title: PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway.
abstract: 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.
authors: Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
authors: Shinichi
authors: S
authors: Oka
authors: Ralph
authors: R
authors: Alcendor
authors: Peiyong
authors: P
authors: Zhai
authors: Ji Yeon
authors: JY
authors: Park
authors: Dan
authors: D
authors: Shao
authors: Jaeyeaon
authors: J
authors: Cho
authors: Takanobu
authors: T
authors: Yamamoto
authors: Bin
authors: B
authors: Tian
authors: Junichi
authors: J
authors: Sadoshima
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001011:Aorta / Q000503:physiopathology / Q000601:surgery; D001665:Binding Sites; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005215:Fasting / Q000378:metabolism; D005786:Gene Expression Regulation; D057895:Haploinsufficiency; D006239:Haplotypes; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D047493:PPAR alpha; D011960:Receptors, Estrogen; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1