دورية أكاديمية
أعرض في EDS

Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis.

التفاصيل البيبلوغرافية
العنوان: Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis.
المؤلفون: Divakaruni AS; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: adivakaruni@mednet.ucla.edu., Hsieh WY; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA., Minarrieta L; 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., Duong TN; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA., Kim KKO; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA., Desousa BR; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA., Andreyev AY; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA., Bowman CE; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Caradonna K; Agilent Technologies, 5301 Stevens Creek Boulevard, Santa Clara, CA 95051, USA., Dranka BP; Agilent Technologies, 5301 Stevens Creek Boulevard, Santa Clara, CA 95051, USA., Ferrick DA; Agilent Technologies, 5301 Stevens Creek Boulevard, Santa Clara, CA 95051, USA., Liesa M; Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Stiles L; Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Rogers GW; Agilent Technologies, 5301 Stevens Creek Boulevard, Santa Clara, CA 95051, USA., Braas D; 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., Ciaraldi TP; Veterans Affairs San Diego Healthcare System, La Jolla, CA 92161, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Wolfgang MJ; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Sparwasser T; 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., Berod L; 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., Bensinger SJ; 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., Murphy AN; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
المصدر: Cell metabolism [Cell Metab] 2018 Sep 04; Vol. 28 (3), pp. 490-503.e7. Date of Electronic Publication: 2018 Jun 28.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 101233170 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-7420 (Electronic) Linking ISSN: 15504131 NLM ISO Abbreviation: Cell Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, Mass. : Cell Press, c2005-
مواضيع طبية MeSH: Macrophages*/drug effects , Macrophages*/metabolism , Mitochondria*/drug effects , Mitochondria*/metabolism, Acyl Coenzyme A/*physiology , Enzyme Inhibitors/*pharmacology , Epoxy Compounds/*pharmacology , Homeostasis/*drug effects, 3T3 Cells ; A549 Cells ; Animals ; Carnitine O-Palmitoyltransferase/metabolism ; Fatty Acids/metabolism ; HCT116 Cells ; Hep G2 Cells ; Humans ; Interleukin-4/metabolism ; Liver/metabolism ; Macrophage Activation/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondrial ADP, ATP Translocases/metabolism ; Oxidative Phosphorylation/drug effects ; Rats ; Rats, Sprague-Dawley
مستخلص: 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 (EC 90  < 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.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
التعليقات: Comment in: Cell Metab. 2018 Oct 2;28(4):538-540. (PMID: 30282046)
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معلومات مُعتمدة: R01 AI122282 United States AI NIAID NIH HHS; R01 NS072241 United States NS NINDS NIH HHS; T32 GM007445 United States GM NIGMS NIH HHS; R01 NS087611 United States NS NINDS NIH HHS; P50 CA211015 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: CPT-1; CPT-2; coenzyme A; interleukin 4; long-chain fatty acid oxidation; macrophage polarization; mitochondria; oxidative phosphorylation; pantothenate
المشرفين على المادة: 0 (Acyl Coenzyme A)
0 (Enzyme Inhibitors)
0 (Epoxy Compounds)
0 (Fatty Acids)
124122-91-4 (etomoxiryl-coenzyme A)
207137-56-2 (Interleukin-4)
9068-80-8 (Mitochondrial ADP, ATP Translocases)
EC 2.3.1.21 (CPT1B protein, mouse)
EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
MSB3DD2XP6 (etomoxir)
تواريخ الأحداث: Date Created: 20180726 Date Completed: 20191004 Latest Revision: 20191023
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC6125190
DOI: 10.1016/j.cmet.2018.06.001
PMID: 30043752
قاعدة البيانات: MEDLINE
الوصف
تدمد:1932-7420
DOI:10.1016/j.cmet.2018.06.001