肉碱O-棕榈酰转移酶
巨噬细胞极化
肉碱
辅酶A
细胞生物学
生物
细胞内
氧化磷酸化
β氧化
化学
生物化学
新陈代谢
酶
巨噬细胞
体外
还原酶
作者
Ajit S. Divakaruni,Wei Yuan Hsieh,Lucía Minarrieta,Tin Duong,Kristen K.O. Kim,Brandon R. Desousa,Alexander Y. Andreyev,Caitlyn Bowman,Kacey L. Caradonna,Brian P. Dranka,David A. Ferrick,Marc Liesa,Linsey Stiles,George W. Rogers,Daniel Braas,Theodore P. Ciaraldi,Michael J. Wolfgang,Tim Sparwasser,Luciana Berod,Steven J. Bensinger,Anne N. Murphy
出处
期刊:Cell Metabolism
[Elsevier]
日期:2018-09-01
卷期号:28 (3): 490-503.e7
被引量:242
标识
DOI:10.1016/j.cmet.2018.06.001
摘要
Long-chain fatty acid (LCFA) oxidation has been shown to play an important role in interleukin-4 (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 coenzyme A (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.
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