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

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.

journal_name

Sci Rep

journal_title

Scientific reports

authors

O'Connor RS,Guo L,Ghassemi S,Snyder NW,Worth AJ,Weng L,Kam Y,Philipson B,Trefely S,Nunez-Cruz S,Blair IA,June CH,Milone MC

doi

10.1038/s41598-018-24676-6

subject

Has Abstract

pub_date

2018-04-19 00:00:00

pages

6289

issue

1

issn

2045-2322

pii

10.1038/s41598-018-24676-6

journal_volume

8

pub_type

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