Transcriptional activation of energy metabolic switches in the developing and hypertrophied heart
Transcriptional activation of energy metabolic switches in the developing and hypertrophied heart
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DOI：
10.1046/j.1440-1681.2002.03655.x
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发表时间：
2002-04-01
影响因子：
2.9
通讯作者：
Kelly, DP
中科院分区：
文献类型：
--
作者：
Lehman, JJ;Kelly, DP
1.本文综述了在发育中的心脏和病理性心脏肥大发生后，参与控制心脏线粒体能量产生的基因调控机制。特别强调的是线粒体脂肪酸氧化（FAO）途径及其控制的核受体转录因子超家族的成员。在围产期心脏发育期间，心脏经历能量底物偏好从胎儿期的葡萄糖到出生后的脂肪酸的转换。这种能量代谢开关是由参与相应途径的酶和蛋白质表达的变化所引起的。线粒体能量产生途径的出生后激活涉及编码FAO酶的核基因以及在线粒体能量转导/产生途径中重要的其他蛋白质的诱导表达。最近的证据表明，这种出生后的基因调控作用涉及核受体过氧化物酶体增殖物激活受体α（PPARalpha）及其共激活因子PPARgamma共激活因子1（PGC-1）的作用. PGC-1不仅激活PPARalpha以诱导出生后心脏中的FAO途径酶，而且它还在控制心脏线粒体数量和功能中起关键作用。因此，PGC-1在成年哺乳动物心脏的高容量线粒体能量产生系统中起着主要的调节作用.在心脏肥大的病理形式的发展过程中，例如由于压力超负荷，心肌能量底物偏好向胎儿模式转移，FAO酶基因的表达相应减少。这种代谢转变是由于PPARalpha /PGC-1复合物的失活。6.在心脏肥大的发展过程中，PPARalpha和PGC-1的失活涉及多个水平的调节，包括这些基因表达的减少，以及由于丝裂原活化蛋白激酶途径引起的翻译后效应。未来的研究旨在确定这种转录“开关”及其对心肌代谢的影响在肥厚心脏中是适应性的还是适应不良的。
1. The present review focuses on the gene regulatory mechanisms involved in the control of cardiac mitochondrial energy production in the developing heart and following the onset of pathological cardiac hypertrophy. Particular emphasis has been given to the mitochondrial fatty acid oxidation (FAO) pathway and its control by members of the nuclear receptor transcription factor superfamily.2. During perinatal cardiac development, the heart undergoes a switch in energy substrate preference from glucose in the fetal period to fatty acids following birth. This energy metabolic switch is paralleled by changes in the expression of the enzymes and protein involved in the respective pathways.3. The postnatal activation of the mitochondrial energy production pathway involves the induced expression of nuclear genes encoding FAO enzymes, as well as other proteins important in mitochondrial energy transduction/production pathways. Recent evidence indicates that this postnatal gene regulatory effect involves the actions of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) and its coactivator the PPARgamma coactivator 1 (PGC-1).4. The PGC-1 not only activates PPARalpha to induce FAO pathway enzymes in the postnatal heart, but it also plays a pivotal role in the control of cardiac mitochondrial number and function. Thus, PGC-1 plays a master regulatory role in the high-capacity mitochondrial energy production system in the adult mammalian heart.5. During the development of pathological forms of cardiac hypertrophy, such as that due to pressure overload, the myocardial energy substrate preference shifts back towards the fetal pattern, with a corresponding reduction in the expression of FAO enzyme genes. This metabolic shift is due to the deactivation of the PPARalpha /PGC-1 complex.6. The deactivation of PPARalpha and PGC-1 during the development of cardiac hypertrophy involves regulation at several levels, including a reduction in the expression of these genes, as well as post-translational effects due to the mitogen-activated protein kinase pathway. Future studies aim at defining whether this transcriptional 'switch' and its effects on myocardial metabolism are adaptive or maladaptive in the hypertrophied heart.