated with a detectable receptor redistribution, nor was it significantly affected by changes in cell density and spatial organization. The formation of a confluent cell monolayer resting on an underlying basement membrane might therefore provide, via a change in membrane dynamics, a mechanism whereby the endothelium of large blood vessels can function as a protective barrier against the high circulating levels of LDL in plasma.     

Effect of contact inhibition on the regulation of cholesterol metabolism in cultured vascular endothelial cells.

Cholesterol synthesis in actively growing bovine vascular endothelial cells is regulated by low density lipoprotein (LDL) at a step prior to mevalonate formation, in a manner comparable to that found in aortic smooth muscle cells. LDL uptake by these cells is associated with induction of cholesterol esterification, an increase in total cell cholesterol, and an inhibition of endogenous sterol synthesis. In contrast, cholesterol metabolism in confluent contact-inhibited endothelial cultures was not significantly affected by LDL even though the cells bind the lipoprotein at high affinity receptor sites. Lysosomal degradation and subsequent regulatory effects on cellular cholesterol metabolism, however, were observed in contact-inhibited endothelial cells incubated with cationized rather than native LDL. Cationized LDL enter the cells independently of the high affinity sites. Therefore, the primary regulation of cholesterol metabolism in these cells is neither through the appropriate intracellular enzymes nor through the high affinity surface receptors, but via an inhibition of LDL internalization. It is suggested that this inhibition is due to a strict contact-inhibited morphology which enables the endothelium of the larger arteries to function as a selective barrier to the high circulating levels of plasma LDL.     

Isolation of NPC1-deficient Chinese hamster ovary cell mutants by gene trap mutagenesis

Chinese hamster ovary cell mutants defective in the NPC1 gene (NPC1-trap) were generated by retrovirus-mediated gene trap mutagenesis from a parental cell line JP17 expressing an ecotropic retrovirus receptor. Insertion of the gene trap vector in the NPC1 gene and the absence of the gene product were verified by 5'RACE and immunological analyses, respectively. NPC1-trap cells showed intracellular accumulation of low-density lipoprotein (LDL)-derived cholesterol and had an increased level of unesterified cellular cholesterol. Cholesterol biosynthesis through the mevalonate pathway was upregulated in the mutant cells as assessed by [(14)C]acetate incorporation into cellular sterols. When JP17 cells were depleted of lipoproteins and then loaded with LDL, cell surface LDL receptors were promptly downregulated and the mature form of the sterol regulatory element-binding protein-1 disappeared from the nucleus. These responses to LDL were obviously retarded in NPC1-trap cells, suggesting an impaired response of the cholesterol-regulatory system to LDL. NPC1-trap cells will be a useful tool to study the regulation of cellular cholesterol homeostasis and the pathogenesis of Niemann-Pick disease type C.     

Role of the low-density lipoprotein receptor in entry of bovine viral diarrhea virus

Among several proposed cellular receptors for bovine viral diarrhea virus (BVDV), the low-density lipoprotein (LDL) receptor is of special interest because it is also considered a receptor for the related hepatitis C virus. It has been reported that an anti-LDL receptor monoclonal antibody blocked the infection of bovine cells by BVDV and that the resistance of bovine CRIB cells (cells resistant to infection with BVDV) (E. F. Flores and R. O. Donis, Virology 208:565-575, 1995) to BVDV infection was due to a lack of the LDL receptor (V. Agnello et al., Proc. Natl. Acad. Sci. USA 96:12766-12771, 1999). In connection with our studies on BVDV entry, we reevaluated the putative role of the LDL receptor as a cellular receptor for BVDV. It was first clearly demonstrated that neither of two monoclonal antibodies against the LDL receptor inhibited BVDV infection of two bovine cell lines. Furthermore, the LDL receptor was detected on the surface of CRIB cells. The functionality of the LDL receptor on CRIB cells was demonstrated by the internalization of fluorescently labeled LDL. In conclusion, at present no experimental evidence supports an involvement of the LDL receptor in BVDV invasion.     

