Nordskog B K, Reagan J W, St Clair R W
Department of Pathology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
J Lipid Res. 1999 Oct;40(10):1806-17.
The extent to which cholesterol synthesis is modulated in macrophage foam cells by changes in cholesterol influx and efflux was determined using thioglycollate-elicited peritoneal macrophages from normal and cholesterol-fed White Carneau (WC) and Show Racer (SR) pigeons. In peritoneal macrophages from normocholesterolemic pigeons, sterol synthesis from [(14)C]-acetate was down-regulated by more than 90% following incubation in vitro with beta-VLDL. Sterol synthesis was increased when the cellular free cholesterol concentration was decreased in response to stimulation of cholesterol efflux with apoHDL/phosphatidylcholine vesicles and cyclodextrin. Peritoneal macrophages isolated from hypercholesterolemic pigeons were loaded with cholesterol to levels similar to foam cells from atherosclerotic plaques (375-614 microg/mg cell protein), and had an extremely low rate of sterol synthesis. When cholesterol efflux was stimulated in these cells, sterol synthesis increased 8 to 10-fold, even though the cells remained grossly loaded with cholesterol. Cholesterol efflux also stimulated HMG-CoA reductase activity and LDL receptor expression. This suggests that only a small portion of the total cholesterol pool in macrophage foam cells was responsible for regulation of sterol synthesis, and that cholesterol generated by hydrolysis of cholesteryl esters was directed away from the regulatory pool by efflux from the cells. When the increase in sterol synthesis was blocked with the HMG-CoA reductase inhibitor mevinolin, there was no difference in the cholesterol content of the cells, or in the mass efflux of cholesterol into the culture medium.Thus, under these conditions, the increase in cholesterol synthesis during stimulation of cholesterol efflux does not appear to contribute significantly to the mass of cholesterol in these macrophage foam cells. Whether a similar situation exists in vivo is unknown.
利用来自正常和喂食胆固醇的白卡诺（WC）鸽及赛鸽（SR）鸽的巯基乙酸盐诱导的腹腔巨噬细胞，确定了胆固醇流入和流出的变化对巨噬细胞泡沫细胞中胆固醇合成的调节程度。在正常胆固醇血症鸽的腹腔巨噬细胞中，体外与β-VLDL孵育后，[（14）C] - 乙酸盐的甾醇合成下调超过90％。当用载脂蛋白HDL/磷脂酰胆碱囊泡和环糊精刺激胆固醇流出，细胞游离胆固醇浓度降低时，甾醇合成增加。从高胆固醇血症鸽分离的腹腔巨噬细胞中的胆固醇含量与动脉粥样硬化斑块中的泡沫细胞相似（375 - 614微克/毫克细胞蛋白），甾醇合成率极低。当这些细胞中的胆固醇流出受到刺激时，甾醇合成增加8至10倍，即使细胞仍然大量负载胆固醇。胆固醇流出还刺激了HMG-CoA还原酶活性和LDL受体表达。这表明巨噬细胞泡沫细胞中总胆固醇池的只有一小部分负责甾醇合成的调节，并且胆固醇酯水解产生的胆固醇通过细胞流出而被引导远离调节池。当用HMG-CoA还原酶抑制剂美伐他汀阻断甾醇合成的增加时，细胞的胆固醇含量或胆固醇向培养基中的大量流出没有差异。因此，在这些条件下，胆固醇流出刺激期间胆固醇合成的增加似乎对这些巨噬细胞泡沫细胞中的胆固醇量没有显著贡献。体内是否存在类似情况尚不清楚。
