The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus
The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus
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DOI：
10.1172/jci200214080
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发表时间：
2002-01-01
影响因子：
15.9
通讯作者：
Kelly, DP
中科院分区：
文献类型：
--
作者：
Finck, BN;Lehman, JJ;Kelly, DP
最近的证据已经确定了PPARalpha在心脏能量代谢的转录控制中的重要作用。为了研究PPARalpha在糖尿病性心肌病的代谢和功能紊乱的发生中的作用，产生并表征了具有PPARalpha心脏限制性过表达（MHC-PPAR）的小鼠。在MHC-PPAR小鼠中，参与心脏脂肪酸摄取和氧化途径的PPARalpha靶基因的表达增加。令人惊讶的是，参与葡萄糖转运和利用的基因的表达在MHC-PPAR心脏中受到抑制。与基因表达谱一致，MHC-PPAR小鼠心肌脂肪酸氧化速率增加，葡萄糖摄取和氧化减少，这是一种与糖尿病心脏惊人相似的代谢表型。MHC-PPAR心脏表现出糖尿病性心肌病的特征，包括心室肥大、病理性肥大性生长的基因标记物的激活和收缩期心室功能障碍的转基因表达依赖性改变。这些结果表明，（a）PPARalpha是心肌脂肪酸摄取和利用的关键调节剂，（B）心脏PPARalpha调节途径的激活导致葡萄糖摄取和利用途径的相互抑制，和（c）糖尿病心脏典型的心肌能量代谢紊乱可能变得适应不良，导致心肌病。
Recent evidence has defined an important role for PPARalpha in the transcriptional control of cardiac energy metabolism. To investigate the role of PPARalpha in the genesis of the metabolic and functional derangements of diabetic cardiomyopathy, mice with cardiac-restricted overexpression of PPARalpha (MHC-PPAR) were produced and characterized. The expression of PPARalpha target genes involved in cardiac fatty acid uptake and oxidation pathways was increased in MHC-PPAR mice. Surprisingly, the expression of genes involved in glucose transport and utilization was reciprocally repressed in MHC-PPAR hearts. Consistent with the gene expression profile, myocardial fatty acid oxidation rates were increased and glucose uptake and oxidation decreased in MHC-PPAR mice, a metabolic phenotype strikingly similar to that of the diabetic heart. MHC-PPAR hearts exhibited signatures of diabetic cardiomyopathy including ventricular hypertrophy, activation of gene markers of pathologic hypertrophic growth, and transgene expression-dependent alteration in systolic ventricular dysfunction. These results demonstrate that (a) PPARalpha is a critical regulator of myocardial fatty acid uptake and utilization, (b) activation of cardiac PPARalpha regulatory pathways results in a reciprocal repression of glucose uptake and utilization pathways, and (c) derangements in myocardial energy metabolism typical of the diabetic heart can become maladaptive, leading to cardiomyopathy.