Sirt1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons

Neuroscience Program, University of Southern California, Los Angeles, CA 90089-2520, USA.
Cell metabolism (Impact Factor: 17.57). 08/2008; 8(1):38-48. DOI: 10.1016/j.cmet.2008.05.004
Source: PubMed


Sirtuins are known to protect cells and extend life span, but our previous studies indicated that S. cerevisiae Sir2 can also increase stress sensitivity and limit life-span extension. Here we provide evidence for a role of the mammalian Sir2 ortholog SirT1 in the sensitization of neurons to oxidative damage. SirT1 inhibition increased acetylation and decreased phosphorylation of IRS-2; it also reduced activation of the Ras/ERK1/2 pathway, suggesting that SirT1 may enhance IGF-I signaling in part by deacetylating IRS-2. Either the inhibition of SirT1 or of Ras/ERK1/2 was associated with resistance to oxidative damage. Markers of oxidized proteins and lipids were reduced in the brain of old SirT1-deficient mice, but the life span of the homozygote knockout mice was reduced under both normal and calorie-restricted conditions. These results are consistent with findings in S. cerevisiae and other model systems, suggesting that mammalian sirtuins can play both protective and proaging roles.

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    • "Previous studies have shown that Nrf2 plays an important role in the protection of hepatocytes from NAFLD [12]. SIRT1 is also known to markedly protect cells from oxidative stress injury [13]. Due to the critical role of SIRT1 and Nrf2 in oxidative stress [14], it might be interesting to explore the synergistic effect of SIRT1/LKB1/AMPK signaling and Nrf2 in NAFLD. "
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    ABSTRACT: Understanding the mechanism by which alpha-lipoic acid supplementation has a protective effect upon nonalcoholic fatty liver disease in vivo and in vitro, may lead to targets for preventing hepatic steatosis. Male C57BL/6 J mice were fed a normal diet, high fat diet or high fat diet supplemented with alpha-lipoic acid for 24 weeks. HepG2 cells were incubated with normal medium, palmitate or alpha-lipoic acid. The lipid-lowering effects were measured. The protein expression and distribution were analyzed by western blot, immunoprecipitation and immunofluorescence, respectively. We found that alpha-lipoic acid enhanced sirtuin 1 deacetylase activity through liver kinase B1 and stimulated AMP-activated protein kinase. By activating the sirtuin 1/liver kinase B1/AMP-activated protein kinase pathway, the translocation of sterol regulatory element-binding protein-1 into the nucleus and forkhead box O1 into the cytoplasm were prevented. Alpha-lipoic acid increased adipose triacylglycerol lipase expression and decreased fatty acid synthase abundance. In in vivo and in vitro studies, alpha-lipoic acid also increased nuclear NF-E2-related factor 2 levels and downstream target amounts via the sirtuin 1 pathway. Alpha-lipoic acid eventually reduced intrahepatic and serum triglyceride content. The protective effects of alpha-lipoic acid on hepatic steatosis appear to be associated with the transcription factors sterol regulatory element-binding protein-1, forkhead box O1 and NF-E2-related factor 2.
    The Journal of Nutritional Biochemistry 11/2014; 25(11). DOI:10.1016/j.jnutbio.2014.06.001 · 3.79 Impact Factor
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    • "On the other hand, IGF-1 has been shown to increase Sirt1 expression in cardiomyocytes in a c-Jun N-terminal kinase 1 (JNK1)-dependent manner (Vinciguerra et al., 2012). Conversely, it was reported that Sirt1 activity enhances IGF-1 signaling through deacetylation of IRS-2 in neuronal cells, which may ultimately compromises neuronal cell survival through oxidative damage resulting from the downstream Ras/Erk1/2 pathway (Li et al., 2008). Pucci et al. now showed the opposite, that Sirt1 activity could potentially reduce signaling from the IGF-1-IGF-1R, at least in some neuronal cell types, by suppressing the expression of both ligand and receptor (Sansone et al., 2013). "
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    ABSTRACT: Sirt1, the class III histone deacetylase, is generally associated with increased life span and with a pro-survival effect in neurons stressed by pathological factors. Recent work, however, suggests that Sirt1 silencing could also promote neuronal survival. A possible reason suggested is Sirt1 silencing enhanced expression of both IGF-1 and IGF-1 receptor, signaling from which promotes survival. This work adds to the small but steady stream of findings that are diametrically opposite to the overwhelmingly large amount of evidence supporting a beneficial effect of sustaining or enhancing Sirt1 activity in neuronal injuries and diseases. We attempt to reconcile this discrepancy below by noting evidence that elevated Sirt1 levels and/or activity may not help, and could even adversely exacerbates demise, during events of acute neuronal damage or death. However, sustained Sirt1 activation will be beneficial in situations of chronic and long-term sub-lethal stresses, and the status of IGF-1 signaling may influence Sirt1 action in a context dependent manner.
    Frontiers in Cellular Neuroscience 10/2013; 7:186. DOI:10.3389/fncel.2013.00186 · 4.29 Impact Factor
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    • "À/À mice on CR displayed a short lifespan (Fig. 1A) (Boily et al., 2008; Li et al., 2008), whereas CR extended the lifespan of both SIRT1 +/À and SIRT1 +/+ mice by 51% (Fig. 1A and Table S1–S2). The deletion of one SIRT1 allele resulted in a trend for decreased maximum lifespan under CR conditions (Fig. 1A). "
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    ABSTRACT: The SIRT1 deacetylase is one of the best-studied potential mediators of some of the anti-aging effects of calorie restriction (CR); but its role in CR-dependent lifespan extension has not been demonstrated. We previously found that mice lacking both copies of SIRT1 displayed a shorter median lifespan than wild type mice on an ad libitum diet. Here we report that median lifespan extension in CR heterozygote SIRT1(+/-) mice was identical (51%) to that observed in wild type mice but SIRT1(+/-) mice displayed a higher frequency of certain pathologies. Although larger studies in different genetic backgrounds are needed, these results provide strong initial evidence for the requirement of SIRT1 for the lifespan extension effects of CR, but suggest that its high expression is not required for CR-induced lifespan extension. This article is protected by copyright. All rights reserved.
    Aging cell 08/2013; 13(1). DOI:10.1111/acel.12151 · 6.34 Impact Factor
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