Acetaldehyde promotes rapamycin-dependent activation of p70S6K and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells
Acetaldehyde promotes rapamycin-dependent activation of p70S6K and glucose uptake despite inhibition of Akt and mTOR in dopaminergic SH-SY5Y human neuroblastoma cells
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DOI：
10.1016/j.expneurol.2006.08.002
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发表时间：
2007-01-01
影响因子：
5.3
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Fang, Cindy X.;Yang, Xiaoping;Ren, Jun
酒精摄入是胰岛素抵抗和2型糖尿病风险的重要生活方式因素之一。乙醛是乙醇的主要代谢产物，其反应活性远高于乙醇，尽管其对胰岛素信号传导的直接影响尚不清楚，但已被假定参与酒精诱导的组织损伤。本研究旨在检测乙醛对人多巴胺能SH-SY5Y细胞葡萄糖摄取和胰岛素信号转导的影响。蛋白质印迹法检测Akt、哺乳动物雷帕霉素靶蛋白（mTOR）、核糖体-S6激酶（p70（S6K））、真核生物翻译起始因子4E（eIF4E）结合蛋白1（4E-BP1）和胰岛素受体底物（IRS）-2。葡萄糖摄取和细胞凋亡分别用[H-3]-2-脱氧葡萄糖摄取和caspase-3测定。短期暴露（12小时）的乙醛（150 μ M）促进葡萄糖摄取雷帕霉素依赖性的方式，而不影响凋亡，IRS-2的表达和胰岛素刺激的葡萄糖摄取SH-SY5Y细胞。乙醛抑制基础和胰岛素刺激的Akt磷酸化，而不影响总Akt表达。乙醛抑制mTOR磷酸化而不影响总mTOR和胰岛素引起的对mTOR磷酸化的反应。雷帕霉素抑制mTOR导致p70（S6K）失活，但不影响乙酰丙酮酸诱导的对Akt和mTOR磷酸化的抑制。有趣的是，乙醛增强了p70（S6K）的激活，抑制了4E-BP1的磷酸化，其作用分别被雷帕霉素减弱和夸大。总的来说，这些数据表明，尽管在Akt和mTOR水平上抑制胰岛素信号级联，但乙醛对葡萄糖摄取没有不利影响，这可能是由于存在负责增强的p70（S6K）磷酸化的某些机制。(c)2006年爱思唯尔公司All rights reserved.
Alcohol intake is one of the important lifestyle factors for the risk of insulin resistance and type 2 diabetes. Acetaldehyde, the major ethanol metabolite which is far more reactive than ethanol, has been postulated to participate in alcohol-induced tissue injury although its direct impact on insulin signaling is unclear. This study was designed to examine the effect of acetaldehyde on glucose uptake and insulin signaling in human dopaminergic SH-SY5Y cells. Akt, mammalian target of rapamycin (mTOR), ribosomal-S6 kinase (p70(S6K)), the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and insulin receptor substrate (IRS)-2 were evaluated by Western blot analysis. Glucose uptake and apoptosis were measured using [H-3]-2-deoxyglucose uptake and caspase-3 assay, respectively. Short-term exposure (12 h) of acetatdehyde (150 mu M) facilitated glucose uptake in a rapamycin-dependent manner without affecting apoptosis, IRS-2 expression and insulin-stimulated glucose uptake in SH-SY5Y cells. Acetaldehyde suppressed basal and insulin-stimulated Akt phosphorylation without affecting total Akt expression. Acetaldehyde inhibited mTOR phosphorylation without affecting total mTOR and insulin-elicited response on mTOR phosphorylation. Rapamycin, which inhibits mTOR leading to inactivation of p70(S6K), did not affect acetaldehyde-induced inhibition on phosphorylation of Akt and mTOR. Interestingly, acetaldehyde enhanced p70(S6K) activation and depressed 4E-BP1 phosphorylation, the effect of which was blunted and exaggerated, respectively, by rapamycin. Collectively, these data suggested that acetaldehyde did not adversely affect glucose uptake despite inhibition of insulin signaling cascade at the levels of Akt and mTOR, possibly due to presence of certain mechanism(s) responsible for enhanced p70(S6K) phosphorylation. (c) 2006 Elsevier Inc. All rights reserved.