Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity.
Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity.
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DOI：
10.1016/j.celrep.2015.10.052
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发表时间：
2015-12-01
期刊：
影响因子：
8.8
通讯作者：
Vanhaesebroeck B
中科院分区：
文献类型：
--
作者：
Alliouachene S;Bilanges B;Chicanne G;Anderson KE;Pearce W;Ali K;Valet C;Posor Y;Low PC;Chaussade C;Scudamore CL;Salamon RS;Backer JM;Stephens L;Hawkins PT;Payrastre B;Vanhaesebroeck B
与I类磷酸肌醇3-激酶（PI 3 Ks）相比，II类PI 3 Ks的激酶活性的生物作用不太清楚。在这里，我们报告说，II类PI 3 K-C2 β激酶死亡的小鼠是可行的和健康的，但显示出意想不到的增强胰岛素敏感性和葡萄糖耐量，以及对高脂肪饮食诱导的肝脏脂肪变性的保护。尽管具有广泛的组织分布，但全身性PI 3 K-C2 β抑制仅在代谢组织中选择性地增强胰岛素信号传导。在原代肝细胞模型中，PI 3 K-C2 β抑制后基础PI 3 P脂质水平降低60%。这导致非常早期APPL 1阳性内体区室的扩展和改变的胰岛素受体运输，与胰岛素诱导的I类PI 3 K依赖性Akt信号传导的扩增相关，而不影响MAPK活性。这些数据揭示了PI 3 K-C2 β是内体运输的关键调节剂，特别是在胰岛素信号传导中，并将PI 3 K-C2 β鉴定为胰岛素增敏的潜在药物靶标。PI 3 K-C2 β激酶死亡小鼠存活，具有增强的葡萄糖耐量PI 3 K-C2 β失活对胰岛素敏感并保护免于肝脏脂肪变性PI 3 K-C2 β失活选择性地增强代谢组织中的胰岛素/Akt信号传导PI 3 K-C2 β活性调节肝细胞中非常早期的内体区室II类PI 3 K的生物学作用尚不清楚。Alliouachene等人显示通过调节胰岛素受体运输，小鼠中II类PI 3 K-C2 β失活增强胰岛素敏感性并防止高脂饮食诱导肝脂肪变性。结果表明，PI 3 K-C2 β是胰岛素增敏的潜在药物靶点。
In contrast to the class I phosphoinositide 3-kinases (PI3Ks), the organismal roles of the kinase activity of the class II PI3Ks are less clear. Here, we report that class II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well as protection against high-fat-diet-induced liver steatosis. Despite having a broad tissue distribution, systemic PI3K-C2β inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2β inhibition. This results in an expansion of the very early APPL1-positive endosomal compartment and altered insulin receptor trafficking, correlating with an amplification of insulin-induced, class I PI3K-dependent Akt signaling, without impacting MAPK activity. These data reveal PI3K-C2β as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2β as a potential drug target for insulin sensitization. PI3K-C2β kinase-dead mice are viable with enhanced glucose tolerance PI3K-C2β inactivation sensitizes to insulin and protects from liver steatosis PI3K-C2β inactivation selectively enhances insulin/Akt signaling in metabolic tissues PI3K-C2β activity regulates very early endosomal compartments in hepatocytes Organismal roles of class II PI3Ks are unclear. Alliouachene et al. show that inactivation of the class II PI3K-C2β in mice, by regulating insulin receptor trafficking, enhances insulin sensitivity and protects against high-fat-diet-induced liver steatosis. The results suggest that PI3K-C2β is a potential drug target for insulin sensitization.