Activation of a novel long-chain free fatty acid generation and export system in mitochondria of diabetic rat hearts
Activation of a novel long-chain free fatty acid generation and export system in mitochondria of diabetic rat hearts
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DOI：
10.1152/ajpcell.00246.2006
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发表时间：
2006-12-01
影响因子：
5.5
通讯作者：
Matlib, Mohammed A.
中科院分区：
文献类型：
--
作者：
Gerber, Lamar K.;Aronow, Bruce J.;Matlib, Mohammed A.
许多报告表明长链游离脂肪酸输出系统可能在线粒体中运行。在这项研究中，我们寻找其在大鼠心脏线粒体中存在的证据。为了确定其潜在作用，我们还寻找其在链脲佐菌素 (STZ) 诱导的糖尿病大鼠心脏线粒体中激活或抑制的证据。如果得到证实，这可能是调节线粒体长链脂肪酸氧化（FAO）的新机制。为了获得其存在的证据，我们测试了与棕榈酰肉碱呈递的心脏线粒体是否可以生成和输出棕榈酸盐。我们发现完整的线粒体确实产生并输出棕榈酸。我们还发现，STZ 糖尿病大鼠心脏线粒体中这些过程的发生率明显更高，其中棕榈酰肉碱氧化也增加。由于线粒体硫酯酶-1 (MTE-1) 将酰基-CoA 水解为 CoA-SH + 游离脂肪酸，并且在脂质体中重建的解偶联蛋白-3 (UCP-3) 转运游离脂肪酸，因此我们检查了这些蛋白质在 STZ 糖尿病大鼠心脏线粒体中是否也增加。我们发现这两种蛋白质确实增加了。基因表达谱分析显示，STZ 糖尿病大鼠心脏中线粒体长链脂肪酸转运和氧化基因显着表达，同时 MTE-1 和 UCP-3 过度表达。我们的研究结果为线粒体中长链游离脂肪酸生成和输出系统的存在及其在 STZ 糖尿病大鼠心脏中的激活提供了第一个直接证据，其中FAO 得到增强。我们认为，其激活可能会促进粮农组织的增强，而抑制可能会限制粮农组织的增强。
A number of reports indicate that a long-chain free fatty acid export system may be operating in mitochondria. In this study, we sought evidence of its existence in rat heart mitochondria. To determine its potential role, we also sought evidence of its activation or inhibition in streptozotocin (STZ)-induced diabetic rat heart mitochondria. If confirmed, it could be a novel mechanism for regulation of long-chain fatty acid oxidation (FAO) in mitochondria. To obtain evidence of its existence, we tested whether heart mitochondria presented with palmitoyl-carnitine can generate and export palmitate. We found that intact mitochondria indeed generate and export palmitate. We have also found that the rates of these processes are markedly higher in STZ-diabetic rat heart mitochondria, in which palmitoyl-carnitine oxidation is also increased. Since mitochondrial thioesterase-1 (MTE-1) hydrolyzes acyl-CoA to CoA-SH + free fatty acid, and uncoupling protein-3 (UCP-3), reconstituted in liposomes, transports free fatty acids, we examined whether these proteins are also increased in STZ-diabetic rat heart mitochondria. We found that both of these proteins are indeed increased. Gene expression profile analysis revealed striking expression of mitochondrial long-chain fatty acid transport and oxidation genes, accompanying overexpression of MTE-1 and UCP-3 in STZ-diabetic rat hearts. Our findings provide the first direct evidence for the existence of a long-chain free fatty acid generation and export system in mitochondria and its activation in STZ-diabetic rat hearts in which FAO is enhanced. We suggest that its activation may facilitate, and inhibition may limit, enhancement of FAO.