@article{c9abfab0c72a4e958222b8e9757427c0,
title = "Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis",
abstract = "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.",
keywords = "CPT-1, CPT-2, coenzyme A, interleukin 4, long-chain fatty acid oxidation, macrophage polarization, mitochondria, oxidative phosphorylation, pantothenate",
author = "Divakaruni, {Ajit S.} and Hsieh, {Wei Yuan} and Luc{\'i}a Minarrieta and Duong, {Tin N.} and Kim, {Kristen K.O.} and Desousa, {Brandon R.} and Andreyev, {Alexander Y.} and Bowman, {Caitlyn E.} and Kacey Caradonna and Dranka, {Brian P.} and Ferrick, {David A.} and Marc Liesa and Linsey Stiles and Rogers, {George W.} and Daniel Braas and Ciaraldi, {Theodore P.} and Wolfgang, {Michael J.} and Tim Sparwasser and Luciana Berod and Bensinger, {Steven J.} and Murphy, {Anne N.}",
note = "Funding Information: This work was supported by the NIH (R01NS087611 to A.N.M., R01AI122282 to S.J.B., and R01NS072241 to M.J.W.), American Heart Association grant-in-aid to S.J.B., and Agilent Technologies (to A.S.D. and A.N.M.). L.B. was funded by HiLF and the Ellen-Schmidt Program from the Medical School Hannover and L.M. by a PhD fellowship from the Boehringer Ingelheim Fonds, Foundation for Basic Research in Medicine. This material is the result of work supported with resources and the use of facilities at the VA San Diego Medical Center. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government. Funding Information: This work was supported by the NIH ( R01NS087611 to A.N.M., R01AI122282 to S.J.B., and R01NS072241 to M.J.W.), American Heart Association grant-in-aid to S.J.B., and Agilent Technologies (to A.S.D. and A.N.M.). L.B. was funded by HiLF and the Ellen-Schmidt Program from the Medical School Hannover and L.M. by a PhD fellowship from the Boehringer Ingelheim Fonds, Foundation for Basic Research in Medicine . This material is the result of work supported with resources and the use of facilities at the VA San Diego Medical Center. The contents do not represent the views of the US Department of Veterans Affairs or the United States Government. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = sep,
day = "4",
doi = "10.1016/j.cmet.2018.06.001",
language = "English (US)",
volume = "28",
pages = "490--503.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "3",
}