Autoregulation of insulin receptor signaling through MFGE8 and the αvβ5 integrin
Autoregulation of insulin receptor signaling through MFGE8 and the αvβ5 integrin
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DOI：
10.1073/pnas.2102171118
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发表时间：
2021-05-04
影响因子：
11.1
通讯作者：
Atabai, Kamran
中科院分区：
文献类型：
--
作者：
Datta, Ritwik;Lizama, Carlos O.;Atabai, Kamran
整合素，尤其是V整合素在调节胰岛素抵抗中的作用尚不完全清楚。我们之前已经证明，整合素配体乳脂球表皮生长因子样8(MFGE8)调节细胞对脂肪酸的摄取。在这项工作中，我们评估了MFGE8对葡萄糖稳态的影响。我们发现，MFGE8/05途径的急性阻断增强，而急性增强抑制胰岛素刺激的葡萄糖摄取。此外，我们还发现，胰岛素本身可以诱导骨骼肌细胞表面MFGE8的表达，进而促进整合素V05与胰岛素受体之间的相互作用，从而抑制骨骼肌胰岛素受体信号传导。阻断MFGE8/05通路也能增强肝脏对胰岛素的敏感性。我们的工作确定了一种自我调节机制，通过其同源受体通过上调MFGE8及其与？V05整合素的相互作用来终止胰岛素刺激信号，从而建立一条潜在的靶向改善胰岛素敏感性的途径。
The role of integrins, in particular ?v integrins, in regulating insulin resistance is incompletely understood. We have previously shown that the ?v05 integrin ligand milk fat globule epidermal growth factor like 8 (MFGE8) regulates cellular uptake of fatty acids. In this work, we evaluated the impact of MFGE8 on glucose homeostasis. We show that acute blockade of the MFGE8/05 pathway enhances while acute augmentation dampens insulin-stimulated glucose uptake. Moreover, we find that insulin itself induces cellsurface enrichment of MFGE8 in skeletal muscle, which then promotes interaction between the ?v05 integrin and the insulin receptor leading to dampening of skeletal-muscle insulin receptor signaling. Blockade of the MFGE8/05 pathway also enhances hepatic insulin sensitivity. Our work identifies an autoregulatory mechanism by which insulin-stimulated signaling through its cognate receptor is terminated through up-regulation of MFGE8 and its consequent interaction with the ?v05 integrin, thereby establishing a pathway that can potentially be targeted to improve insulin sensitivity.