Dissociation of inositol-requiring enzyme (IRE1α)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice.
Dissociation of inositol-requiring enzyme (IRE1α)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice.
复制标题
在条件X-box结合蛋白-1（XBP1）敲除小鼠中，从肝胰岛素抵抗中从肝胰岛素抵抗中解离肌醇提取酶（IRE1α）介导的C-JUN N末端激酶激活。
DOI：
10.1074/jbc.m111.316760
复制
发表时间：
2012-01-20
期刊：
影响因子：
--
通讯作者：
Shulman GI
中科院分区：
文献类型：
--
作者：
Jurczak MJ;Lee AH;Jornayvaz FR;Lee HY;Birkenfeld AL;Guigni BA;Kahn M;Samuel VT;Glimcher LH;Shulman GI
背景：内质网(ER)应激与肝脏胰岛素抵抗有关。结果：果糖喂养的XBP1基因敲除小鼠尽管肝脏ER应激和JNK活性增加，但仍能保护肝脏免受胰岛素抵抗。结论：内质网应激和肝脏JNK活性与肝脏胰岛素抵抗无关。意义：肝脏内质网应激不是肝脏胰岛素抵抗的直接原因。肝脏胰岛素抵抗既与内质网(ER)应激增加有关，又与细胞内脂质积聚有关，尤其是二酰甘油(DAG)。内质网应激反应蛋白X盒结合蛋白-1(XBP1)最近被发现可调节肝脏脂肪生成，提示内质网应激模型中的肝脏胰岛素抵抗可能是由于脂质储存缺陷所致，而不是内质网特有的应激信号。本研究旨在分离内质网应激信号通路的激活和肝脏脂质堆积，从而阐明内质网应激和肝脂含量在肝脏胰岛素抵抗发病机制中的个体作用。条件基因敲除小鼠(XBP1Δ)和对照组小鼠分别饲喂果糖饲料1周。确定了影响全身能量平衡、体重和成分的决定因素。测量肝脏脂质，包括甘油三酯、DAG和神经酰胺，以及内质网应激标志物。通过高胰岛素-正常血糖钳夹试验测定全身和组织特异性胰岛素敏感性。果糖饲料喂养的XBP1Δ小鼠肝脏ER应激信号增强，表现为磷酸化eIF2mRNA和HSPA5mRNA的增加，以及肝脏JNK活性的2倍增加。尽管JNK被激活，XBP1IRS2在高胰岛素-正常血糖钳夹实验中表现出对肝脏胰岛素敏感性的增加，这与胰岛素刺激的Δ酪氨酸磷酸化增加、肝脏DAG含量降低和蛋白激酶Cϵ活性降低有关。这些研究表明，内质网应激和IRE1JNK激活与肝脏胰岛素抵抗无关，支持内质网应激模型中肝脏胰岛素抵抗可能继发于内质网应激对肝脏脂肪生成的调节作用的假说。
Background: Endoplasmic reticulum (ER) stress has been implicated in causing hepatic insulin resistance. Results: Fructose-fed XBP1 knock-out mice were protected from hepatic insulin resistance despite increased hepatic ER stress and JNK activation. Conclusion: ER stress and hepatic JNK activation can be disassociated from hepatic insulin resistance. Significance: Hepatic ER stress is not a direct causal factor in hepatic insulin resistance. Hepatic insulin resistance has been attributed to both increased endoplasmic reticulum (ER) stress and accumulation of intracellular lipids, specifically diacylglycerol (DAG). The ER stress response protein, X-box-binding protein-1 (XBP1), was recently shown to regulate hepatic lipogenesis, suggesting that hepatic insulin resistance in models of ER stress may result from defective lipid storage, as opposed to ER-specific stress signals. Studies were designed to dissociate liver lipid accumulation and activation of ER stress signaling pathways, which would allow us to delineate the individual contributions of ER stress and hepatic lipid content to the pathogenesis of hepatic insulin resistance. Conditional XBP1 knock-out (XBP1Δ) and control mice were fed fructose chow for 1 week. Determinants of whole-body energy balance, weight, and composition were determined. Hepatic lipids including triglyceride, DAGs, and ceramide were measured, alongside markers of ER stress. Whole-body and tissue-specific insulin sensitivity were determined by hyperinsulinemic-euglycemic clamp studies. Hepatic ER stress signaling was increased in fructose chow-fed XBP1Δ mice as reflected by increased phosphorylated eIF2α, HSPA5 mRNA, and a 2-fold increase in hepatic JNK activity. Despite JNK activation, XBP1Δ displayed increased hepatic insulin sensitivity during hyperinsulinemic-euglycemic clamp studies, which was associated with increased insulin-stimulated IRS2 tyrosine phosphorylation, reduced hepatic DAG content, and reduced PKCϵ activity. These studies demonstrate that ER stress and IRE1α-mediated JNK activation can be disassociated from hepatic insulin resistance and support the hypothesis that hepatic insulin resistance in models of ER stress may be secondary to ER stress modulation of hepatic lipogenesis.