Abstract
Chronic and heavy alcohol consumption is one of the causes of heart diseases. However, the effects of ethanol on insulin sensitivity in myocardium has been unclear. To investigate the effects of ethanol on the expression of AMP-activated protein kinase (AMPK), myocyte enhancer factor 2 (MEF2) and glucose transporter 4 (GLUT4), all of which are involved in the regulation of insulin sensitivity, in the myocardium, we performed three parts of experiments in vivo and in vitro. I: Rats were injected with 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR, 0.8 mg.kg(-l)) for 2 h. II: Rats received different dose (0.5, 2.5 or 5 g.kg(-l).d(-l)) of ethanol for 22-week. III: Primary neonatal rat cardiomyocytes were isolated and treated with or without 100 mM ethanol or 1 mM AICAR for 4 h. The cardiac protein and mRNA expression of AMPKalpha subunits, MEF2 and GLUT4 were observed by western-blotting and RT-PCR, respectively. Serum TNFalpha levels were assessed by ELISA. The results showed chronic ethanol exposure induced insulin resistance. Ethanol decreased the mRNA levels of AMPKalpha1 and alpha2, the protein levels of total- and phospho-AMPKalpha in cardiomyocytes. Similarly, ethanol showed inhibitory effects on both the mRNA and protein levels of MEF2A and 2D, and GLUT4 in a dose-response-like fashion. Correlation analysis implied an association between phospho-AMPKalpha and MEF2A or MEF2D, and between the levels of MEF2 protein and GLUT4 transcription. In addition, ethanol elevated serum TNFalpha level. Taken together, chronic ethanol exposure decreases the expression of AMPKalpha and MEF2, and is associated with GLUT4 decline in rat myocardium.
Highlights
Ethanol exposure is associated with impaired glucose homeostasis
In order to explore the association among AMP-activated protein kinase (AMPK), myocyte enhancer factor 2 (MEF2) and glucose transporter 4 (GLUT4) in the myocardium, we examined their cardiac expression levels in rats and cardiomyocytes treated with 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR)
AICAR caused a 0.24-fold (P < 0.05) and 4.5-fold (P < 0.01) increase in the level of GLUT4 mRNA in cardiomyocytes (Figure 1C) and myocardium of the rats (Figure 1D) respectively. These results suggest, that the expression of GLUT4 in myocardium can be stimulated by AMPK activation and the subsequent upregulation of MEF2A
Summary
The consumption of heavy amounts of alcohol increases serum glucose levels (Fowman, 1988), impairs glucose intolerance and induces insulin resistance (Risinger and Cunningham, 1992). The mechanism by which ethanol disrupts glucose homeostasis,especially in heart, the recognized target organ of diabetes, remains obscure. The effect of ethanol on GLUT4 expression, and its corresponding mechanism, is complex and unclear. There is considerable evidence that activation of AMP-activated protein kinase (AMPK) is involved in GLUT4 translocation and glucose uptake. In cardiac myocytes increased glucose uptake induced by the translocation of GLUT4 requires the activation of AMPK (Russell et al, 1999). The induction of myocardial GLUT4 translocation via AMPK phosphorylation by resveratrol and niacin-bound chromium treatments in diabetic rats has further confirmed the regulatory effect of
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