Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis

Ajit S. Divakaruni, Wei Yuan Hsieh, Lucía Minarrieta, Tin N. Duong, Kristen K.O. Kim, Brandon R. Desousa, Alexander Y. Andreyev, Caitlyn E. Bowman, Kacey 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. BensingerAnne N. Murphy

Research output: Contribution to journalArticlepeer-review

103 Scopus citations


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. 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.

Original languageEnglish (US)
Pages (from-to)490-503.e7
JournalCell Metabolism
Issue number3
StatePublished - Sep 4 2018


  • CPT-1
  • CPT-2
  • coenzyme A
  • interleukin 4
  • long-chain fatty acid oxidation
  • macrophage polarization
  • mitochondria
  • oxidative phosphorylation
  • pantothenate

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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