Nuclear receptors PPARβ/δ and PPARα direct distinct metabolic regulatory programs in the mouse heart
Nuclear receptors PPARβ/δ and PPARα direct distinct metabolic regulatory programs in the mouse heart
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DOI：
10.1172/jci32578
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发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Kelly, Daniel P.
中科院分区：
文献类型：
--
作者：
Burkart, Eileen M.;Sambandam, Nandakurnar;Kelly, Daniel P.
在糖尿病心脏中，PPAR α途径的慢性激活会导致过多的脂肪酸（FA）氧化、脂质积累、葡萄糖利用降低和心肌病。相关的核受体PPAR β / δ在心脏中也高度表达，但其功能尚未完全确定。为了研究其在心肌代谢中的作用，我们培育了心肌特异性表达PPAR β / δ的转基因小鼠，由肌球蛋白重链驱动（MHC-PPAR β / δ小鼠）。与MHC-PPAR α小鼠形成鲜明对比的是，MHC-PPAR β / δ小鼠心肌葡萄糖利用增加，心肌脂质不积累，心功能正常。与这些观察到的代谢表型一致，我们发现参与细胞FA运输的基因表达被PPARa激活，但不被PPAR β / δ激活。相反，心肌葡萄糖转运和糖酵解基因在MHC-PPAR β / δ小鼠中被激活，而在MHC-PPAR α小鼠中被抑制。在报告者实验中，我们发现PPAR β / δ和PPAR对GLUT4启动子施加了不同的转录控制，这可能解释了观察到的对葡萄糖摄取的同型特异性影响。此外，与对照组或MHC-PPAR α小鼠相比，MHC-PPAR β / δ小鼠因缺血/再灌注损伤引起的心肌损伤显著减少，这与心肌葡萄糖利用能力增加一致。这些结果表明，PPAR α和PPAR β / δ驱动不同的心脏代谢调节程序和。确定PPAR β / δ作为针对糖尿病和缺血引起的心功能障碍的代谢调节治疗的潜在靶点。
In the diabetic heart, chronic activation of the PPAR alpha pathway drives excessive fatty acid (FA) oxidation, lipid accumulation, reduced glucose utilization, and cardiomyopathy. The related nuclear receptor, PPAR beta/delta, is also highly expressed in the heart, yet its function has not been fully delineated. To address its role in myocardial metabolism, we generated transgenic mice with cardiac-specific expression of PPAR beta/delta, driven by the myosin heavy chain (MHC-PPAR beta/delta mice). In striking contrast to MHC-PPAR alpha mice, MHC-PPAR beta/delta mice had increased myocardial glucose utilization, did not accumulate myocardial lipid, and had normal cardiac function. Consistent with these observed metabolic phenotypes, we found that expression of genes involved in cellular FA transport were activated by PPARa but not by PPAR beta/delta. Conversely, cardiac glucose transport and glycolytic genes were activated in MHC-PPAR beta/delta mice, but repressed in MHC-PPAR alpha mice. In reporter assays, we showed that PPAR beta/delta and PPARa exerted differential transcriptional control of the GLUT4 promoter, which may explain the observed isotype-specific effects on glucose uptake. Furthermore, myocardial injury due to ischemia/reperfusion injury was significantly reduced in the MHC-PPAR beta/delta mice compared with control or MHC-PPAR alpha mice, consistent with an increased capacity for myocardial glucose utilization. These results demonstrate that PPAR alpha and PPAR beta/delta drive distinct cardiac metabolic regulatory programs and. identify PPAR beta/delta as a potential target for metabolic modulation therapy aimed at cardiac dysfunction caused by diabetes and ischemia.