Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Metab. 2018 Sep 4;28(3):490-503.e7. doi: 10.1016/j.cmet.2018.06.001. Epub 2018 Jun 28.
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 (EC < 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.
长链脂肪酸 (LCFA) 的氧化被证明在白细胞介素-4 (IL-4) 介导的巨噬细胞极化 (M(IL-4)) 中发挥重要作用。然而，这些结论中的许多都是基于用高浓度的 etomoxir 抑制肉毒碱棕榈酰转移酶-1 得出的，而这种浓度远远超过抑制酶活性所需的浓度 (EC < 3 μM)。我们利用遗传和药理学模型证明，LCFA 的氧化对于 IL-4 驱动的极化作用在很大程度上是可有可无的。出乎意料的是，高浓度的 etomoxir 在没有 Cpt1a 或 Cpt2 表达的情况下仍保留了破坏 M(IL-4)极化的能力。尽管过量的 etomoxir 抑制了腺嘌呤核苷酸转位酶，但氧化磷酸化对于 M(IL-4)来说却是可有可无的。相反，极化的阻断可以追溯到细胞内游离辅酶 A (CoA) 的耗竭，这可能是由于前药 etomoxir 转化为活性 etomoxiryl CoA 所致。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认识的作用。
