Division of Biopharmaceutics, University Medical Center Groningen, The Netherlands.
Circ Res. 2010 Dec 10;107(12):e20-31. doi: 10.1161/CIRCRESAHA.110.226282. Epub 2010 Nov 11.
macrophages cannot limit the uptake of lipids and rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ATP-binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol to lipid-poor apolipoprotein AI, and scavenger receptor class B type I (SR-BI), which promotes efflux to mature high-density lipoprotein.
the aim of the present study was to increase the insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis.
low-density lipoprotein receptor knockout (LDLr KO) mice were transplanted with bone marrow from ABCA1/SR-BI double knockout mice, the respective single knockouts, or wild-type littermates. Serum cholesterol levels were lower in ABCA1/SR-BI double knockout transplanted animals, as compared to the single knockout and wild-type transplanted animals on Western-type diet. Despite the lower serum cholesterol levels, massive foam cell formation was found in macrophages from spleen and the peritoneal cavity. Interestingly, ABCA1/SR-BI double knockout transplanted animals also showed a major increase in proinflammatory KC (murine interleukin-8) and interleukin-12p40 levels in the circulation. Furthermore, after 10 weeks of Western-type diet feeding, atherosclerotic lesion development in the aortic root was more extensive in the LDLr KO mice reconstituted with ABCA1/SR-BI double knockout bone marrow.
deletion of ABCA1 and SR-BI in bone marrow-derived cells enhances in vivo macrophage foam cell formation and atherosclerotic lesion development in LDLr KO mice on Western diet, indicating that under high dietary lipid conditions, both macrophage ABCA1 and SR-BI contribute significantly to cholesterol homeostasis in the macrophage in vivo and are essential for reducing the risk for atherosclerosis.
巨噬细胞不能限制脂质的摄取，并且依赖胆固醇外排机制来维持细胞内胆固醇的稳态。胆固醇外排的重要介质是 ATP 结合盒转运体 1（ABCA1），它介导胆固醇向富含脂质的载脂蛋白 AI 的外排，以及清道夫受体 B 类 I 型（SR-BI），它促进向成熟的高密度脂蛋白的外排。
本研究旨在深入了解 ABCA1 和 SR-BI 在泡沫细胞形成和动脉粥样硬化中的协同作用。
低密度脂蛋白受体敲除（LDLr KO）小鼠接受 ABCA1/SR-BI 双敲除小鼠、各自的单敲除小鼠或野生型同窝小鼠的骨髓移植。与单敲除和野生型移植动物相比，在西方饮食中，ABCA1/SR-BI 双敲除移植动物的血清胆固醇水平较低。尽管血清胆固醇水平较低，但在来自脾脏和腹腔的巨噬细胞中发现了大量泡沫细胞形成。有趣的是，ABCA1/SR-BI 双敲除移植动物的循环中促炎 KC（鼠白细胞介素-8）和白细胞介素-12p40 水平也显著增加。此外，在西方饮食喂养 10 周后，ABCA1/SR-BI 双敲除骨髓重建的 LDLr KO 小鼠主动脉根部的动脉粥样硬化病变发展更为广泛。
骨髓源性细胞中 ABCA1 和 SR-BI 的缺失增强了 LDLr KO 小鼠在西方饮食中的体内巨噬细胞泡沫细胞形成和动脉粥样硬化病变发展，表明在高膳食脂质条件下，巨噬细胞 ABCA1 和 SR-BI 都显著有助于体内巨噬细胞胆固醇稳态，并有助于降低动脉粥样硬化风险。
