Aldehyde dehydrogenase-2 (ALDH2) ameliorates chronic alcohol ingestion-induced myocardial insulin resistance and endoplasmic reticulum stress.
Aldehyde dehydrogenase-2 (ALDH2) ameliorates chronic alcohol ingestion-induced myocardial insulin resistance and endoplasmic reticulum stress.
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DOI：
10.1016/j.yjmcc.2009.03.017
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发表时间：
2009-08
影响因子：
5
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Li, Shi-Yan;Gilbert, Sara A. B.;Li, Qun;Ren, Jun
慢性酒精摄入导致胰岛素抵抗和酒精性心肌病，这似乎是基因和环境之间复杂相互作用的结果。本研究旨在探讨乙醛脱氢酶2（ALDH 2）转基因过表达对酒精诱导的胰岛素抵抗和心肌损伤的影响。使用鸡β-肌动蛋白启动子产生ALDH 2转基因小鼠。野生型FVB和ALDH 2小鼠喂食4%酒精或对照饮食12周，使用边缘检测系统评估细胞缩短。Western blot分析在受体、IRS、Akt、GSK-3β、转录因子Foxo 3a、c-Jun氨基末端激酶（JNK）和c-Jun水平上的胰岛素信号传导。ALDH 2显著减弱酒精诱导的胰岛素刺激的IRS酪氨酸磷酸化的降低和IRS丝氨酸磷酸化的增加。酒精摄入后Akt、GSK-3β和Foxo 3a的磷酸化降低，其作用被ALDH 2消除。慢性酒精摄入后JNK、c-Jun及其磷酸化水平升高，ALDH 2可消除这些变化。用Foxo 3a腺病毒转染H9 C2成肌细胞模拟乙酰丙酮酸诱导的JNK激活和葡萄糖摄取缺陷，而显性阴性Foxo 3a消除乙酰丙酮酸引起的胰岛素不敏感性。此外，ALDH 2逆转酒精诱导的心肌ER应激。这些数据表明，ALDH 2过表达拮抗慢性酒精摄入诱导的心脏胰岛素不敏感性和收缩缺陷，可能通过改善胰岛素受体，IRS，Akt，Foxo 3a和JNK水平的胰岛素信号转导。
Chronic alcohol intake leads to insulin resistance and alcoholic cardiomyopathy, which appears to be a result of the complex interaction between genes and environment. This study was designed to examine the impact of aldehyde dehydrogenase-2 (ALDH2) transgenic overexpression on alcohol-induced insulin resistance and myocardial injury. ALDH2 transgenic mice were produced using chicken β-actin promoter. Wild-type FVB and ALDH2 mice were fed a 4% alcohol or control diet for 12 wks. Cell shortening was evaluated using an edge-detection system. Western blot analysis was used to assess insulin signaling at the levels of receptor, IRS, Akt, GSK-3β, the transcription factors Foxo3a, c-Jun amino-terminal kinase (JNK) and c-Jun. Chronic alcohol intake led to glucose intolerance, reduced glucose uptake, cardiac hypertrophy and reduced cell shortening, the effects of which were alleviated by ALDH2. ALDH2 significantly attenuated alcohol-induced decrease in the insulin-stimulated tyrosine phosphorylation and increase in serine phosphorylation of IRS. Phosphorylation of Akt, GSK-3β and Foxo3a was reduced following alcohol intake, the effect of which was abrogated by ALDH2. Levels of JNK, c-Jun and their phosphorylation were elevated following chronic alcohol intake, which were obliterated by ALDH2. Transfection of H9C2 myoblast cells with Foxo3a adenovirus mimicked acetaldehyde-induced JNK activation and glucose uptake defect whereas the dominant negative Foxo3a ablated acetaldehyde-elicited insulin insensitivity. In addition, ALDH2 reversed alcohol-induced myocardial ER stress. These data revealed that ALDH2 overexpression antagonizes chronic alcohol intake-induced cardiac insulin insensitivity and contractile defect, possibly via improvement of insulin signaling at the levels of insulin receptor, IRS, Akt, Foxo3a and JNK.
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DOI：
10.1152/ajpheart.00780.2001
发表时间：
2002-04-01
影响因子：
4.8
作者：
Duan, JH;McFadden, GE;Ren, J
通讯作者：
Ren, J
影响因子：
5.1
作者：
Chen, Yi-Chyan;Peng, Giia-Sheun;Yin, Shih-Jiun
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Yin, Shih-Jiun
影响因子：
5.3
作者：
Fang, Cindy X.;Yang, Xiaoping;Ren, Jun
通讯作者：
Ren, Jun
影响因子：
8.2
作者：
Li, SY;Yang, X;Ren, J
通讯作者：
Ren, J
影响因子：
5
作者：
Li, SY;Li, Q;Ren, J
通讯作者：
Ren, J