EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance

Abstract

We previously showed that global deletion of the cytochrome P450 epoxygenase Cyp2c44, a major epoxyeicosatrienoic acid (EET)–producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water-soluble EET analog restores insulin signaling in vivo in Cyp2c44−/− mice and investigated the underlying mechanisms by which this effect is exerted. Cyp2c44−/− mice treated with the analog disodium 13-(3-pentylureido)tridec-8(Z)-enoyl)-LL-aspartate2 (EET-A) for 4 weeks improved fasting glucose and glucose tolerance compared with Cyp2c44−/− mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes, and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor-β (IRβ) is impaired in primary Cyp2c44−/− hepatocytes and that this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRβ in membrane-rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRβ and potentiating insulin signaling.