Abstract 15843: PPARalpha/Sirt1 Heterodimer Suppresses Fatty Acid Oxidation Genes in the Heart Under Pressure Overload
The healthy heart utilizes fatty acids as a primary source of energy, yet fatty acid oxidation (FAO) declines in the failing heart. The PPARα/RXR dimer transcribes genes involved in FAO through PPAR response element (PPRE). However, how PPARα targets are downregulated in the failing heart remains unknown. Here we report that the PPARα dimerization partner switches from RXR to Sirt1, a histone deacetylase that interacts with PPAR, thereby suppressing FAO gene expression during pressure overload (PO). The expression of Sirt1 was increased, whereas that of RXR was decreased in response to PO in mice. A consistent observation was made that demonstrated Sirt1 binding to PPARα increased, while RXR binding to PPARα decreased during PO (relative proteins bound to PPARα under PO conditions vs sham, Sirt1 3.7*, RXR 0.37*, p<0.05). Thus, the PPARα/RXR dimer switches to PPARα/Sirt1 in the failing heart. We observed similar expression changes of Sirt1 and RXR in the failing human heart, suggesting dimer conversion occurs in heart failure patients. Chromatin immunoprecipitation assays reveal that Sirt1 is recruited to flanking regions of the PPRE in the Mcad or Vldlr promoters under PO conditions, whereas Sirt1 recruitment was attenuated in PPARα knockout (PPARα-/-) mice (relative occupancy on Mcad promoter vs Wild type (WT) sham, WT PO 2.8. PPARα-/- 1.75, PPARα-/- PO 1.2*, p<0.05 vs WT TAC). This result suggests that PPARα recruits Sirt1 to the PPREs under PO conditions. PPARα targets downregulated by PO were normalized in mice with heterozygous knockout of Sirt1 (Sirt1+/-) (relative mRNA vs WT sham, Mcad: WT PO 0.49, Sit1+/- sham 1.15, Sirt1+/- PO 0.73*, Vldlr: WT PO 0.49, Sirt1+/- sham 0.98, Sirt1+/- TAC 0.74*, p<0.05 vs WT PO) and PPARα (PPARα+/-) (relative mRNA vs WT sham, Mcad: WT PO 0.49, PPARα+/- sham 1.1, PPARα+/- PO 0.77*, Vldlr: WT PO 0.61, PPARα+/- sham 1.0, PPARα+/- PO 1.21*, p<0.05 vs WT TAC). Thus, Sirt1 recruited by PPARα to the PPREs negatively regulates FAO gene expression. Importantly, PO-induced impaired FAO and contractile dysfunction were normalized in Sirt1+/- and PPARα+/- mice. These results suggest that the PPARα/Sirt1 heterodimer downregulates PPAR targets, thereby promoting failing heart phenotypes such as impaired FAO and contractile dysfunction.
Author Disclosures: S. Oka: None. P. Zhai: None. T. Yamamoto: None. Y. Ikeda: None. J. Sadoshima: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.