Perilipin 2 (PLIN2)-deficiency does not increase cholesterol-induced toxicity in macrophages.
Perilipin 2 (PLIN2)-deficiency does not increase cholesterol-induced toxicity in macrophages.
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DOI：
10.1371/journal.pone.0033063
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Paul A
中科院分区：
文献类型：
--
作者：
Son SH;Goo YH;Chang BH;Paul A
对巨噬细胞/泡沫细胞进行干预，将细胞内胆固醇转向外排途径，可能成为我们对抗动脉粥样硬化治疗武器库中非常有价值的补充。然而，对胆固醇酯循环的某些操作，如抑制ACAT1（一种内质网驻留酶，可使胆固醇再酯化），并不能很好地耐受。先前我们发现，靶向巨噬细胞中的主要脂滴（LD）相关蛋白periilipin -2 （PLIN2）可以阻止泡沫细胞的形成并防止动脉粥样硬化。在这里，我们评估了plin2缺陷的骨髓源性巨噬细胞（BMM）对几种类似于动脉粥样硬化发展过程中发现的脂质负荷条件的耐受性，包括暴露于改性低密度脂蛋白（mLDL）和7-酮胆固醇（7-KC），一种游离胆固醇（FC）代谢物，在有或没有胆固醇受体的培养基中。从表达或不表达PLIN2的小鼠分离的BMM进行细胞凋亡（TUNEL和cleaved caspase-3）、内质网应激（CHOP诱导和XBP-1剪接）和炎症（TNF-α和IL-6 mRNA水平）的检测。与其他细胞类型一样，PLIN2缺乏会损害BMM中LD的积累。然而，在ACAT抑制和7-KC负荷下，巨噬细胞中的大多数应激参数升高，PLIN2失活的耐受性良好。这些数据支持靶向PLIN2预防泡沫细胞形成和动脉粥样硬化的安全性。
Interventions on macrophages/foam cells to redirect intracellular cholesterol towards efflux pathways could become a very valuable addition to our therapeutic arsenal against atherosclerosis. However, certain manipulations of the cholesteryl ester cycle, such as the inhibition of ACAT1, an ER-resident enzyme that re-esterifies cholesterol, are not well tolerated. Previously we showed that targeting perilipin-2 (PLIN2), a major lipid droplet (LD)-associated protein in macrophages, prevents foam cell formation and protects against atherosclerosis. Here we have assessed the tolerance of PLIN2-deficient bone marrow derived macrophages (BMM) to several lipid loading conditions similar to the found during atherosclerosis development, including exposure to modified low-density lipoprotein (mLDL) and 7-ketocholesterol (7-KC), a free cholesterol (FC) metabolite, in media with or without cholesterol acceptors. BMM isolated from mice that do or do not express PLIN2 were tested for apoptosis (TUNEL and cleaved caspase-3), ER stress (CHOP induction and XBP-1 splicing), and inflammation (TNF-α and IL-6 mRNA levels). Like in other cell types, PLIN2 deficiency impairs LD buildup in BMM. However, while most stress parameters were elevated in macrophages under ACAT inhibition and 7-KC loading, PLIN2 inactivation was well tolerated. The data support the safety of targeting PLIN2 to prevent foam cell formation and atherosclerosis.
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影响因子：
64.5
作者：
Moore KJ;Tabas I
通讯作者：
Tabas I
影响因子：
6.5
作者：
Kimmel AR;Brasaemle DL;McAndrews-Hill M;Sztalryd C;Londos C
通讯作者：
Londos C
DOI：
10.1161/01.atv.0000115638.27381.97
发表时间：
2004-03-01
影响因子：
8.7
作者：
Larigauderie, G;Furman, C;Rouis, M
通讯作者：
Rouis, M
DOI：
10.1016/s1388-1981(01)00121-4
发表时间：
2001-05-31
影响因子：
4.8
作者：
Buechler, C;Ritter, M;Schmitz, G
通讯作者：
Schmitz, G
影响因子：
21.3
作者：
Feng, B;Yao, PM;Tabas, I
通讯作者：
Tabas, I