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Cell Metab. 2018 Sep 4;28(3):490-503.e7. doi: 10.1016/j.cmet.2018.06.001. Epub 2018 Jun 28.

Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis.

Author information

1
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: adivakaruni@mednet.ucla.edu.
2
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
4
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
5
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
6
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
7
Agilent Technologies, 5301 Stevens Creek Boulevard, Santa Clara, CA 95051, USA.
8
Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
9
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; UCLA Metabolomics Center and Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
10
Veterans Affairs San Diego Healthcare System, La Jolla, CA 92161, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
11
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.

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.

KEYWORDS:

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

PMID:
30043752
PMCID:
PMC6125190
[Available on 2019-09-04]
DOI:
10.1016/j.cmet.2018.06.001

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