Department of Orthopedic Surgery and.
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California, USA.
JCI Insight. 2022 Jan 11;7(1):e141344. doi: 10.1172/jci.insight.141344.
While current thinking posits that insulin signaling to glucose transporter 4 (GLUT4) exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle caused a complete loss of insulin-stimulated glucose uptake. Similarly, brief (i.e., 1 hour) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulated this phenotype in human and rodent myotubes, 3T3-L1 adipocytes, and mouse muscle. Mechanistically, these effects were due to p300/CBP-mediated regulation of GLUT4 exocytic translocation and occurred downstream of Akt signaling. Taken together, we highlight a fundamental role for acetylation and p300/CBP in the direct regulation of insulin-stimulated glucose transport in skeletal muscle and adipocytes.
虽然目前的观点认为胰岛素信号转导至葡萄糖转运蛋白 4 (GLUT4) 胞吐易位和骨骼肌及脂肪细胞的葡萄糖摄取受磷酸化信号通路控制，但该通路中的许多蛋白在赖氨酸残基上发生乙酰化。然而，乙酰化和赖氨酸乙酰转移酶对胰岛素刺激的葡萄糖摄取的重要性尚未完全确定。在这里，我们证明了在小鼠骨骼肌中同时缺失乙酰转移酶 E1A 结合蛋白 p300 (p300) 和 cAMP 反应元件结合蛋白结合蛋白 (CBP) 会导致胰岛素刺激的葡萄糖摄取完全丧失。同样，短暂（即 1 小时）药理学抑制 p300/CBP 乙酰转移酶活性可在人类和啮齿动物肌管、3T3-L1 脂肪细胞和小鼠肌肉中重现这种表型。从机制上讲，这些作用是由于 p300/CBP 介导的 GLUT4 胞吐易位调节，并且发生在 Akt 信号转导的下游。综上所述，我们强调了乙酰化和 p300/CBP 在骨骼肌和脂肪细胞中直接调节胰岛素刺激的葡萄糖转运中的基本作用。
