p38 mitogen-activated protein kinase-dependent transactivation of ErbB receptor family: a novel common mechanism for stress-induced IRS-1 serine phosphorylation and insulin resistance.
p38 mitogen-activated protein kinase-dependent transactivation of ErbB receptor family: a novel common mechanism for stress-induced IRS-1 serine phosphorylation and insulin resistance.
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作者：
Hemi R;Yochananov Y;Barhod E;Kasher-Meron M;Karasik A;Tirosh A;Kanety H
应激刺激如肿瘤坏死因子（TNF）已显示通过ErbB受体的反式激活诱导胰岛素受体底物（IRS）-1丝氨酸磷酸化和胰岛素抵抗。我们的目的是阐明p38丝裂原活化蛋白激酶（p38 MAPK）在介导应激诱导的ErbB受体活化中的潜在作用。在暴露于应激刺激的Fao或HepG 2细胞中评估p38 MAPK对ErbB反式激活和胰岛素信号传导的作用，以及对ob/ob和C57/BL 6小鼠中代谢参数的作用。高脂饮食喂养的小鼠和ob/ob小鼠表现出与葡萄糖耐受不良和高胰岛素血症相关的肝脏p38 MAPK活化升高。在ob/ob小鼠肝脏中显性阴性（DN）-p38 MAPK α表达降低空腹胰岛素水平并改善葡萄糖耐量，而过度表达野生型p38 MAPK α的C57/BL 6小鼠表现出增强的IRS-1丝氨酸磷酸化和减少胰岛素刺激的IRS-1酪氨酸磷酸化。暴露于TNF、茴香霉素或鞘磷脂酶的Fao或HepG 2细胞表现出ErbB受体的快速反式激活，导致PI 3-激酶/Akt激活和IRS-1丝氨酸磷酸化。通过SB 203580、小干扰RNA或DN-p38 MAPK α抑制p38 MAPK可降低ErbB受体反式激活和IRS-1丝氨酸磷酸化，并部分恢复胰岛素刺激的IRS-1酪氨酸磷酸化。当细胞与特定的ErbB受体拮抗剂或在缺乏ErbB受体的细胞中孵育时，茴香霉素和TNF诱导的IRS-1丝氨酸磷酸化减弱，尽管完整的p38 MAPK激活。应激诱导的p38 MAPK激活导致ErbB受体反式激活与细胞内活性氧的产生有关，并通过抗氧化剂治疗减弱。肝脏p38 MAPK在各种应激刺激后被激活。该事件是ErbB受体反式激活的上游，并且在应激诱导的IRS-1丝氨酸磷酸化和胰岛素抵抗中起重要作用。
Stress stimuli such as tumor necrosis factor (TNF) have been shown to induce insulin receptor substrate (IRS)-1 serine phosphorylation and insulin resistance by transactivation of ErbB receptors. We aimed at elucidating the potential role of p38 mitogen-activated protein kinase (p38MAPK) in mediating stress-induced ErbB receptors activation. p38MAPK effect on ErbBs transactivation and insulin signaling was assessed in Fao or HepG2 cells, exposed to stress stimuli, and on metabolic parameters in ob/ob and C57/BL6 mice. High-fat diet–fed mice and ob/ob mice exhibited elevated hepatic p38MAPK activation associated with glucose intolerance and hyperinsulinemia. Liver expression of dominant-negative (DN)-p38MAPKα in ob/ob mice reduced fasting insulin levels and improved glucose tolerance, whereas C57/BL6 mice overexpressing wild-type p38MAPKα exhibited enhanced IRS-1 serine phosphorylation and reduced insulin-stimulated IRS-1 tyrosine phosphorylation. Fao or HepG2 cells exposed to TNF, anisomycin, or sphingomyelinase demonstrated rapid transactivation of ErbB receptors leading to PI3-kinase/Akt activation and IRS-1 serine phosphorylation. p38MAPK inhibition either by SB203580, by small interfering RNA, or by DN-p38MAPKα decreased ErbB receptors transactivation and IRS-1 serine phosphorylation and partially restored insulin-stimulated IRS-1 tyrosine phosphorylation. When cells were incubated with specific ErbB receptors antagonists or in cells lacking ErbB receptors, anisomycin- and TNF-induced IRS-1 serine phosphorylation was attenuated, despite intact p38MAPK activation. The stress-induced p38MAPK activation leading to ErbB receptors transactivation was associated with intracellular reactive oxygen species generation and was attenuated by treatment with antioxidants. Hepatic p38MAPK is activated following various stress stimuli. This event is upstream to ErbB receptors transactivation and plays an important role in stress-induced IRS-1 serine phosphorylation and insulin resistance.
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影响因子：
15.9
作者：
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通讯作者：
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DOI：
10.1152/ajpendo.00723.2009
发表时间：
2010-06-01
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