Cardiac Metabolism Research Group, Department of Physiology, Anatomy, and Genetics, University of Oxford, UK.
Circ Heart Fail. 2013 Sep 1;6(5):1058-66. doi: 10.1161/CIRCHEARTFAILURE.112.000342. Epub 2013 Aug 12.
Fatty acid and glucose transporters translocate between the sarcolemma and intracellular compartments to regulate substrate metabolism acutely. We hypothesised that during ischemia fatty acid translocase (FAT/CD36) would translocate away from the sarcolemma to limit fatty acid uptake when fatty acid oxidation is inhibited.
Wistar rat hearts were perfused during preischemia, low-flow ischemia, and reperfusion, using (3)H-substrates for measurement of metabolic rates, followed by metabolomic analysis and subcellular fractionation. During ischemia, there was a 32% decrease in sarcolemmal FAT/CD36 accompanied by a 95% decrease in fatty acid oxidation rates, with no change in intramyocardial lipids. Concomitantly, the sarcolemmal content of the glucose transporter, GLUT4, increased by 90% during ischemia, associated with an 86% increase in glycolytic rates, 45% decrease in glycogen content, and a 3-fold increase in phosphorylated AMP-activated protein kinase. Following reperfusion, decreased sarcolemmal FAT/CD36 persisted, but fatty acid oxidation rates returned to preischemic levels, resulting in a 35% decrease in myocardial triglyceride content. Elevated sarcolemmal GLUT4 persisted during reperfusion; in contrast, glycolytic rates decreased to 30% of preischemic rates, accompanied by a 5-fold increase in intracellular citrate levels and restoration of glycogen content.
During ischemia, FAT/CD36 moved away from the sarcolemma as GLUT4 moved toward the sarcolemma, associated with a shift from fatty acid oxidation to glycolysis, while intramyocardial lipid accumulation was prevented. This relocation was maintained during reperfusion, which was associated with replenishing glycogen stores as a priority, occurring at the expense of glycolysis and mediated by an increase in citrate levels.
脂肪酸和葡萄糖转运蛋白在肌膜和细胞内隔室之间移位，以调节底物代谢的急性变化。我们假设，在脂肪酸氧化受到抑制时，脂肪酸转运蛋白（FAT/CD36）会从肌膜移位，以限制脂肪酸的摄取。
使用（3）H-底物在缺血前、低流量缺血和再灌注期间对 Wistar 大鼠心脏进行灌注，以测量代谢率，然后进行代谢组学分析和亚细胞分离。在缺血期间，肌膜 FAT/CD36 减少了 32%，同时脂肪酸氧化率下降了 95%，心肌内脂质没有变化。同时，葡萄糖转运体 GLUT4 的肌膜含量在缺血期间增加了 90%，伴随着糖酵解率增加了 86%，糖原含量减少了 45%，磷酸化 AMP 激活的蛋白激酶增加了 3 倍。再灌注后，肌膜 FAT/CD36 的减少仍然存在，但脂肪酸氧化率恢复到缺血前的水平，导致心肌三酰甘油含量减少 35%。在再灌注期间，升高的肌膜 GLUT4 仍然存在；相反，糖酵解率下降到缺血前的 30%，伴随着细胞内柠檬酸水平增加 5 倍，糖原含量恢复。
在缺血期间，FAT/CD36 从肌膜上移开，而 GLUT4 向肌膜移动，与从脂肪酸氧化向糖酵解的转变有关，同时防止了心肌内脂质的积累。这种再定位在再灌注期间得以维持，再灌注期间优先补充糖原储存，以牺牲糖酵解为代价，由柠檬酸水平的增加介导。
