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Nicotinic acid synergizes with leucine to stimulate AMPK/Sirt1 signaling and regulates lipid accumulation and lifespan in C. elegans (269.7)
Author(s) -
Bruckbauer Antje,
Zemel Michael
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.269.7
Subject(s) - ampk , chemistry , lipid metabolism , nad+ kinase , amp activated protein kinase , signal transduction , microbiology and biotechnology , sirtuin 1 , endocrinology , sterol regulatory element binding protein , medicine , biochemistry , pharmacology , biology , downregulation and upregulation , cholesterol , protein kinase a , phosphorylation , enzyme , sterol , gene
Previous data demonstrate the BCAA leucine (Leu) to stimulate AMPK and Sirt1 signaling in vitro and in vivo. Nicotinic acid (NA) has been used as a highly effective treatment of dislipidemias; however, its poorly tolerated side effects (severe vasodilation and flushing at high doses) limits its use as a drug. Since it increases NAD+ and thereby activates Sirt1, we tested the synergistic effects of leucine (0.5 mM) and low dose NA (10 nM) on AMPK/Sirt1 signaling and downstream effects in cell culture and C. elegans. The NA‐Leucine combination increased P‐AMPK by 80%, P‐AMPK/AMPK ratio by 114% (p<0.001) and Sirt1 by 25% (p=0.04) in adipocytes and myotubes, while the individual components exerted no independent effect. In C. elegans, NA‐Leu increased P‐AMPK and DAF‐16 (FOXO) signaling by 66% (p=0.018) and 105% (p=0.004), respectively. This was associated with a reduction in lipid accumulation by 49% (p=0.017) and a 28% increase in median survival (p=0.0001) under mild oxidative stress conditions (0.2 mM paraquat). These data indicate that low concentrations of NA synergize with leucine to modulate sirtuin signaling and lipid metabolism, and may therefore be a potential therapeutic for treatment of metabolic diseases. Grant Funding Source : NuSirt Sciences Inc.