Abstract 16038: Oscillatory Gene Promoter Regulation by Pgc-1α and Sirt1 in Cardiac Energy Metabolism
Impaired energy metabolism is a hallmark of heart failure. PGC-1α is a transcriptional coactivator that stimulates energy metabolism through activation of target transcription factors such as PPARα, and PGC-1α target metabolic genes are downregulated in heart failure. Sirt1, a protein deacetylase, regulates PGC-1α through direct deacetylation. However, whether Sirt1 activates or inhibits PGC-1α and the pathophysiological significance of Sirt1-PGC-1α signaling in cardiac energy metabolism remain controversial. Here we showed that many PGC-1α targets were commonly downregulated in cardiac-specific Sirt1 homozygous knockout and overexpression mice, indicating that Sirt1 was essential for PGC-1α activity, but at the same time, a gain of Sirt1 function inhibited PGC-1α. Upon stimulation of PPARα, PGC-1α and Sirt1 were periodically and alternatively recruited to a PPARα target gene (Acox1) promoter, representing 80-minutes-per-cycle oscillatory gene promoter regulation. Sirt1 inhibition inhibited the periodic PGC-1α release and RNA polymerase II (Pol II) recruitment, suggesting that Sirt1 periodically released PGC-1α from promoters, which allowed PGC-1α to recruit Pol II for the next cycle to activate transcription. On the other hand, Sirt1 overexpression kept PGC-1α away from the promoter, thereby inhibiting Pol II recruitment. Sirt1 dissociated PGC-1α from PPARα through deacetylation at Lysine 144 of PGC-1α, thereby releasing PGC-1α from promoters. In the pressure-overload (PO)-induced heart failure model, Sirt1 was upregulated and PGC-1α was deacetylated. PO-induced PGC-1α deacetylation and downregulation of PGC-1α targets were normalized in Sirt1 heterozygous knockout (Sirt1+/-) mice. Consistently, PO-induced impaired fatty acid oxidation (FAO) and contractile dysfunction were normalized in Sirt1+/- mice (relative FAO: wild-type (WT) sham: 1; WT PO: 0.61; Sirt1+/- sham: 1.24; Sirt1+/- PO: 0.86*, p<0.05 vs. WT PO). These results suggest that Sirt1 releases PGC-1α from target gene promoters, which is essential for PGC-1α-induced Pol II recruitment to activate transcription in the healthy heart, whereas increased Sirt1 activity keeps PGC-1α away from the promoter to suppress transcription in the failing heart.
Author Disclosures: S. Oka: None. P. Zhai: None. T. Yamamoto: None. Y. Ikeda: None. A. Shirakabe: None. S. Bhat: None. K. Schesing: None. S. Ikeda: None. J. Park: None. B. Tian: None. M. Abdellatif: None. J. Sadoshima: None.
- © 2016 by American Heart Association, Inc.