Impact of hepatic HSP72 on insulin signaling
Impact of hepatic HSP72 on insulin signaling
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DOI：
10.1152/ajpendo.00215.2018
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发表时间：
2019-02-01
影响因子：
5.1
通讯作者：
Araki, Eiichi
中科院分区：
文献类型：
--
作者：
Kitano, Sayaka;Kondo, Tatsuya;Araki, Eiichi
热休克蛋白72（HSP 72）是热休克反应中的主要诱导分子，可增强细胞内的应激耐受性。在2型糖尿病中观察到HSP 72表达减少，这可能有助于胰岛素抵抗和慢性炎症的发展。我们使用HSP 72敲除（HSP 72-KO）小鼠研究HSP 72对葡萄糖代谢和内质网（ER）应激的影响，特别是在肝脏中。在高脂饮食（HFD）条件下，HSP 72-KO小鼠表现出葡萄糖耐受不良、胰岛素抵抗、胰岛素分泌受损和肝细胞增殖活性增强。此外。c-Jun NH 2-末端激酶（JNK）的活性增加，并且肝脏中的胰岛素信号传导被抑制。在HFD喂养的HSP 72-KO小鼠中，通过慢病毒（lenti）肝脏特异性表达HSP 72改善了胰岛素抵抗和肝脏致炎活性。此外，HFD诱导的脂肪细胞大小增加和肝脂肪变性在HSP 72-KO lenti-HSP 72小鼠中得到抑制。在HSP 72-KO lenti-HSP 72小鼠的肝脏以及白色脂肪组织中，HFD后JNK活性和ER应激的增加受到抑制。因此，HSP 72 KO导致葡萄糖代谢、肝致炎活性和β细胞功能的恶化。而且。肝脏特异性HSP 72的恢复恢复了葡萄糖稳态。因此，肝脏HSP 72可能在2型糖尿病的发病机制中起着重要作用。
Heat shock protein 72 (HSP72) is a major inducible molecule in the heat shock response that enhances intracellular stress tolerance. Decreased expression of HSP72 is observed in type 2 diabetes, which may contribute to the development of insulin resistance and chronic inflammation. We used HSP72 knockout (HSP72-KO) mice to investigate the impact of HSP72 on glucose metabolism and endoplasmic reticulum (ER) stress, particularly in the liver. Under a high-fat diet (HFD) condition, HSP72-KO mice showed glucose intolerance, insulin resistance, impaired insulin secretion, and enhanced hepatic gluconeogenic activity. Furthermore. activity of the c-Jun NH2-terminal kinase (JNK) was increased and insulin signaling suppressed in the liver. Liver-specific expression of HSP72 by lentivirus (lenti) in HFD-fed HSP72-KO mice ameliorated insulin resistance and hepatic gluconeogenic activity. Furthermore, increased adipocyte size and hepatic steatosis induced by the HFD were suppressed in HSP72-KO lenti-HSP72 mice. Increased JNK activity and ER stress upon HFD were suppressed in the liver as well as the white adipose tissue of HSP72-KO lenti-HSP72 mice. Thus, HSP72 KO caused a deterioration in glucose metabolism, hepatic gluconeogenic activity, and beta-cell function. Moreover. liver-specific recovery of HSP72 restored glucose homeostasis. Therefore, hepatic HSP72 may play a critical role in the pathogenesis of type 2 diabetes.