Acyl-coenzyme A:cholesterol acyltransferase promotes oxidized LDL/oxysterol-induced apoptosis in macrophages Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.M500101-JLR200
Acyl-coenzyme A:cholesterol acyltransferase promotes oxidized LDL/oxysterol-induced apoptosis in macrophages Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.M500101-JLR200
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酰基辅酶 A：胆固醇酰基转移酶促进氧化 LDL/氧甾醇诱导的巨噬细胞细胞凋亡已出版，JLR 论文出版，2005 年 7 月 1 日。DOI 10.1194/jlr.M500101-JLR200
作者：
Natalie E. Freeman;Antonio E. Rusiñol;M. Linton;D. Hachey;S. Fazio;M. Sinensky;D. Thewke
7-酮胆固醇 (7KC) 是氧化低密度脂蛋白 (OxLDL) 的细胞毒性成分，通过涉及胞质磷脂酶 A2 (cPLA2) 激活的机制诱导巨噬细胞凋亡。在当前的研究中，我们研究了 ACAT 在 7KC 诱导和 OxLDL 诱导的小鼠巨噬细胞凋亡中的作用。 ACAT 抑制剂 Sandoz 58-035 可抑制 7KC 诱导的 P388D1 细胞凋亡，以及 7KC 诱导和 OxLDL 诱导的小鼠腹膜巨噬细胞 (MPM) 细胞凋亡。此外，与野生型 MPM 相比，ACAT-1 缺陷的 MPM 对 7KC 诱导的和 OxLDL 诱导的细胞凋亡具有显着的抵抗力。用7KC处理的巨噬细胞积累了ACAT衍生的[14C]胆固醇和[3H]7-酮胆固醇酯。串联 LC-MS 显示 7KC 酯主要含有饱和和单不饱和脂肪酸。 cPLA2 的抑制剂花生四烯基三氟甲基酮可防止 7KC 酯的积累并抑制 7KC 诱导的 P388D1 细胞凋亡。通过补充油酸或花生四烯酸 (AA)，可以逆转因抑制 cPLA2 而导致的 7KC 酯积累减少；然而，只有补充AA才能恢复7KC对细胞凋亡的诱导。这些结果表明，7KC 不仅通过激活 cPLA2 启动细胞凋亡途径（如我们之前报道的那样），而且当被 ACAT 酯化形成 7KC-花生四烯酸时，还参与下游信号传导途径。
7-Ketocholesterol (7KC) is a cytotoxic component of oxidized low density lipoproteins (OxLDLs) and induces apoptosis in macrophages by a mechanism involving the activation of cytosolic phospholipase A2 (cPLA2). In the current study, we examined the role of ACAT in 7KC-induced and OxLDL-induced apoptosis in murine macrophages. An ACAT inhibitor, Sandoz 58-035, suppressed 7KC-induced apoptosis in P388D1 cells and both 7KC-induced and OxLDL-induced apoptosis in mouse peritoneal macrophages (MPMs). Furthermore, compared with wild-type MPMs, ACAT-1-deficient MPMs demonstrated significant resistance to both 7KC-induced and OxLDL-induced apoptosis. Macrophages treated with 7KC accumulated ACAT-derived [14C]cholesteryl and [3H]7-ketocholesteryl esters. Tandem LC-MS revealed that the 7KC esters contained primarily saturated and monounsaturated fatty acids. An inhibitor of cPLA2, arachidonyl trifluoromethyl ketone, prevented the accumulation of 7KC esters and inhibited 7KC-induced apoptosis in P388D1 cells. The decrease in 7KC ester accumulation produced by the inhibition of cPLA2 was reversed by supplementing with either oleic or arachidonic acid (AA); however, only AA supplementation restored the induction of apoptosis by 7KC. These results suggest that 7KC not only initiates the apoptosis pathway by activating cPLA2, as we have reported previously, but also participates in the downstream signaling pathway when esterified by ACAT to form 7KC-arachidonate.
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DOI：
10.1016/s0021-9258(19)57389-6
发表时间：
1988-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
K. M. Cadigan;J G Heider;T Y Chang
通讯作者：
K. M. Cadigan;J G Heider;T Y Chang
影响因子：
15.9
作者：
Accad, M;Smith, SJ;Farese, RV
通讯作者：
Farese, RV
影响因子：
6.5
作者：
K. Underwood;B. Andemariam;G. L. McWilliams;L. Liscum
通讯作者：
K. Underwood;B. Andemariam;G. L. McWilliams;L. Liscum
氧化低密度脂蛋白中发现的胆固醇氧化产物对内皮细胞损伤的表征。
影响因子：
6.5
作者：
Sevanian,A;Hodis,HN;Hwang,J;McLeod,LL;Peterson,H
通讯作者：
Peterson,H
花生四烯酸代谢和氧化 LDL/氧甾醇诱导细胞凋亡的信号通路。
影响因子：
6.5
作者：
Panini,SR;Yang,L;Rusinol,AE;Sinensky,MS;Bonventre,JV;Leslie,CC
通讯作者：
Leslie,CC