Abstract 13631: PPARalpha-Sirt1 Complex Mediates Metabolic Adaptation in Response to Starvation in the Heart

Minimizing energy consumption contributes to survival in organisms under starved conditions, such as fasting and hibernation. The heart consumes a large amount of nutrition and oxygen in the process of mitochondrial ATP production. However, it remains unknown how mitochondrial gene expression is regulated in the heart during starvation. Here we show that a PPARα-Sirt1 complex mediates downregulation of mitochondrial gene expression during starvation in the heart. Co-immunoprecipitation assays revealed that PPARα binds to Sirt1 in primary cultured myocytes. After 24 hours of fasting, mitochondrial genes, such as Sdha and Atp5g1, were downregulated in wild type (WT) mice, but this downregulation was partially prevented in PPARα^+/- and Sirt1^+/- mice. Chromatin immunoprecipitation assays revealed that the occupancy of both PPARα and Sirt1 increased on the flanking region of the Sdha promoter during fasting. These results suggest that both PPARα and Sirt1 play an important role in fasting-induced downregulation of mitochondrial gene expression through direct interaction with the promoter. During fasting, cardiac systolic function was slightly reduced in WT mice, but not in PPARα^+/- and Sirt1^+/- mice (ejection fraction (%): Fed WT 74, Fasted WT 68*, Fed PPARα^+/- 76, Fasted PPARα^+/- 75, Fed Sirt1^+/- 74, Fasted Sirt1^+/- 74, p<0.05 vs Fed WT). Body weight loss after 24 hours of fasting increased in PPARα^+/- mice, compared to WT mice (WT -9%, PPARα^+/- -14%*, p<0.05 vs WT). Glucose deprivation (GD)-induced cell death was cooperatively prevented by overexpression of PPARα and Sirt1 in primary cultured myocytes 3 days after GD (Cell survival rate (%): control 54, PPARα 75*, Sirt1 60, PPARα with Sirt1 94*, PPARα with Sirt1 knockdown 52, p<0.05 vs control). Prior to cell death, 2 days after GD, protein content was significantly reduced in control cells, an effect that was cooperatively prevented by PPARα and Sirt1 (Reduction of protein content (%): control 21, PPARα 12*, Sirt1 18.7, PPARα with Sirt1 8.3*, p<0.05 vs control). These results suggest that PPARα and Sirt1 are crucial regulators of adaptation to starvation and prevent cell death by reducing nutrient consumption, possibly through downregulation of mitochondrial gene expression in the heart.