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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??M. Concentrations of ETO above 5??M 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??M, 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.

SUBMITTER: O'Connor RS

PROVIDER: S-EPMC5908836 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other

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

O'Connor Roddy S RS Guo Lili L Ghassemi Saba S Snyder Nathaniel W NW Worth Andrew J AJ Weng Liwei L Kam Yoonseok Y Philipson Benjamin B Trefely Sophie S Nunez-Cruz Selene S Blair Ian A IA June Carl H CH Milone Michael C MC

Scientific reports 20180419 1

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 sho ...[more]

PMID: 29674640

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Project description:BACKGROUND:Hypernatraemia is common in inpatients and is associated with substantial morbidity. Its differential diagnosis is challenging, and delayed treatment may have devastating consequences. The most important hormone for the regulation of water homeostasis is arginine vasopressin, and copeptin, the C-terminal portion of the precursor peptide of arginine vasopressin, might be a reliable new parameter with which to assess the underlying cause of hypernatraemia. METHODS:In this prospective, multicentre, observational study conducted in two tertiary referral centres in Switzerland, 92 patients with severe hyperosmolar hypernatraemia (Na+ > 155 mmol/L) were included. After a standardised diagnostic evaluation, the underlying cause of hypernatraemia was identified and copeptin levels were measured. RESULTS:The most common aetiology of hypernatraemia was dehydration (DH) (n = 65 [71%]), followed by salt overload (SO) (n = 20 [22%]), central diabetes insipidus (CDI) (n = 5 [5%]) and nephrogenic diabetes insipidus (NDI) (n = 2 [2%]). Low urine osmolality was indicative for patients with CDI and NDI (P < 0.01). Patients with CDI had lower copeptin levels than patients with DH or SO (both P < 0.01) or those with NDI. Copeptin identified CDI with an AUC of 0.99 (95% CI 0.97-1.00), and a cut-off value ≤ 4.4pmol/L showed a sensitivity of 100% and a specificity of 99% to predict CDI. Similarly, urea values were lower in CDI than in DH or SO (P < 0.05 and P < 0.01, respectively) or NDI. The AUC for diagnosing CDI was 0.98 (95% CI 0.96-1.00), and a cut-off value < 5.05 mmol/L showed high specificity and sensitivity for the diagnosis of CDI (98% and 100%, respectively). Copeptin and urea could not differentiate hypernatraemia induced by DH from that induced by SO (P = 0.66 and P = 0.30, respectively). CONCLUSIONS:Copeptin and urea reliably identify patients with CDI and are therefore helpful tools for therapeutic management in patients with severe hypernatraemia. TRIALS REGISTRATION:ClinicalTrials.gov, NCT01456533 . Registered on 20 October 2011.

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

Publications

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

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