Inhibition of CYP2E1 attenuates myocardial dysfunction in a murine model of insulin resistance through NLRP3-mediated regulation of mitophagy

Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):206-217. doi: 10.1016/j.bbadis.2018.08.017. Epub 2018 Aug 16.


Insulin resistance leads to myocardial contractile dysfunction and deranged autophagy although the underlying mechanism or targeted therapeutic strategy is still lacking. This study was designed to examine the impact of inhibition of the cytochrome P450 2E1 (CYP2E1) enzyme on myocardial function and mitochondrial autophagy (mitophagy) in an Akt2 knockout model of insulin resistance. Adult wild-type (WT) and Akt2-/- mice were treated with the CYP2E1 inhibitor diallyl sulfide (100 mg/kg/d, i.p.) for 4 weeks. Cardiac geometry and function were assessed using echocardiographic and IonOptix systems. Western blot analysis was used to evaluate autophagy, mitophagy, inducible NOS (iNOS), and the NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex. Akt2 deletion triggered insulin resistance, compromised cardiac contractile and intracellular Ca2+ property, mitochondrial ultrastructural damage, elevated O2- production, as well as suppressed autophagy and mitophagy, accompanied with elevated levels of NLRP3 and iNOS, the effects of which were significantly attenuated or ablated by diallyl sulfide. In vitro studies revealed that the NLRP3 activator nigericin nullified diallyl sulfide-offered benefit against Akt2 knockout on cardiomyocyte mechanical function and mitophagy (using Western blot and colocalization of GFP-LC3 and MitoTracker Red). Moreover, inhibition of iNOS but not mitochondrial ROS production attenuated Akt2 deletion-induced activation of NLRP3, substantiating a role for iNOS-mediated NLRP3 in insulin resistance-induced changes in mitophagy and cardiac dysfunction. In conclusion, these data depict that insulin resistance through CYP2E1 may contribute to the pathogenesis of myopathic changes including myocardial contractile dysfunction, oxidative stress and mitochondrial injury, possibly through activation of iNOS and NLRP3 signaling.

Keywords: CYP2E1; Cardiac function; Insulin resistance; Mitophagy; NLRP3; iNOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Cardiomyopathies / metabolism*
  • Cytochrome P-450 CYP2E1 / drug effects
  • Cytochrome P-450 CYP2E1 / metabolism*
  • Cytochrome P-450 CYP2E1 Inhibitors / pharmacology
  • Disease Models, Animal
  • Inflammasomes / metabolism
  • Insulin Resistance / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitophagy / physiology*
  • Myocardial Contraction
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Nitric Oxide Synthase Type II / metabolism
  • Oxidative Stress
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction


  • Cytochrome P-450 CYP2E1 Inhibitors
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Cytochrome P-450 CYP2E1
  • cytochrome P-450 2E1, mouse
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt