Kunjathoor Vidya V, Febbraio Maria, Podrez Eugene A, Moore Kathryn J, Andersson Lorna, Koehn Stephanie, Rhee Jeongmi S, Silverstein Roy, Hoff Henry F, Freeman Mason W
Lipid Metabolism Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
J Biol Chem. 2002 Dec 20;277(51):49982-8. doi: 10.1074/jbc.M209649200. Epub 2002 Oct 9.
Modification of low density lipoprotein (LDL) can result in the avid uptake of these lipoproteins via a family of macrophage transmembrane proteins referred to as scavenger receptors (SRs). The genetic inactivation of either of two SR family members, SR-A or CD36, has been shown previously to reduce oxidized LDL uptake in vitro and atherosclerotic lesions in mice. Several other SRs are reported to bind modified LDL, but their contribution to macrophage lipid accumulation is uncertain. We generated mice lacking both SR-A and CD36 to determine their combined impact on macrophage lipid uptake and to assess the contribution of other SRs to this process. We show that SR-A and CD36 account for 75-90% of degradation of LDL modified by acetylation or oxidation. Cholesteryl ester derived from modified lipoproteins fails to accumulate in macrophages taken from the double null mice, as assessed by histochemistry and gas chromatography-mass spectrometry. These results demonstrate that SR-A and CD36 are responsible for the preponderance of modified LDL uptake in macrophages and that other scavenger receptors do not compensate for their absence.
低密度脂蛋白（LDL）的修饰可导致这些脂蛋白通过一类被称为清道夫受体（SRs）的巨噬细胞跨膜蛋白被大量摄取。先前已表明，两种SR家族成员SR-A或CD36中的任何一种发生基因失活，均可在体外减少氧化LDL的摄取，并减少小鼠的动脉粥样硬化病变。据报道，其他几种SR也可结合修饰的LDL，但其对巨噬细胞脂质蓄积的作用尚不确定。我们培育出同时缺乏SR-A和CD36的小鼠，以确定它们对巨噬细胞脂质摄取的联合影响，并评估其他SR在这一过程中的作用。我们发现，SR-A和CD36占乙酰化或氧化修饰LDL降解的75%-90%。通过组织化学和气相色谱-质谱分析评估，来自修饰脂蛋白的胆固醇酯未能在双敲除小鼠的巨噬细胞中蓄积。这些结果表明，SR-A和CD36是巨噬细胞摄取修饰LDL的主要原因，且其他清道夫受体无法弥补它们的缺失。