Effect of low-density lipoprotein on the expression of high affinity Fc gamma receptors

A substrain of the human monocyte-like cell line U937, which is a cholesterol auxotroph, was used to study the effect of cellular cholesterol depletion on the expression of the type I Fc receptor for IgG (Fc gamma RI). Measurement of Fc gamma RI expression was performed by immunofluorescence and flow cytometry using the monoclonal antibody (mAb) 32.2, which is specific for an epitope on Fc gamma RI, and monomeric IgG2a, which binds to the ligand binding site of Fc gamma RI. Incubation of these cells for 24 h in growth medium containing delipidated fetal calf serum depletes cellular cholesterol without affecting growth or viability. While incubation of U937 cells with human interferon-gamma (IFN-gamma) increased Fc gamma RI expression, cholesterol depletion after cell growth in media containing delipidated serum and IFN-gamma resulted in reduced binding of both mAb 32.2 and IgG2a. A significant decrease in the number of cell surface binding sites, as measured by mean fluorescence intensity, was observed after cholesterol depletion. Supplementation of the delipidated serum medium with pure cholesterol in an ethanol/bovine serum albumin mixture, which replenished cellular cholesterol and supported growth, failed to restore antibody binding significantly. In contrast, low-density lipoprotein (LDL) which also delivered cholesterol to the cells restored binding both in terms of the number of the reactive cells and cell surface receptor density. High-density lipoprotein (HDL3), which does not deliver cholesterol to the cells, showed results similar to those obtained with pure cholesterol. This indicates that either LDL cholesterol is better utilized for membrane synthesis than pure cholesterol or that LDL provides another component, in addition to cholesterol, which is required for expression of Fc gamma RI, but not for growth. These studies indicate a role for LDL in regulating the expression of Fc gamma RI on the cell surface.     

Low density lipoprotein receptor-related protein is required for macrophage-mediated oxidation of low density lipoprotein by 12/15-lipoxygenase

The oxidative modification of low density lipoprotein (LDL) has been implicated in the early stage of atherosclerosis through multiple potential pathways, and 12/15-lipoxygenase is suggested to be involved in this oxidation process. We demonstrated previously that the 12/15-lipoxygenase overexpressed in mouse macrophage-like J774A.1 cells was required for the cell-mediated LDL oxidation. However, the mechanism of the oxidation of extracellular LDL by the intracellular 12/15-lipoxygenase has not yet been elucidated. In the present study, we found that not only the LDL receptor but also LDL receptor-related protein (LRP), both of which are cell surface native LDL-binding receptors, were down-regulated by the preincubation of the cells with cholesterol or LDL and up-regulated by lipoprotein-deficient serum. Moreover, 12/15-lipoxygenase-expressing cell-mediated LDL oxidation was decreased by the preincubation of the cells with LDL or cholesterol and increased by the preincubation with lipoprotein-deficient serum. Heparin-binding protein 44, an antagonist of the LDL receptor family, also suppressed the cell-mediated LDL oxidation in a dose-dependent manner. The cell-mediated LDL oxidation was dose-dependently blocked by an anti-LRP antibody but not by an anti-LDL receptor antibody. Furthermore, antisense oligodeoxyribonucleotides against LRP reduced the cell-mediated LDL oxidation under the conditions in which the expression of LRP was decreased. The results taken together indicate that LRP was involved essentially for the cell-mediated LDL oxidation by 12/15-lipoxygenase expressed in J774A.1 cells, suggesting an important pathophysiological role of this receptor-enzyme system as the initial trigger of the progression of atherosclerosis.     

Cholesterol metabolism in pigeon aortic smooth muscle cells lacking a functional low density lipoprotein receptor pathway

