2. Academic Validation
  3. The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations

The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations

  • Sci Rep. 2018 Apr 19;8(1):6289. doi: 10.1038/s41598-018-24676-6.
Roddy S O'Connor 1 2,  Lili Guo 3,  Saba Ghassemi 1 2,  Nathaniel W Snyder 4,  Andrew J Worth 3,  Liwei Weng 3,  Yoonseok Kam 5,  Benjamin Philipson 6,  Sophie Trefely 4,  Selene Nunez-Cruz 1 2,  Ian A Blair 3,  Carl H June 1 2,  Michael C Milone 7 8
Affiliations

Affiliations

  • 1 Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 2 Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
  • 3 Penn SRP center, Center of Excellence in Environmental Toxicology, and Department of Systems Pharmacology and Translational Therapeutics at the University of Pennsylvania, Philadelphia, PA, USA.
  • 4 A.J. Drexel Autism Institute, Drexel University, Philadelphia, PA, USA.
  • 5 Agilent Technologies Inc, Lexington, MA, USA.
  • 6 University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
  • 7 Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 8 Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. [email protected].
PMID: 29674640 DOI: 10.1038/s41598-018-24676-6
Abstract

Etomoxir (ETO) is a widely used small-molecule inhibitor of fatty acid oxidation (FAO) through its irreversible inhibitory effects on the carnitine palmitoyl-transferase 1a (CPT1a). We used this compound to evaluate the role of fatty acid oxidation in rapidly proliferating T cells following costimulation through the CD28 receptor. We show that ETO has a moderate effect on T cell proliferation with no observable effect on memory differentiation, but a marked effect on oxidative metabolism. We show that this oxidative metabolism is primarily dependent upon glutamine rather than FAO. Using an shRNA approach to reduce CPT1a in T cells, we further demonstrate that the inhibition of oxidative metabolism in T cells by ETO is independent of its effects on FAO at concentrations exceeding 5 μM. Concentrations of ETO above 5 μM induce acute production of ROS with associated evidence of severe oxidative stress in proliferating T cells. In aggregate, these data indicate that ETO lacks specificity for CTP1a above 5 μM, and caution should be used when employing this compound for studies in cells due to its non-specific effects on oxidative metabolism and cellular redox.

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