Increased CYP2J3 Expression Reduces Insulin Resistance in Fructose-Treated Rats and db/db Mice

Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Diabetes (Impact Factor: 8.1). 04/2010; 59(4):997-1005. DOI: 10.2337/db09-1241
Source: PubMed


Accumulating evidence suggests that cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play crucial and diverse roles in cardiovascular homeostasis. The anti-inflammatory, antihypertensive, and pro-proliferative effects of EETs suggest a possible beneficial role for EETs on insulin resistance and diabetes.
This study investigated the effects of CYP2J3 epoxygenase gene therapy on insulin resistance and blood pressure in diabetic db/db mice and in a model of fructose-induced hypertension and insulin resistance in rats.
CYP2J3 gene delivery in vivo increased EET generation, reduced blood pressure, and reversed insulin resistance as determined by plasma glucose levels, homeostasis model assessment insulin resistance index, and glucose tolerance test. Furthermore, CYP2J3 treatment prevented fructose-induced decreases in insulin receptor signaling and phosphorylation of AMP-activated protein kinases (AMPKs) in liver, muscle, heart, kidney, and aorta. Thus, overexpression of CYP2J3 protected against diabetes and insulin resistance in peripheral tissues through activation of insulin receptor and AMPK pathways.
These results highlight the beneficial roles of the CYP epoxygenase-EET system in diabetes and insulin resistance.

