PPARα-Sirt1 Complex Mediates Cardiac Hypertrophy and Failure through Suppression of the ERR Transcriptional Pathway

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 PPAR alpha and Sirt1 are upregulated by pressure overload in the heart. Haploinsufficiency of either PPAR alpha or Sirt1 attenuated pressure overload-induced cardiac hypertrophy and failure, whereas simultaneous upregulation of PPAR alpha and Sirt1 exacerbated the cardiac dysfunction. PPAR alpha and Sirt1 coordinately suppressed genes involved in mitochondrial function that are regulated by estrogen-related receptors (ERRs). PPAR alpha 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 PPAR alpha/Sirt1, a physiological fasting response, is involved in the progression of heart failure by promoting mitochondria! dysfunction.