Effects of cellular cholesterol loading on macrophage foam cell lysosome acidification
Effects of cellular cholesterol loading on macrophage foam cell lysosome acidification
复制标题
DOI：
10.1194/jlr.m600390-jlr200
复制
发表时间：
2007-05-01
影响因子：
6.5
通讯作者：
Jerome, W. Gray
中科院分区：
文献类型：
--
作者：
Cox, Brian E.;Griffin, Evelyn E.;Jerome, W. Gray
巨噬细胞与轻度氧化的低密度脂蛋白(OxLDL)、聚集的低密度脂蛋白(AggLDL)或富含胆固醇酯的脂类分散体(DISPs)孵育后，在溶酶体中积累胆固醇，随后抑制溶酶体胆固醇酯(CE)的水解。含胆固醇颗粒的多样性表明，抑制作用可能与溶酶体的一般变化有关。溶酶体的pH是活性的关键介体，因此也是脂类诱导抑制的潜在机制。我们研究了胆固醇积聚对THP-1巨噬细胞溶酶体pH的影响。用OxLDL、AggLDL和DISPs处理后，溶酶体维持活性pH的能力受到抑制，CE水解率随之降低。与溶酶体功能的全面破坏一致，暴露于OxLDL或AggLDL可减少溶酶体载脂蛋白B的降解。在使用乙酰化低密度脂蛋白(AcLDL)负载的相当于胆固醇的细胞中，没有观察到溶酶体胆固醇的隔离和失活。然而，在黄体酮存在的情况下，AcLDL衍生的胆固醇(以阻止溶酶体的胆固醇外泄)抑制了溶酶体的酸化。溶酶体抑制不能归因于空泡ATPase总水平的降低。然而，在分离的溶酶体中，膜胆固醇的增加抑制了液泡ATPase依赖的H1离子向溶酶体的泵入。这些数据表明，溶酶体胆固醇积聚改变溶酶体的方式可能会加剧泡沫细胞的形成，并影响动脉粥样硬化病变的发展。
Macrophages incubated with mildly oxidized low density lipoprotein (OxLDL), aggregated low density lipoprotein (AggLDL), or cholesteryl ester-rich lipid dispersions (DISPs) accumulate cholesterol in lysosomes followed by an inhibition of lysosomal cholesteryl ester (CE) hydrolysis. The variety of cholesterol-containing particles producing inhibition of hydrolysis suggests that inhibition may relate to general changes in lysosomes. Lysosome pH is a key mediator of activity and thus is a potential mechanism for lipid-induced inhibition. We investigated the effects of cholesterol accumulation on THP-1 macrophage lysosome pH. Treatment with OxLDL, AggLDL, and DISPs resulted in inhibition of the lysosome's ability to maintain an active pH and concomitant decreases in CE hydrolysis. Consistent with an overall disruption of lysosome function, exposure to OxLDL or AggLDL reduced lysosomal apolipoprotein B degradation. The lysosomal cholesterol sequestration and inactivation are not observed in cholesterol-equivalent cells loaded using acetylated low density lipoprotein ( AcLDL). However, AcLDL-derived cholesterol in the presence of progesterone ( to block cholesterol egression from lysosomes) inhibited lysosome acidification. Lysosome inhibition was not attributable to a decrease in the overall levels of vacuolar ATPase. However, augmentation of membrane cholesterol in isolated lysosomes inhibited vacuolar ATPase-dependent pumping of H 1 ions into lysosomes. These data indicate that lysosomal cholesterol accumulation alters lysosomes in ways that could exacerbate foam cell formation and influence atherosclerotic lesion development.