Enhanced SCAP glycosylation by inflammation induces macrophage foam cell formation.
Enhanced SCAP glycosylation by inflammation induces macrophage foam cell formation.
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炎症增强的 SCAP 糖基化诱导巨噬细胞泡沫细胞形成
DOI：
10.1371/journal.pone.0075650
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ruan XZ
中科院分区：
文献类型：
--
作者：
Zhou C;Lei H;Chen Y;Liu Q;Li LC;Moorhead JF;Varghese Z;Ruan XZ
炎症应激通过破坏巨噬细胞中的LDL受体反馈调节促进泡沫细胞的形成。甾醇调节元件结合蛋白（SREBPs）裂解激活蛋白（SCAP）糖基化在调节LDL受体和3-羟基-3-甲基戊二酰辅酶a还原酶（HMGCoAR）反馈调节中起着至关重要的作用。本研究旨在探讨炎症应激是否通过影响THP-1巨噬细胞中SCAP糖基化而破坏LDL受体和HMGCoAR反馈调节。采用油红O染色定量测定细胞内胆固醇含量。采用实时定量RT-PCR和Western blotting检测控制胆固醇稳态的分子表达。用共聚焦显微镜检测SCAP从内质网（ER）向高尔基体的移位。我们证明，暴露于炎症细胞因子会增加THP-1巨噬细胞中的脂质积累，即使在高浓度LDL存在的情况下，SCAP表达也会增加。这些炎性细胞因子还通过高尔基甘露糖苷酶II的表达升高而增强SCAP的糖基化，从而延长SCAP的半衰期。这可能会促进内质网和高尔基体之间SCAP的易位和再循环，将更多的SREBP2从内质网运送到高尔基体，通过蛋白水解裂解激活，SREBP2的n端增加（活性形式）就是证据。结果，LDL受体和HMGCoAR表达上调。有趣的是，这些作用可以被高尔基甘露糖苷酶抑制剂阻断。我们的研究结果表明，炎症增加了天然LDL的摄取和内源性胆固醇的新生合成，从而通过增加巨噬细胞中SCAP的转录和蛋白糖基化导致泡沫细胞的形成。这些数据表明，高尔基加工酶抑制剂可能在预防动脉粥样硬化泡沫细胞形成方面具有潜在的血管保护作用。
Inflammatory stress promotes foam cell formation by disrupting LDL receptor feedback regulation in macrophages. Sterol Regulatory Element Binding Proteins (SREBPs) Cleavage-Activating Protein (SCAP) glycosylation plays crucial roles in regulating LDL receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR) feedback regulation. The present study was to investigate if inflammatory stress disrupts LDL receptor and HMGCoAR feedback regulation by affecting SCAP glycosylation in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assay. The expression of molecules controlling cholesterol homeostasis was examined using real-time quantitative RT-PCR and Western blotting. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. We demonstrated that exposure to inflammatory cytokines increased lipid accumulation in THP-1 macrophages, accompanying with an increased SCAP expression even in the presence of a high concentration of LDL. These inflammatory cytokines also prolonged the half-life of SCAP by enhancing glycosylation of SCAP due to the elevated expression of the Golgi mannosidase II. This may enhance translocation and recycling of SCAP between the ER and the Golgi, escorting more SREBP2 from the ER to the Golgi for activation by proteolytic cleavages as evidenced by an increased N-terminal of SREBP2 (active form). As a consequence, the LDL receptor and HMGCoAR expression were up-regulated. Interestingly, these effects could be blocked by inhibitors of Golgi mannosidases. Our results indicated that inflammation increased native LDL uptake and endogenous cholesterol de novo synthesis, thereby causing foam cell formation via increasing transcription and protein glycosylation of SCAP in macrophages. These data imply that inhibitors of Golgi processing enzymes might have a potential vascular-protective role in prevention of atherosclerotic foam cell formation.
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影响因子：
64.5
作者：
DUNPHY, WG;BRANDS, R;ROTHMAN, JE
通讯作者：
ROTHMAN, JE
影响因子：
56.9
作者：
BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL
影响因子：
2.8
作者：
Kzhyshkowska, Julia;Neyen, Claudine;Gordon, Siamon
通讯作者：
Gordon, Siamon
DOI：
10.1038/nri3073
发表时间：
2011-10-14
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
动脉粥样硬化的炎症。
DOI：
10.1161/atvbaha.108.179705
发表时间：
2012-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Libby P
通讯作者：
Libby P