Cholesterol metabolism was examined in aortic smooth muscle cells from atherosclerosis-susceptible White Carneau pigeons that have been shown to lack a functional LDL receptor pathway. In cells incubated in the presence of whole serum or low density lipoprotein (LDL) the rate of cholesterol synthesis from [1-14C]acetate or of HMG-CoA reductase activity was 20-100 times greater than for mammalian cells incubated under the same conditions. Unexpectedly, cholesterol synthesis decreased by nearly 50% after preincubation for 24 hr with lipoprotein-deficient serum (LPDS). This occurred without a change in cellular cholesterol content. Neither the high rate of cholesterol synthesis nor the effect of LPDS could be accounted for by differences in cell turnover or state of growth. Cholesterol added in ethanol was ineffective in altering cellular cholesterol synthesis or esterification even though a near doubling in cellular free cholesterol content occurred. Cholesterol synthesis and esterification were, however, able to be regulated with 25-OH cholesterol and mevalonolactone, as indicated by their ability to suppress cholesterol synthesis and to stimulate cholesterol esterification. In spite of the high rate of endogenous cholesterol synthesis, cellular cholesterol content was maintained at a constant level by the efficient efflux of the newly synthesized cholesterol from the cell. Unlike mammalian cells that require a cholesterol acceptor in the medium for efflux to occur, cholesterol efflux from pigeon cells occurred in the absence of a cholesterol acceptor. This suggests either that pigeon cells utilize a different mechanism for cholesterol efflux or that they produce their own cholesterol acceptor. As a result of a lack of a functional LDL receptor pathway, pigeon smooth muscle cells do not maintain cholesterol homeostasis through the controlled uptake of exogenous LDL cholesterol, as do mammalian cells. Rather, pigeon smooth muscle cells would appear to regulate cholesterol concentrations at the level of either cholesterol synthesis or efflux.     

Stimulation of receptor-mediated low density lipoprotein endocytosis in neuraminidase-treated cultured bovine aortic endothelial cells

Sialic acids, occupying a terminal position in cell surface glycoconjugates, are major contributors to the net negative charge of the vascular endothelial cell surface. As integral membrane glycoproteins, LDL receptors also bear terminal sialic acid residues. Pretreatment of near-confluent, cultured bovine aortic endothelial cells (BAEC) with neuraminidase (50 mU/ml, 30 min, 37 degrees C) stimulated a significant increase in receptor-mediated 125I-LDL internalization and degradation relative to PBS-treated control cells. Binding studies at 4 degrees C revealed an increased affinity of LDL receptor sites on neuraminidase-treated cells compared to control BAEC (6.9 vs. 16.2 nM/10(6) BAEC) without a change in receptor site number. This enhanced LDL endocytosis in neuraminidase-treated cells was dependent upon the enzymatic activity of the neuraminidase and the removal of sialic acid from the cell surface. Furthermore, enhanced endocytosis due to enzymatic alteration of the 125I-LDL molecules was excluded. In contrast to BAEC, neuraminidase pretreatment of LDL receptor-upregulated cultured normal human fibroblasts resulted in an inhibition of 125I-LDL binding, internalization, and degradation. Specifically, a significant inhibition in 125I-LDL internalization was observed at 1 hr after neuraminidase treatment, which was associated with a decrease in the number of cell surface LDL receptor sites. Like BAEC, neuraminidase pretreatment of human umbilical vein endothelial cells resulted in enhanced receptor-mediated 125I-LDL endocytosis. These results indicate that sialic acid associated with either adjacent endothelial cell surface molecules or the endothelial LDL receptor itself may modulate LDL receptor-mediated endocytosis and suggest that this regulatory mechanism may be of particular importance to endothelial cells.     

Uptake of chylomicron remnants causes cholesterol accumulation in cultured human arterial smooth muscle cells

Chylomicron remnants (Sf greater than 100) were prepared by treating human chylomicrons (Sf greater than 400) with human post heparin plasma. Chylomicron remnants recovered after 70-80% of chylomicron triacylglycerol was hydrolyzed, suppressed LDL-receptor activity and increased cell cholesterol esterification to the same extent as did LDL when added to cultured human arterial smooth muscle cells at an equal cholesterol concentration. Cell cholesterol mass increased 36% after incubation with 25 micrograms LDL cholesterol/ml and 35% with 25 micrograms chylomicron-remnant cholesterol/ml. Addition of 30 microM chloroquine plus LDL or chylomicron remnants further increased cholesterol content of cells (74% and 87%, respectively) and caused a significant rise in cell esterified cholesterol (344% and 369%, respectively). Cholesterol content per unit of apolipoprotein B mass of remnants was 2-3-fold higher than that of LDL. Therefore, if lipoprotein particles were added at equivalent apolipoprotein B mass chylomicron remnants increased cell cholesterol content and cholesterol esterification and suppressed LDL receptor activity significantly more than did LDL. This suggests that an additional determinant, presumably apolipoprotein E, is important for receptor recognition of chylomicron remnants. These results may be relevant to the delivery of chylomicron-derived cholesterol to arterial cells proposed as a feature of atherogenesis.