Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis.
Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis.
复制标题
依托莫西酯通过破坏CoA稳态抑制巨噬细胞极化。
DOI：
10.1016/j.cmet.2018.06.001
复制
发表时间：
2018-09-04
期刊：
影响因子：
29
通讯作者：
Murphy AN
中科院分区：
文献类型：
--
作者：
Divakaruni AS;Hsieh WY;Minarrieta L;Duong TN;Kim KKO;Desousa BR;Andreyev AY;Bowman CE;Caradonna K;Dranka BP;Ferrick DA;Liesa M;Stiles L;Rogers GW;Braas D;Ciaraldi TP;Wolfgang MJ;Sparwasser T;Berod L;Bensinger SJ;Murphy AN
已证明长链脂肪酸（LCFA）氧化在IL-4介导的巨噬细胞极化中起重要作用[M（IL-4）]。然而，这些结论中的许多是基于高浓度的依托莫西对肉毒碱棕榈酰转移酶-1的抑制作用，该浓度远远超过抑制酶活性所需的浓度（EC 90 < 3 μM）。我们采用遗传学和药理学模型来证明LCFA氧化在很大程度上是IL-4驱动的极化。出乎意料的是，高浓度的依托莫西在没有Cpt 1a或Cpt 2表达的情况下保留了破坏M（IL-4）极化的能力。尽管过量的依托莫西抑制腺嘌呤核苷酸移位酶，但令人惊讶的是M（IL-4）的氧化磷酸化被抑制。相反，极化的阻断被追踪到细胞内游离CoA的消耗，这可能是由前药etomoxir转化为活性etomoxiryl-CoA引起的。这些研究有助于解释过量etomoxir对免疫细胞的影响，并揭示了CoA代谢在巨噬细胞极化中的未被重视的作用。CPT-1抑制剂etomoxir已被用于表明长链脂肪酸（LCFA）氧化是替代性巨噬细胞活化所必需的。Divakaruni及其同事现在表明，LCFA氧化是可逆的。他们证明了依托莫西的多种脱靶效应，并显示依托莫西对辅酶A的消耗阻断了M（IL-4）分化。
Long chain fatty acid (LCFA) oxidation has been shown to play an important role in IL-4-mediated macrophage polarization [M(IL-4)]. However, many of these conclusions are based on the inhibition of carnitine palmitoyltransferase-1 with high concentrations of etomoxir that far exceed what is required to inhibit enzyme activity (EC90 < 3 μM). We employ genetic and pharmacologic models to demonstrate that LCFA oxidation is largely dispensable for IL-4-driven polarization. Unexpectedly, high concentrations of etomoxir retained the ability to disrupt M(IL-4) polarization in the absence of Cpt1a or Cpt2 expression. Although excess etomoxir inhibits the adenine nucleotide translocase, oxidative phosphorylation is surprisingly dispensable for M(IL-4). Instead, the block in polarization was traced to depletion of intracellular free CoA, likely resulting from conversion of the pro-drug etomoxir into active etomoxiryl-CoA. These studies help explain the effect(s) of excess etomoxir on immune cells, and reveal an unappreciated role for CoA metabolism in macrophage polarization. The CPT-1 inhibitor etomoxir has been used to suggest long chain fatty acid (LCFA) oxidation is necessary for alternative macrophage activation. Divakaruni and colleagues now show that LCFA oxidation is dispensable. They demonstrate multiple off-target effects of etomoxir, and show that depletion of coenzyme A by etomoxir blocks M(IL-4) differentiation.
登录
查看更多内容
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caton ML;Smith-Raska MR;Reizis B
通讯作者：
Reizis B
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
DOI：
10.1083/jcb.201612067
发表时间：
2017-04-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Divakaruni AS;Wallace M;Buren C;Martyniuk K;Andreyev AY;Li E;Fields JA;Cordes T;Reynolds IJ;Bloodgood BL;Raymond LA;Metallo CM;Murphy AN
通讯作者：
Murphy AN
影响因子：
14.8
作者：
Chen WW;Freinkman E;Sabatini DM
通讯作者：
Sabatini DM