Deactivation of peroxisome proliferator-activated receptor-α during cardiac hypertrophic growth
Deactivation of peroxisome proliferator-activated receptor-α during cardiac hypertrophic growth
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DOI：
10.1172/jci9056
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发表时间：
2000-06-01
影响因子：
15.9
通讯作者：
Kelly, DP
中科院分区：
文献类型：
--
作者：
Barger, PM;Brandt, JM;Kelly, DP
我们试图描述心脏肥大生长期间能量底物偏好从脂肪酸到葡萄糖的转换所涉及的分子调节事件，α(1)-肾上腺素能激动剂诱导的培养中的心肌细胞肥大导致棕榈酸氧化速率显着降低，并且编码肌肉肉毒碱棕榈酰转移酶I (M-CPT I)的基因表达减少，M-CPT I是一种参与线粒体脂肪酸摄取的酶。心肌细胞转染研究表明，M-CPT I 启动子活性在心肌细胞肥大生长过程中受到抑制，这种效应映射到过氧化物酶体增殖物激活受体-α (PPAR α) 反应元件。小鼠心室压力超负荷研究以及心肌细胞 PPAR α 过度表达研究表明，在肥大生长过程中，心脏 PPAR α 基因表达下降，并且其活性通过细胞外信号调节激酶丝裂原激活蛋白激酶途径在转录后水平发生改变。肥大的肌细胞表现出细胞脂质稳态能力降低，如响应油酸负荷的细胞内脂肪积累所证明的那样。这些结果表明，在心脏肥大生长过程中，PPARα 在多个水平上失活，导致心肌脂质和能量稳态能力下降。
We sought to delineate the molecular regulatory events involved in the energy substrate preference switch from fatty acids to glucose during cardiac hypertrophic growth, alpha(1)-adrenergic agonist-induced hypertrophy of cardiac myocytes in culture resulted in a significant decrease in palmitate oxidation rates and a reduction in the expression of the gene encoding muscle carnitine palmitoyltransferase I (M-CPT I), an enzyme involved in mitochondrial fatty acid uptake. Cardiac myocyte transfection studies demonstrated that M-CPT I promoter activity is repressed during cardiac myocyte hypertrophic growth, an effect that mapped to a peroxisome proliferator-activated receptor-alpha (PPAR alpha) response element. Ventricular pressure overload studies in mice, together with PPAR alpha overexpression studies in cardiac myocytes, demonstrated that, during hypertrophic growth, cardiac PPAR alpha gene expression falls and its activity is altered at the posttranscriptional level via the extracellular signal-regulated kinase mitogen-activated protein kinase pathway. Hypertrophied myocytes exhibited reduced capacity for cellular lipid homeostasis, as evidenced by intracellular fat accumulation in response to oleate loading. These results indicate that during cardiac hypertrophic growth, PPAR alpha is deactivated at several levels, leading to diminished capacity for myocardial lipid and energy homeostasis.