Journal
CELL METABOLISM
Volume 28, Issue 3, Pages 490-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2018.06.001
Keywords
-
Categories
Funding
- NIH [R01NS087611, R01AI122282, R01NS072241]
- American Heart Association
- Agilent Technologies
- HiLF and the Ellen-Schmidt Program from the Medical School Hannover
- Boehringer Ingelheim Fonds, Foundation for Basic Research in Medicine
Ask authors/readers for more resources
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 mM). 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available