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Pharmacological activation of Sirt1 ameliorates polyglutamine-induced toxicity through the regulation of autophagy.

ABSTRACT: Intracellular accumulation of polyglutamine (polyQ)-expanded Huntingtin (Htt) protein is a hallmark of Huntington's disease (HD). This study evaluated whether activation of Sirt1 by the anti-cancer agent, ?-lapachone (?-lap), induces autophagy in human neuroblastoma SH-SY5Y cells, thereby reducing intracellular levels of polyQ aggregates and their concomitant cytotoxicity. Treatment of cells with ?-lap markedly diminished the cytotoxicity induced by forced expression of Htt exon 1 containing a pathogenic polyQ stretch fused to green fluorescent protein (HttEx1(97Q)-GFP). ?-lap increased autophagy in SH-SY5Y cells, as evidenced by the increased formation of LC3-II and autolysosomes. Furthermore, ?-lap reduced HttEx1(97Q)-GFP aggregation, which was significantly prevented by co-incubation with 3-methyladenine, an inhibitor of autophagy. ?-lap increased Sirt1 activity, as shown by the increased deacetylation of the Sirt1 substrates, PARP-1 and Atg5, and the nuclear translocation of FOXO1. Both the induction of autophagy and attenuation of HttEx1(97Q)-GFP aggregation by ?-lap were significantly prevented by co-incubation with sirtinol, a general sirtuin inhibitor or by co-transfection with shRNA against Sirt1. The pro-autophagic actions of ?-lap were further investigated in a transgenic Caenorhabditis elegans (C. elegans) line that expressed Q67 fused to cyanine fluorescent protein (Q67). Notably, ?-lap reduced the number of Q67 puncta and restored Q67-induced defects in motility, which were largely prevented by pre-treatment with RNAi against sir-2.1, the C. elegans orthologue of Sirt1. Collectively, these data suggest that ?-lap induces autophagy through activation of Sirt1, which in turn leads to a reduction in polyQ aggregation and cellular toxicity. Thus, ?-lap provides a novel therapeutic opportunity for the treatment of HD.

SUBMITTER: Shin BH

PROVIDER: S-EPMC3677867 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Pharmacological activation of Sirt1 ameliorates polyglutamine-induced toxicity through the regulation of autophagy.

Shin Bae Hyun BH Lim Yunki Y Oh Hye Jin HJ Park Sang Min SM Lee Sun-Kyung SK Ahnn Joohong J Kim Do Han DH Song Woo Keun WK Kwak Tae Hwan TH Park Woo Jin WJ

PloS one 20130610 6

Intracellular accumulation of polyglutamine (polyQ)-expanded Huntingtin (Htt) protein is a hallmark of Huntington's disease (HD). This study evaluated whether activation of Sirt1 by the anti-cancer agent, β-lapachone (β-lap), induces autophagy in human neuroblastoma SH-SY5Y cells, thereby reducing intracellular levels of polyQ aggregates and their concomitant cytotoxicity. Treatment of cells with β-lap markedly diminished the cytotoxicity induced by forced expression of Htt exon 1 containing a p ...[more]

PMID: 23762270

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Project description:Poria cocos Wolf (PCW) is an edible, pharmaceutical mushroom with remarkable biological properties including anti-tumor, anti-inflammation, anti-oxidation, anti-ageing, and anti-diabetic effects. In the current study, we investigated the effects of PCW extract on hepatic steatosis under in vitro and in vivo conditions, and elucidated the underlying mechanisms. In this study, a mixture of HepG2 cells treated with free fatty acid (FFA)-palmitic and oleic acid-and high-fat diet (HFD)-fed obese mice were used; in this background, the triglyceride (TG) levels in HepG2 cells and mice liver were measured, and the expression levels of genes associated with lipogenesis, fatty acid oxidation, endoplasmic reticulum (ER) stress, and autophagy were determined. Treatment of HepG2 cells with FFA enhanced intracellular TG levels in HepG2 cells, but co-treatment with PCW significantly attenuated the TG levels. Notably, PCW significantly enhanced the phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), and sterol regulatory element-binding protein-1c (SREBP-1c) in FFA-treated HepG2 cells. PCW downregulated the expression of lipogenesis-related genes, but upregulated the expression of genes associated with fatty acid oxidation. Further, PCW inhibited FFA-induced expression of ER stress markers and induced autophagy proteins. However, inhibition of AMPK significantly attenuated the beneficial effects of PCW in HepG2 cells. Moreover, PCW efficiently decreased HFD-induced hepatic TG accumulation in vivo and increased the phosphorylation of hepatic AMPK. Three compounds present in PCW including poricoic acid, pachymic acid, and ergosterol, significantly decreased FFA-induced increase in intracellular TG levels, consistent with increased AMPK phosphorylation, suggesting that poricoic acid, pachymic acid, and ergosterol are responsible for PCW-mediated amelioration of hepatic steatosis. Taken together, these results demonstrated that PCW ameliorates hepatic steatosis through the regulation of lipid metabolism, inhibition of ER stress, and activation of autophagy in an AMPK-dependent manner. This suggested that PCW can be potentially used for the treatment of hepatic steatosis.

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Pharmacological activation of Sirt1 ameliorates polyglutamine-induced toxicity through the regulation of autophagy.

Publications

Pharmacological activation of Sirt1 ameliorates polyglutamine-induced toxicity through the regulation of autophagy.

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