AMPK control of myocardial fatty acid metabolism fluctuates with the intensity of insulin-deficient diabetes
AMPK control of myocardial fatty acid metabolism fluctuates with the intensity of insulin-deficient diabetes
复制标题
DOI：
10.1016/j.yjmcc.2006.11.010
复制
发表时间：
2007-02-01
影响因子：
5
通讯作者：
Rodrigues, Brian
中科院分区：
文献类型：
--
作者：
Kewalramani, Girish;An, Ding;Rodrigues, Brian
底物选择的灵活性对心脏维持能量生产和收缩功能是必不可少的，并通过多种机制进行管理，包括PPAR-α和AMP激活的蛋白激酶(AMPK)。大鼠注射链脲佐菌素55 mg/kg(D55)，连续4天(急性糖尿病，D55-A)。D55-A心脏的脂肪酸(FA)氧化增加，PPAR-α或其下游靶点的基因表达没有显著变化。然而，在这些心脏中，AMPK和ACC的磷酸化水平显著升高，这一效应可被胰岛素逆转。出乎意料的是，当D55大鼠的糖尿病病程延长到6周(慢性糖尿病；D55-C)时，AMPK和ACC磷酸化在对照组和D55-C心脏中是相似的。在D55-C大鼠心脏中，AMPK活性缺乏与血浆和心脏脂质过载密切相关。为了验证血脂与心肌AMPK激活的关系，我们要么诱导更严重的糖尿病(100 mg/kg STZ急性诱发高血糖和高脂血症；D100-A)，要么注入脂(IL)以扩大循环脂质。D100-A组大鼠心肌AMPK和ACC的磷酸化水平与对照组相比无明显差异。对对照和D55-A心脏AMPK和ACC磷酸化的测定表明，急性脂肪内注射可抑制它们的磷酸化。我们的数据表明，AMPK的激活是一种适应，当葡萄糖利用受到影响时，它将确保足够的心脏能量产生。然而，在严重糖尿病中，随着血浆和心脏脂质的增加，AMPK的激活被阻止，并且可能通过替代机制来控制FA的氧化。鉴于AMPK在预防心脏缺血/再灌注损伤中起重要作用，有可能在这些糖尿病心脏中，暴露于缺血/再灌注过程中观察到的加速损伤可能是AMPK活性受损的结果。(C)2006 Elsevier Inc.保留所有权利。
Flexibility in substrate selection is essential for the heart to maintain production of energy and contractile function, and is managed through multiple mechanisms including PPAR-alpha and AMP-activated protein kinase (AMPK). Rats injected with 55 mg/kg STZ (D55) were kept for 4 days (acute diabetes; D55-A) prior to termination. Fatty acid (FA) oxidation increased in D55-A hearts, with no significant change in gene expression of PPAR-alpha, or its downstream targets. However, both AMPK and ACC phosphorylation were significantly higher in these hearts, effects that were reversed by insulin. Unexpectedly, when the duration of diabetes in D55 rats was extended to 6 weeks (chronic diabetes; D55-C), AMPK and ACC phosphorylation were comparable in control and D55-C hearts. In D55-C rat hearts, lack of AMPK activation was closely associated to an overload of plasma and cardiac lipids. To validate the relationship between lipids and cardiac AMPK activation, we either induced more severe diabetes (100 mg/kg STZ to provoke both hyperglycemia and hyperlipidemia acutely; D100-A) or infused intralipid (IL) to enlarge circulating lipids. There was no difference in cardiac AMPK and ACC phosphorylation in D100-A rats compared to control. Measurement of AMPK and ACC phosphorylation in control and D55-A hearts revealed that their phosphorylation was inhibited by acute intralipid infusion. Our data suggest that activation of AMPK is an adaptation that would ensure adequate cardiac energy production when glucose utilization is compromised. However, in severe diabetes, with the addition of augmented plasma and heart lipids, AMPK activation is prevented, and control of FA oxidation is likely through alternate mechanisms. Given that AMPK plays an important role in preventing cardiac ischemic/reperfusion damage, it is possible that in these diabetic hearts, the accelerated damage observed during exposure to ischemia/reperfusion could be a likely outcome of a compromised activation of AMPK. (c) 2006 Elsevier Inc. All rights reserved.