Programmed cell death 5 improves skeletal muscle insulin resistance by inhibiting IRS-1 ubiquitination through stabilization of MDM2
Programmed cell death 5 improves skeletal muscle insulin resistance by inhibiting IRS-1 ubiquitination through stabilization of MDM2
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程序性细胞死亡 5 通过稳定 MDM2 抑制 IRS-1 泛素化，改善骨骼肌胰岛素抵抗
DOI：
10.1016/j.lfs.2021.119918
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发表时间：
2021
期刊：
影响因子：
6.1
通讯作者：
Zheng Ming
中科院分区：
文献类型：
--
作者：
Li Bo;Ye Jingjing;Liu Ruxia;Weng Lin;Cao Yangpo;Jia Shi;Xu Chunling;Liu Yingying;Yan Saifang;Zheng Ming
目的胰岛素抵抗（Insulin resistance，IR）是指组织器官对胰岛素敏感性的降低，是代谢综合征的主要病理基础。PDCD 5广泛表达于骨骼肌和肝脏等组织中，但其确切功能及其在胰岛素抵抗中的作用尚未研究。本研究旨在探讨PDCD 5对胰岛素最大靶器官骨骼肌胰岛素抵抗的影响及其机制。C2 C12成肌细胞分化为肌管，然后用棕榈酸酯处理以诱导胰岛素抵抗。用含PDCD 5 cDNA或PDCD 5 shRNA的腺病毒感染C2 C12细胞，进行功能获得和功能丧失实验，主要发现PDCD 5蛋白在高脂饮食诱导的肥胖小鼠骨骼肌和棕榈酸诱导的胰岛素抵抗的C2 C12肌管中先增加后减少。过表达PDCD 5不影响C2 C12细胞对胰岛素的敏感性，但抑制棕榈酸诱导的胰岛素抵抗，而敲低PDCD 5则加重胰岛素抵抗。PDCD 5与泛素连接酶MDM 2相互作用，过表达PDCD 5可降低MDM 2蛋白水平，抑制MDM 2与IRS-1相互作用的增加以及棕榈酸刺激对IRS-1的降解。增加的PDCD 5抑制IRS-1泛素化，通过与MDM 2相互作用并降解MDM 2来增加IRS-1的稳定性，从而对骨骼肌中的胰岛素抵抗提供保护作用。
AimsInsulin resistance is defined as the decreased sensitivity of tissues and organs to insulin and it is the main pathological basis of metabolic syndrome. PDCD5 is widely expressed in tissues including skeletal muscle and liver, but its exact function and the role in insulin resistance has not been studied. The present study is to explore the effect of PDCD5 on insulin resistance in skeletal muscle, the largest target organ of insulin, and its mechanism.Materials and methodsMice were fed with high-fat diet to establish obesity model. C2C12 myoblasts differentiated into myotubes and then were treated with palmitate to induce insulin resistance. Gain-of-function and loss-of-function experiments were performed by infecting C2C12 with adenovirus containing PDCD5 cDNA or PDCD5 shRNA.Key findingsPDCD5 protein was first increased and then decreased in the skeletal muscle from high-fat diet induced obese mice and consistently in palmitate induced insulin resistance C2C12 myotubes. Overexpression of PDCD5 in C2C12 cells did not affect the sensitivity to insulin but inhibited the palmitate induced insulin resistance, while knockdown of PDCD5 aggravated the insulin resistance. Mechanistically, PDCD5 interacted with ubiquitin ligase MDM2; overexpression of PDCD5 decreased MDM2 protein level, inhibited the increased interaction of MDM2 with IRS-1 and the degradation of IRS-1 by palmitate stimulation.SignificancePDCD5 is upregulated during the early stage of insulin resistance in skeletal muscle. The increased PDCD5 inhibits IRS-1 ubiquitination, increases the stability of IRS-1 by interacting with and degrading MDM2, thus providing a protective effect on insulin resistance in skeletal muscle.