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Available from: Matthew L Edin, Mar 19, 2014
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    • "Similar to the reduction in blood glucose levels, in the HFD+STZ/NA mice, t-AUCB caused a 17% reduction in post-ischemic insulin levels compared to vehicle-treated HFD+STZ/NA, although this effect was not statistically significant. Likewise, enhancing EETs has been shown to enhance insulin signaling and improve insulin sensitivity [39], [44]–[46]. Luo et al. showed that either deletion of the sEH-coding gene or pharmacological inhibition of sEH attenuated hyperglycemia in STZ-treated mice, a model for type 1 diabetes [46]. They found that sEH inhibition improved STZ hyperglycemia by directly limiting STZ-mediated damage to pancreatic β-cells [46]. "
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    ABSTRACT: Inhibition of soluble epoxide hydrolase (sEH) is a potential target of therapy for ischemic injury. sEH metabolizes neuroprotective epoxyeicosatrienoic acids (EETs). We recently demonstrated that sEH inhibition reduces infarct size after middle cerebral artery occlusion (MCAO) in type 1 diabetic mice. We hypothesized that inhibition of sEH would protect against ischemic injury in type 2 diabetic mice. Type 2 diabetes was produced by combined high-fat diet, nicotinamide and streptozotocin in male mice. Diabetic and control mice were treated with vehicle or the sEH inhibitor t-AUCB then subjected to 60-min MCAO. Compared to chow-fed mice, high fat diet-fed mice exhibited an upregulation of sEH mRNA and protein in brain, but no differences in brain EETs levels were observed between groups. Type 2 diabetic mice had increased blood glucose levels at baseline and throughout ischemia, decreased laser-Doppler perfusion of the MCA territory after reperfusion, and sustained larger cortical infarcts compared to control mice. t-AUCB decreased fasting glucose levels at baseline and throughout ischemia, improved cortical perfusion after MCAO and significantly reduced infarct size in diabetic mice. We conclude that sEH inhibition, as a preventative treatment, improves glycemic status, post-ischemic reperfusion in the ischemic territory, and stroke outcome in type 2 diabetic mice.
    PLoS ONE 05/2014; 9(5):e97529. DOI:10.1371/journal.pone.0097529 · 3.23 Impact Factor
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    • "Furthermore, γ-ENaC has been described to be involved in the anti-apoptotic role of EETs, but the signaling mechanisms are still unclear. The data from our work and others indicated that EETs by CYP2C and/or CYP2J significantly promoted endothelial cell proliferation and attenuated apoptosis, which was associated with PI3K/AKT and MAPK signaling pathways [35]–[37]. Naomi Niisato and some other scientists have shown that three members of the MAPK family, p38, JNK and ERK, and the EGFR-JNK-PI3K pathway contribute to the stimulation of sodium reabsorption in response to hypotonic stress [38]–[40]. Therefore, MAPK family and PI3K/AKT pathway may be involved in the anti-apoptotic role of EETs via γ-ENaC in IMCD cells exposed to hypotonic stress. "
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    ABSTRACT: Inner medulla collecting duct (IMCD) cells are the key part for urinary concentration. Hypotonic stress may trigger apoptosis of IMCD cells and induce renal injury. Epoxyeicosatrienoic acids (EETs) play an important role in anti-apoptosis, but their roles in hypotonic-induced apoptosis of IMCD cells are still unclear. Here we found increasing exogenous 11, 12-EET or endogenous EETs with Ad-CMV-CYP2C23-EGFP transfection decreased apoptosis of IMCD cells induced by hypotonic stress. Moreover, up-regulation of γ-ENaC induced by hypotonic stress was abolished by elevation of exogenous or endogenous EETs. Collectively, this study illustrated that EETs attenuated hypotonic-induced apoptosis of IMCD cells, and that regulation of γ-ENAC may be a possible mechanism contributing to the anti-apoptotic effect of EETs in response to hypotonic stress.
    PLoS ONE 04/2014; 9(4):e94400. DOI:10.1371/journal.pone.0094400 · 3.23 Impact Factor
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    • "Candidates underlying mechanisms for increments in the arterial pressure values and insulin resistance has been associated with increased sympathetic activity [25], and endothelial dysfunction due to reduction of endothelial nitric oxide synthase, and impairment of insulin receptor substrate 1 signaling pathways in muscle, liver, heart, kidney, and aorta [26,27]. Furthermore, uric acid production, hypertriglyceridemia, aldehyde formation, altered vascular reactivity, oxidative stress, augmented activity of renin angiotensin system, increased sodium reabsorption, and reduced baroreflex sensitivity have also been implicated [9,11,12,23,28,29]. "
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    ABSTRACT: Background The increase in fructose consumption is paralleled by a higher incidence of metabolic syndrome, and consequently, cardiovascular disease mortality. We examined the effects of 8 weeks of low intensity exercise training (LET) on metabolic, hemodynamic, ventricular and vascular morphological changes induced by fructose drinking in male rats. Methods Male Wistar rats were divided into (n = 8 each) control (C), sedentary fructose (F) and ET fructose (FT) groups. Fructose-drinking rats received D-fructose (100 g/l). FT rats were assigned to a treadmill training protocol at low intensity (30% of maximal running speed) during 1 h/day, 5 days/week for 8 weeks. Measurements of triglyceride concentrations, white adipose tissue (WAT) and glycemia were carried out together with insulin tolerance test to evaluate metabolic profile. Arterial pressure (AP) signals were directly recorded. Baroreflex sensitivity (BS) was evaluated by the tachycardic and bradycardic responses. Right atria, left ventricle (LV) and ascending aorta were prepared to morphoquantitative analysis. Results LET reduced WAT (−37.7%), triglyceride levels (−33%), systolic AP (−6%), heart weight/body weight (−20.5%), LV (−36%) and aortic (−76%) collagen fibers, aortic intima-media thickness and circumferential wall tension in FT when compared to F rats. Additionally, FT group presented improve of BS, numerical density of atrial natriuretic peptide granules (+42%) and LV capillaries (+25%), as well as the number of elastic lamellae in aorta compared with F group. Conclusions Our data suggest that LET, a widely recommended practice, seems to be particularly effective for preventing metabolic, hemodynamic and morphological disorders triggered by MS.
    Cardiovascular Diabetology 06/2013; 12(1):89. DOI:10.1186/1475-2840-12-89 · 4.02 Impact Factor
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