Role of hepatic neuregulin 4 in the regulation of gluconeogenesis in mice
Role of hepatic neuregulin 4 in the regulation of gluconeogenesis in mice
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DOI：
10.1016/j.lfs.2018.12.006
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发表时间：
2019-01
期刊：
影响因子：
6.1
通讯作者：
Linlin Zhang;Mengyao Bai;Hongju Tang;Feiye Zhou;Qin Zhu;Shushu Wang;Kecheng Zhu;Qianqian Liu;Yun Liu;Xiao Wang;Yabin Ma;Libin Zhou
中科院分区：
文献类型：
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作者：
Linlin Zhang;Mengyao Bai;Hongju Tang;Feiye Zhou;Qin Zhu;Shushu Wang;Kecheng Zhu;Qianqian Liu;Yun Liu;Xiao Wang;Yabin Ma;Libin Zhou
目的肝脏糖异生增强是 2 型糖尿病高血糖的重要原因。然而，肝脏糖异生紊乱的调控机制仍不清楚。在本研究中，我们研究了肝神经调节蛋白4（Nrg4）在小鼠糖异生调节中的潜在作用。主要方法在用或不用8-Br-cAMP处理的原代小鼠肝细胞中进行微阵列分析。用Nrg4过表达或shRNA腺病毒转染的原代小鼠肝细胞用于检测关键糖异生基因的表达和葡萄糖输出。在禁食的 C57/BL6 小鼠、obeseob/obmice、diabetesdb/dbmice 和 Goto-Kakisaki (GK) 大鼠中测量肝脏 Nrg4 表达水平。将 Nrg4 shRNA 腺病毒注射到雄性 C57BL/6 和 db/db 小鼠后 7 天，进行丙酮酸耐受性测试并检测糖异生基因表达。主要发现微阵列分析显示，原代小鼠肝细胞中 8-Br-cAMP 显着诱导 Nrg4 表达，同时上调磷酸烯醇丙酮酸羧激酶 (PEPCK) 和葡萄糖-6-磷酸酶(G6P酶)。腺病毒介导的原代小鼠肝细胞中 Nrg4 的过度表达或敲低会增加或减少 PEPCK 和 G6Pase 的表达以及肝葡萄糖的产生。正常 C57/BL6 小鼠禁食可诱导肝脏 Nrg4 表达，并且在 obeseob/obmice、diabetesdb/dbmice 和 GK 大鼠中显着上调。 C57BL/6 和 db/db 小鼠中肝脏 Nrg4 敲低可改善丙酮酸耐受性，同时 PEPCK、G6Pase 和过氧化物酶体增殖物激活受体-γ 共激活剂-1α (PGC-1α) 下调。意义肝脏 Nrg4 在糖异生调节中起着至关重要的作用，可能是 2 型糖尿病的治疗靶点。
AimsEnhanced hepatic gluconeogenesis is an important cause of hyperglycemia in type 2 diabetes. However, the regulatory mechanisms underlying disordered hepatic gluconeogenesis remains largely unclear. In the present study, we investigated the potential role of hepatic neuregulin 4 (Nrg4) in the regulation of gluconeogenesis in mice.Main methodsMicroarray analysis was performed in primary mouse hepatocytes treated with or without 8-Br-cAMP. Primary mouse hepatocytes transfected with Nrg4 overexpressing or shRNA adenovirus were used to detect the expressions of the key gluconeogenic genes and glucose output. Hepatic Nrg4 expression levels were measured in fasted C57/BL6 mice, obeseob/obmice, diabeticdb/dbmice and Goto-Kakisaki (GK) rats. Pyruvate tolerance test was performed and gluconeogenic gene expressions were detected 7 days after Nrg4 shRNA adenovirus was injected into male C57BL/6 anddb/dbmice.Key findingsMicroarray analysis revealed that Nrg4 expression was significantly induced by 8-Br-cAMP in primary mouse hepatocytes, along with the upregulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Adenovirus-mediated overexpression or knockdown of Nrg4 in primary mouse hepatocytes increased or decreased PEPCK and G6Pase expressions as well as hepatic glucose production. Hepatic Nrg4 expression was induced by fasting in normal C57/BL6 mice, and markedly upregulated in obeseob/obmice, diabeticdb/dbmice and GK rats. Hepatic Nrg4 knockdown in C57BL/6 anddb/dbmice improved pyruvate tolerance, with the downregulation of PEPCK, G6Pase, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α).SignificanceHepatic Nrg4 plays a crucial role in the regulation of gluconeogenesis and may be a therapeutic target of type 2 diabetes.