Abstract 18845: PPARalpha/Sirt1 Complex is Involved in the Deterioration of Fatty Acid Metabolism During the Pathological Development of Heart Failure

Abstract

The major substrate shifts from fatty acid to glucose during the pathological development of heart failure, which may promote left ventricular (LV) dysfunction through energetic shortage. PPARα transcribes fatty acid oxidation (FAO) genes through the PPAR response element /direct repeat 1 (DR1), which is composed of two units of AGGTCA-like sequences that directionally align, separated by a single spacer. In addition to activating transcription through DR1, PPARα, in complex with Sirt1, suppresses transcription through an isolated single hexad element which is not configured into a DR1. Since many PPREs have imperfect DR1s in which one AGGTCA sequence is conserved but the other is not, we hypothesized that the PPARα/Sirt1 complex suppresses a subset of PPAR target genes harboring the imperfect DR1 under pressure overload (PO) conditions. Both PPARα and Sirt1 are upregulated in the heart during PO, and PO-induced cardiac systolic dysfunctions are attenuated in PPARα+/- (LV ejection fraction (EF) (%), WT 51, PPARα+/- 68*, p<0.05 vs WT), and Sirt1+/- (LV EF (%), WT 40, Sirt1+/- 62*, p<0.05 vs WT) mice. PO-induced downregulation of a subset of PPAR target genes harboring imperfect DR1s, such as Cpt2 and Mcad, was partly normalized in PPARα+/- (relative mRNA vs Wild type (WT) sham, Cpt2: WT TAC 0.7, PPARα+/- sham 1.1, PPARα+/- TAC 1.05*, Mcad: WT TAC 0.49, PPARα+/- sham 1.1, PPARα+/- TAC 0.77* p<0.05 vs WT TAC) and Sirt1+/- (relative mRNA vs WT sham, Cpt2: WT TAC 0.37, Sirt1+/- sham 1.1, Sirt1+/- TAC 0.78*, Mcad: WT TAC 0.49, Sirt1+/- sham 1.2, Sirt1+/- TAC 0.73* p<0.05 vs WT TAC) mice. Forced expression of PPARα resulted in increased occupancies of PPARα and Sirt1 on the proximal regions of the imperfect DR1s of the Cpt2 and Mcad promoters in the heart, indicating that PPARα recruits Sirt1 to the imperfect DR1. FAO activity was impaired by PO, but was partly normalized in PPARα+/- mice (relative FAO activity vs WT sham, WT TAC 0.50, PPARα+/- Sham 0.88, PPARα+/- TAC 0.89*, * p<0.05 vs WT TAC). PPARα and Sirt1 cooperatively suppressed reporter gene activity driven by the imperfect DR1 in the Mcad promoter. These results suggest that PPARα and Sirt1 play a role in the impaired FAO in the failing heart though transcriptional suppression of imperfect DR1s.