Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
Cell Metab. 2011 Nov 2;14(5):598-611. doi: 10.1016/j.cmet.2011.10.001.
High energy production in mitochondria is essential for maintaining cardiac contraction in the heart. Genes regulating mitochondrial function are commonly downregulated during heart failure. Here we show that both PPARα and Sirt1 are upregulated by pressure overload in the heart. Haploinsufficiency of either PPARα or Sirt1 attenuated pressure overload-induced cardiac hypertrophy and failure, whereas simultaneous upregulation of PPARα and Sirt1 exacerbated the cardiac dysfunction. PPARα and Sirt1 coordinately suppressed genes involved in mitochondrial function that are regulated by estrogen-related receptors (ERRs). PPARα bound and recruited Sirt1 to the ERR response element (ERRE), thereby suppressing ERR target genes in an RXR-independent manner. Downregulation of ERR target genes was also observed during fasting, and this appeared to be an adaptive response of the heart. These results suggest that suppression of the ERR transcriptional pathway by PPARα/Sirt1, a physiological fasting response, is involved in the progression of heart failure by promoting mitochondrial dysfunction.
线粒体中高能的产生对于维持心脏的收缩功能至关重要。在心力衰竭过程中，调节线粒体功能的基因通常会下调。在这里，我们发现 PPARα 和 Sirt1 都受到心脏压力超负荷的上调。PPARα 或 Sirt1 的单倍不足可减轻压力超负荷诱导的心脏肥大和衰竭，而同时上调 PPARα 和 Sirt1 则加剧了心脏功能障碍。PPARα 和 Sirt1 协同抑制了由雌激素相关受体 (ERRs) 调节的与线粒体功能相关的基因。PPARα 结合并募集 Sirt1 到 ERR 反应元件 (ERRE)，从而以不依赖于 RXR 的方式抑制 ERR 靶基因。在禁食期间也观察到 ERR 靶基因的下调，这似乎是心脏的一种适应反应。这些结果表明，PPARα/Sirt1 对 ERR 转录途径的抑制，一种生理性的禁食反应，通过促进线粒体功能障碍参与心力衰竭的进展。
