Kruth H S, Zhang W Y, Skarlatos S I, Chao F F
Section of Experimental Atherosclerosis, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 1999 Mar 12;274(11):7495-500. doi: 10.1074/jbc.274.11.7495.
Much of the cholesterol that accumulates in atherosclerotic plaques is found within monocyte-macrophages transforming these cells into "foam cells." Native low density lipoprotein (LDL) does not cause foam cell formation. Treatment of LDL with cholesterol esterase converts LDL into cholesterol-rich liposomes having >90% cholesterol in unesterified form. Similar cholesterol-rich liposomes are found in early developing atherosclerotic plaques surrounding foam cells. We now show that cholesterol-rich liposomes produced from cholesterol esterase-treated LDL can cause human monocyte-macrophage foam cell formation inducing a 3-5-fold increase in macrophage cholesterol content of which >60% is esterified. Although cytochalasin D inhibited LDL liposome-induced macrophage cholesteryl ester accumulation, LDL liposomes did not enter macrophages by phagocytosis. Rather, the LDL liposomes induced and entered surface-connected compartments within the macrophages, a unique endocytic pathway in these cells that we call patocytosis. LDL liposome apoB rather than LDL liposome lipid mediated LDL liposome uptake by macrophages. This was shown by the findings that: 1) protease treatment of the LDL liposomes prevented macrophage cholesterol accumulation; 2) liposomes prepared from LDL lipid extracts did not cause macrophage cholesterol accumulation; and 3) purified apoB induced and accumulated within macrophage surface-connected compartments. Although apoB mediated the macrophage uptake of LDL liposomes, this uptake did not occur through LDL, LDL receptor-related protein, or scavenger receptors. Also, LDL liposome uptake was not sensitive to treatment of macrophages with trypsin or heparinase. Cholesterol esterase-mediated transformation of LDL into cholesterol-rich liposomes is an LDL modification that: 1) stimulates uptake of LDL cholesterol by apoB-dependent endocytosis into surface-connected compartments, and 2) causes human monocyte-macrophage foam cell formation.
在动脉粥样硬化斑块中积聚的大部分胆固醇存在于单核细胞 - 巨噬细胞内，这些细胞会转化为“泡沫细胞”。天然低密度脂蛋白（LDL）不会导致泡沫细胞形成。用胆固醇酯酶处理LDL会将其转化为富含胆固醇的脂质体，其中未酯化形式的胆固醇含量>90%。在围绕泡沫细胞的早期动脉粥样硬化斑块中也发现了类似的富含胆固醇的脂质体。我们现在表明，由胆固醇酯酶处理的LDL产生的富含胆固醇的脂质体可导致人类单核细胞 - 巨噬细胞形成泡沫细胞，使巨噬细胞胆固醇含量增加3 - 5倍，其中>60%被酯化。虽然细胞松弛素D抑制LDL脂质体诱导的巨噬细胞胆固醇酯积累，但LDL脂质体并非通过吞噬作用进入巨噬细胞。相反，LDL脂质体诱导并进入巨噬细胞内与表面相连的区室，这是这些细胞中一种独特的内吞途径，我们称之为胞膜窖介导的内吞作用。巨噬细胞摄取LDL脂质体是由LDL脂质体载脂蛋白B（apoB）而非LDL脂质体脂质介导的。以下发现证明了这一点：1）对LDL脂质体进行蛋白酶处理可阻止巨噬细胞胆固醇积累；2）由LDL脂质提取物制备的脂质体不会导致巨噬细胞胆固醇积累；3）纯化的apoB诱导并积聚在巨噬细胞与表面相连的区室中。虽然apoB介导巨噬细胞对LDL脂质体的摄取，但这种摄取并非通过LDL、LDL受体相关蛋白或清道夫受体发生。此外，LDL脂质体的摄取对用胰蛋白酶或肝素酶处理巨噬细胞不敏感。胆固醇酯酶介导的LDL向富含胆固醇的脂质体的转化是一种LDL修饰，它：1）通过apoB依赖的内吞作用刺激LDL胆固醇摄取进入与表面相连的区室，2）导致人类单核细胞 - 巨噬细胞形成泡沫细胞。
