Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-α/PGC-1α gene regulatory pathway
Insulin-resistant heart exhibits a mitochondrial biogenic response driven by the peroxisome proliferator-activated receptor-α/PGC-1α gene regulatory pathway
复制标题
DOI：
10.1161/circulationaha.106.662296
复制
发表时间：
2007-02-20
期刊：
影响因子：
37.8
通讯作者：
Kelly, Daniel P.
中科院分区：
文献类型：
--
作者：
Duncan, Jennifer G.;Fong, Juliet L.;Kelly, Daniel P.
背景-肥胖和糖尿病是大流行比例的复杂代谢问题，导致显著的心血管死亡。最近的研究表明，糖尿病动物的心脏线粒体功能发生了变化。我们假设参与线粒体功能控制的调控事件在糖尿病前期、胰岛素抵抗阶段被激活。方法和结果-形态计量分析表明，与同年龄对照组相比，胰岛素抵抗解偶联蛋白-白喉毒素A(UCP-DTA)转基因小鼠心肌细胞线粒体体积密度增加。在胰岛素抵抗的UCP-DTA心脏中，线粒体DNA含量和参与多条线粒体途径的基因表达也增加。核受体，过氧化物酶体增殖物激活受体-α(PPARα)，已知激活糖尿病心脏中的代谢基因。因此，我们评估了PPARα在观察到的胰岛素抵抗心脏线粒体生物发生反应中的作用。进入PPARα零背景的胰岛素抵抗UCP-DTA小鼠没有表现出线粒体生物发生或诱导线粒体基因表达的证据。相反，心脏特异性过表达PPARα的转基因小鼠表现出心肌线粒体生物发生的特征。对PPARα驱动的线粒体生物发生反应的候选介体的筛选显示，已知的线粒体生物发生调节因子PPARγ辅活化子-1α(PGC-1α)的表达在野生型UCP-DTA小鼠中被激活，但在PPARα缺陷的UCP-DTA小鼠中不被激活。结论--这些结果表明，线粒体的生物发生发生在糖尿病心脏功能障碍的早期发生，其转录调控电路涉及脂肪酸激活的核受体PPARα激活PGC-1α基因的表达。
Background - Obesity and diabetes mellitus are complex metabolic problems of pandemic proportion, contributing to significant cardiovascular mortality. Recent studies have shown altered mitochondrial function in the hearts of diabetic animals. We hypothesized that regulatory events involved in the control of mitochondrial function are activated in the prediabetic, insulin-resistant stage.Methods and Results - Morphometric analyses demonstrated that cardiac myocyte mitochondrial volume density was increased in insulin- resistant uncoupling protein- diptheria toxin A ( UCP- DTA) transgenic mice, a murine model of metabolic syndrome, compared with littermate controls. Mitochondrial DNA content and expression of genes involved in multiple mitochondrial pathways were also increased in insulin- resistant UCP- DTA hearts. The nuclear receptor, peroxisome proliferator- activated receptor-alpha ( PPAR alpha), is known to activate metabolic genes in the diabetic heart. Therefore, we evaluated the role of PPAR alpha in the observed mitochondrial biogenesis response in the insulin- resistant heart. Insulin- resistant UCP- DTA mice crossed into a PPAR alpha- null background did not exhibit evidence of mitochondrial biogenesis or induction of mitochondrial gene expression. Conversely, transgenic mice with cardiac-specific overexpression of PPAR alpha exhibited signatures of cardiac mitochondrial biogenesis. A screen for candidate mediators of the PPAR alpha- driven mitochondrial biogenic response revealed that expression of PPAR gamma coactivator- 1 alpha ( PGC-1 alpha), a known regulator of mitochondrial biogenesis, was activated in wild- type UCP- DTA mice but not in PPAR alpha- deficient UCP- DTA mice.Conclusions - These results demonstrate that mitochondrial biogenesis occurs early in the development of diabetic cardiac dysfunction through a transcriptional regulatory circuit that involves activation of PGC-1 alpha gene expression by the fatty acid - activated nuclear receptor PPAR alpha.