Polarity Protein AF6 Controls Hepatic Glucose Homeostasis and Insulin Sensitivity by Modulating IRS1/AKT Insulin Pathway in an SHP2-Dependent Manner
Polarity Protein AF6 Controls Hepatic Glucose Homeostasis and Insulin Sensitivity by Modulating IRS1/AKT Insulin Pathway in an SHP2-Dependent Manner
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极性蛋白 AF6 通过以 SHP2 依赖性方式调节 IRS1/AKT 胰岛素途径来控制肝葡萄糖稳态和胰岛素敏感性
DOI：
10.2337/db18-0695
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发表时间：
2019-08-01
期刊：
影响因子：
7.7
通讯作者：
Zhan, Lixing
中科院分区：
文献类型：
--
作者：
Dai, Cheng;Wang, Xinyu;Zhan, Lixing
胰岛素抵抗是代谢性疾病发生的一个重要因素。虽然极性蛋白AF6 （afadin和MLLT4）的许多功能已经被确定，但对胰岛素敏感性的直接影响尚未被描述。我们发现AF6在饮食性和遗传性糖尿病小鼠模型的肝组织中升高。我们培育了肝脏特异性AF6敲除小鼠，发现这些动物表现出胰岛素敏感性和肝糖原储存增强，而在野生型小鼠中，通过腺病毒表达AF6过表达会导致相反的表型。在体外研究中也得到了类似的观察结果。此外，我们发现AF6通过与Src同源2结构域磷酸酶2 （SHP2）的相互作用以及对SHP2酪氨酸磷酸酶活性的调节，直接调节IRS1/AKT激酶介导的胰岛素信号转导。最后，我们发现，在高脂肪饮食喂养或db/db糖尿病小鼠中，肝脏AF6的敲低可以改善高血糖和胰岛素抵抗。这些结果证明了肝脏AF6在胰岛素敏感性调节中的新功能，为AF6的代谢作用提供了重要的见解。
Insulin resistance is a major contributing factor in the development of metabolic disease. Although numerous functions of the polarity protein AF6 (afadin and MLLT4) have been identified, a direct effect on insulin sensitivity has not been previously described. We show that AF6 is elevated in the liver tissues of dietary and genetic mouse models of diabetes. We generated liver-specific AF6 knockout mice and show that these animals exhibit enhanced insulin sensitivity and liver glycogen storage, whereas overexpression of AF6 in wild-type mice by adenovirus-expressing AF6 led to the opposite phenotype. Similar observations were obtained from in vitro studies. In addition, we discovered that AF6 directly regulates IRS1/AKT kinase-mediated insulin signaling through its interaction with Src homology 2 domain-containing phosphatase 2 (SHP2) and its regulation of SHP2’s tyrosine phosphatase activity. Finally, we show that knockdown of hepatic AF6 ameliorates hyperglycemia and insulin resistance in high-fat diet–fed or db/db diabetic mice. These results demonstrate a novel function for hepatic AF6 in the regulation of insulin sensitivity, providing important insights about the metabolic role of AF6.