Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism.
Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism.
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DOI：
10.1074/jbc.m111.228817
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发表时间：
2011-10-21
期刊：
影响因子：
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通讯作者：
Shulman GI
中科院分区：
文献类型：
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作者：
Birkenfeld AL;Lee HY;Majumdar S;Jurczak MJ;Camporez JP;Jornayvaz FR;Frederick DW;Guigni B;Kahn M;Zhang D;Weismann D;Arafat AM;Pfeiffer AF;Lieske S;Oyadomari S;Ron D;Samuel VT;Shulman GI
最近的研究表明内质网应激与胰岛素抵抗和热量过剩有关。在连续3天高脂饮食的小鼠中，我们发现eIF2α信号增强，肝脏脂质积累和胰岛素抵抗也随之增加。为了阐明肝脏内质网应激依赖性磷酸化- eif2 α (eIF2α-P)途径在肝脏和肌肉糖脂代谢急性热量过剩中的作用，我们研究了转基因小鼠，在这些小鼠中，肝脏内质网应激依赖性eif2 α (eIF2α-P)途径通过过表达GADD34/PPP1R15a（磷酸酶的一个调节亚基，通过磷酸化- eif2 α终止内质网应激信号）的组成活性片段来抑制肝脏内质网应激依赖性eif2 α (eIF2α-P)途径。抑制肝脏中eIF2α-P信号导致基础和钳位状态下肝脏葡萄糖生成减少，这可能是由于糖异生基因表达减少，导致基础血浆葡萄糖浓度降低。令人惊讶的是，肝脏eIF2α抑制也会损害胰岛素刺激的肌肉和脂肪组织的胰岛素敏感性。后一种效应可能至少部分归因于转基因动物体内循环IGFBP-3水平的增加。此外，在高胰岛素-正糖钳夹期间输注胰岛素可引起3天高脂饮食小鼠明显的内质网应激，并通过持续的eIF2α去磷酸化而加重。总之，这些数据表明，肝脏内质网应激eIF2α信号通路影响肝脏葡萄糖产生，而不改变肝脏胰岛素敏感性。此外，肝脏内质网应激依赖的eIF2α-P信号可能通过IGFBP-3参与肝脏和外周器官之间意想不到的串扰，从而影响胰岛素敏感性。最后，eIF2α对于胰岛素诱导内质网应激的正确解决至关重要。
Recent studies have implicated endoplasmic reticulum (ER) stress in insulin resistance associated with caloric excess. In mice placed on a 3-day high fat diet, we find augmented eIF2α signaling, together with hepatic lipid accumulation and insulin resistance. To clarify the role of the liver ER stress-dependent phospho-eIF2α (eIF2α-P) pathway in response to acute caloric excess on liver and muscle glucose and lipid metabolism, we studied transgenic mice in which the hepatic ER stress-dependent eIF2α-P pathway was inhibited by overexpressing a constitutively active C-terminal fragment of GADD34/PPP1R15a, a regulatory subunit of phosphatase that terminates ER stress signaling by phospho-eIF2α. Inhibition of the eIF2α-P signaling in liver led to a decrease in hepatic glucose production in the basal and clamped state, which could be attributed to reduced gluconeogenic gene expression, resulting in reduced basal plasma glucose concentrations. Surprisingly, hepatic eIF2α inhibition also impaired insulin-stimulated muscle and adipose tissue insulin sensitivity. This latter effect could be attributed at least in part by an increase in circulating IGFBP-3 levels in the transgenic animals. In addition, infusion of insulin during a hyperinsulinemic-euglycemic clamp induced conspicuous ER stress in the 3-day high fat diet-fed mice, which was aggravated through continuous dephosphorylation of eIF2α. Together, these data imply that the hepatic ER stress eIF2α signaling pathway affects hepatic glucose production without altering hepatic insulin sensitivity. Moreover, hepatic ER stress-dependent eIF2α-P signaling is implicated in an unanticipated cross-talk between the liver and peripheral organs to influence insulin sensitivity, probably via IGFBP-3. Finally, eIF2α is crucial for proper resolution of insulin-induced ER stress.