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Diabetes:肥胖相关的肝脏胰岛素抵抗新机制

2017-11-02 fengxiangxin MedSci原创

在此项研究者,作者建立了一种在肥胖和糖尿病中功能被扰乱的蛋白质,S-亚硝基谷胱甘肽还原酶(GSNOR),这是调节炎症和自噬间关键环节的主要蛋白质。

肥胖与细胞内一氧化氮(NO)产生增加有关,增加的NO通过促进肝脏和骨骼肌等代谢组织中的亚硝化应激,这有助于胰岛素抵抗的形成。肥胖相关的胰岛素抵抗的发病是由于肝脏的自噬妥协,这是一个溶酶体降解细胞成分的过程。然而,NO生物活性如何影响肥胖中的自噬尚不清楚。

在此项研究者,作者建立了一种在肥胖和糖尿病中功能被扰乱的蛋白质,S-亚硝基谷胱甘肽还原酶(GSNOR),这是调节炎症和自噬间关键环节的主要蛋白质。

研究者发现,肥胖能够促进肝脏中溶酶体蛋白的S-亚硝基化,从而损害溶酶体的酶活性。此外,在小鼠和人类中,肥胖和糖尿病伴随著GSNOR活性降低(产生亚硝化应激)的发生而发生。在GSNOR缺失的小鼠中,饮食诱导的肥胖增加了溶酶体的亚硝化应激,并损害肝脏中的自噬,从而导致肝胰岛素抵抗的发生。

相反,在肥胖小鼠肝脏中特异性过表达GSNOR显著增强了溶酶体功能、自噬,同时显著改善了胰岛素作用和葡萄糖的体内平衡。此外,溶酶体酶的S-亚硝基抗性变体的过表达增强了自噬。并且药理学和遗传学增强的自噬改善了GSNOR缺陷型肝细胞中的胰岛素敏感性。

总之,作者的研究数据表明,肥胖诱导的蛋白质S-亚硝基化是影响肝脏自噬的关键机制,有助于肝胰岛素抵抗的形成。

原始出处:

Qian Q, Zhang Z, Orwig A.et al. S-nitrosoglutathione Reductase Dysfunction Contributes to Obesity-Associated Hepatic Insulin Resistance via Regulating Autophagy.Diabetes. 2017 Oct 26. pii: db170223. doi: 10.2337/db17-0223.

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    2018-08-02 baoya
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    2017-11-03 明天会更好!

    很好的文章.谢谢分享

    0

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