NGBR is required to ameliorate type 2 diabetes in mice by enhancing insulin sensitivity.
NGBR is required to ameliorate type 2 diabetes in mice by enhancing insulin sensitivity.
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NGBR 通过增强胰岛素敏感性来改善小鼠 2 型糖尿病
DOI：
10.1016/j.jbc.2021.100624
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Duan Y
中科院分区：
文献类型：
--
作者：
Chen Y;Hu W;Li Q;Zhao S;Zhao D;Zhang S;Wei Z;Yang X;Chen Y;Li X;Liao C;Han J;Miao QR;Duan Y
减少胰岛素抵抗或改善胰岛素敏感性是治疗2型糖尿病(T2D)最有效的方法。我们先前报道了由NUS1基因编码的Nogo-B受体(NGBR)通过阻断肝脏X受体α的核转位来抑制肝脏脂肪生成，提示它在调节肝脂代谢中起重要作用。在这里，我们证明了NGBR在肥胖相关的T2D患者和db/db小鼠的肝脏中的表达减少。小鼠肝细胞中的NGBR基因敲除导致血糖、胰岛素抵抗和β细胞丢失增加。高脂饮食(HFD)/链脲佐菌素(STZ)处理的小鼠表现出T2D表型，表现为肝脏和血浆中非酯化脂肪酸(NEFA)和甘油三酯(TG)增加，胰岛素抵抗和β细胞丢失增加。AAV介导的NGBR在肝脏中的过表达降低了肝脏和循环中的NEFA和TG，并改善了肝功能。因此，肝脏NGBR过表达的HFD/STZ治疗小鼠提高了胰岛素敏感性，减少了β细胞损失。NGBR过表达从机制上恢复了AMPKAK1依赖的αβ磷酸化的胰岛素信号转导。NGBR的过表达还减少了内质网应激相关基因在肝脏和骨骼肌中的表达，从而改善了胰岛素敏感性。总之，我们的结果表明NGBR需要改善小鼠的T2D，为肝脏NGBR在胰岛素敏感性和T2D治疗中的作用提供了新的见解。
The reduction of insulin resistance or improvement of insulin sensitivity is the most effective treatment for type 2 diabetes (T2D). We previously reported that Nogo-B receptor (NGBR), encoded by the NUS1 gene, is required for attenuating hepatic lipogenesis by blocking nuclear translocation of liver X receptor alpha, suggesting its important role in regulating hepatic lipid metabolism. Herein, we demonstrate that NGBR expression was decreased in the liver of obesity-associated T2D patients and db/db mice. NGBR knockout in mouse hepatocytes resulted in increased blood glucose, insulin resistance, and beta-cell loss. High-fat diet (HFD)/streptozotocin (STZ)-treated mice presented the T2D phenotype by showing increased nonesterified fatty acid (NEFA) and triglyceride (TG) in the liver and plasma and increased insulin resistance and beta-cell loss. AAV-mediated NGBR overexpression in the liver reduced NEFA and TG in the liver and circulation and improved liver functions. Consequently, HFD/STZ-treated mice with hepatic NGBR overexpression had increased insulin sensitivity and reduced beta-cell loss. Mechanistically, NGBR overexpression restored insulin signaling of AMPKα1-dependent phosphorylation of AKT and GSK3β. NGBR overexpression also reduced expression of endoplasmic reticulum stress-associated genes in the liver and skeletal muscle to improve insulin sensitivity. Together, our results reveal that NGBR is required to ameliorate T2D in mice, providing new insight into the role of hepatic NGBR in insulin sensitivity and T2D treatment.
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影响因子：
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作者：
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DOI：
10.1161/atvbaha.114.305116
发表时间：
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影响因子：
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