Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis

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 (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.

Keywords: CPT-1; CPT-2; coenzyme A; interleukin 4; long-chain fatty acid oxidation; macrophage polarization; mitochondria; oxidative phosphorylation; pantothenate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • A549 Cells
  • Acyl Coenzyme A / physiology*
  • Animals
  • Carnitine O-Palmitoyltransferase / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Epoxy Compounds / pharmacology*
  • Fatty Acids / metabolism
  • HCT116 Cells
  • Hep G2 Cells
  • Homeostasis / drug effects*
  • Humans
  • Interleukin-4 / metabolism
  • Liver / metabolism
  • Macrophage Activation / drug effects
  • Macrophages* / drug effects
  • Macrophages* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria* / drug effects
  • Mitochondria* / metabolism
  • Mitochondrial ADP, ATP Translocases / metabolism
  • Oxidative Phosphorylation / drug effects
  • Rats
  • Rats, Sprague-Dawley


  • Acyl Coenzyme A
  • Enzyme Inhibitors
  • Epoxy Compounds
  • Fatty Acids
  • etomoxiryl-coenzyme A
  • Interleukin-4
  • Mitochondrial ADP, ATP Translocases
  • CPT1B protein, mouse
  • Carnitine O-Palmitoyltransferase
  • etomoxir