Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of PPARα in mice

Abstract

Calorie restriction (CR) extends lifespans in a wide variety of species. CR induces an increase in the NAD(+)/NADH ratio in cells and results in activation of SIRT1, an NAD(+)-dependent protein deacetylase that is thought to be a metabolic master switch linked to the modulation of lifespans. CR also affects the expression of peroxisome proliferator-activated receptors (PPARs). The three subtypes, PPARalpha, PPARgamma, and PPARbeta/delta, are expressed in multiple organs. They regulate different physiological functions such as energy metabolism, insulin action and inflammation, and apparently act as important regulators of longevity and aging. SIRT1 has been reported to repress the PPARgamma by docking with its co-factors and to promote fat mobilization. However, the correlation between SIRT1 and other PPARs is not fully understood. CR initially induces a fasting-like response. In this study, we investigated how SIRT1 and PPARalpha correlate in the fasting-induced anti-aging pathways. A 24-h fasting in mice increased mRNA and protein expression of both SIRT1 and PPARalpha in the livers, where the NAD(+) levels increased with increasing nicotinamide phosphoribosyltransferase (NAMPT) activity in the NAD(+) salvage pathway. Treatment of Hepa1-6 cells in a low glucose medium conditions with NAD(+) or NADH showed that the mRNA expression of both SIRT1 and PPARalpha can be enhanced by addition of NAD(+), and decreased by increasing NADH levels. The cell experiments using SIRT1 antagonists and a PPARalpha agonist suggested that PPARalpha is a key molecule located upstream from SIRT1, and has a role in regulating SIRT1 gene expression in fasting-induced anti-aging pathways.

Mitochondrial Matrix Ca2+ Accumulation Regulates Cytosolic NAD+/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

“…Several pathways have been proposed to explain SIRT1 upregulation upon nutrient withdrawal, including Forkhead box O3a (FOXO3a)-p53 (70), peroxisome proliferatoractivated receptor ␣ (PPAR␣) (71), cyclic AMP response elementbinding protein (CREB) (72), and PPAR␦ (73). Our studies demonstrate an inverse relationship between protein acetylation and sirtuin expression.…”

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…Activation of PPAR α can regulate SIRT1 expression in a positive manner (Hayashida et al. 2010). In addition, an intricate crosstalk exists between NF‐ κ B and SIRT1 signaling (Kauppinen et al.…”

Sirtuin 1: A Target for Kidney Diseases

“…PPARα induced SIRT1 expression, presumably by binding to the PPAR responsive element within the SIRT1 gene promoter (133). Interestingly, although there was no evidence that PPARα was a deacetylation target of SIRT1, SIRT1 increased PPARα activity through its coactivators, indicating a positive feedback loop between SIRT1 and PPARα (142).…”

“…In energy excess conditions such as high-fat diets, SIRT1 activity decreased because of the decreased NAD + :NADH ratio (128,129), whereas a low-energy status such as fasting, calorie restriction, nutrient deprivation and exercise could increase SIRT1 activity by increasing the NAD + :NADH ratio (130)(131)(132). The levels of NAD + not only affected the activity of SIRT1 but also coordinately altered SIRT1 expression levels (133,134).…”