Li Bo, Ye Jingjing, Liu Ruxia, Weng Lin, Cao Yangpo, Jia Shi, Xu Chunling, Liu Yingying, Yan Saifang, Zheng Ming
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China.
Trauma Medicine Center, Peking University People's Hospital; Key Laboratory of Trauma and Neural Regeneration (Peking University), National Center for Trauma Medicine, Beijing 100044, P.R. China; Department of Central Laboratory & Institute of Clinical Molecular Biology, Peking University People's Hospital, Beijing 100044, P.R. China.
Life Sci. 2021 Nov 15;285:119918. doi: 10.1016/j.lfs.2021.119918. Epub 2021 Sep 1.
Insulin 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.
Mice 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.
PDCD5 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.
PDCD5 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.
胰岛素抵抗被定义为组织和器官对胰岛素的敏感性降低，它是代谢综合征的主要病理基础。程序性细胞死亡蛋白5（PDCD5）在包括骨骼肌和肝脏在内的组织中广泛表达，但其确切功能以及在胰岛素抵抗中的作用尚未得到研究。本研究旨在探讨PDCD5对胰岛素最大靶器官骨骼肌中胰岛素抵抗的影响及其机制。
给小鼠喂食高脂饮食以建立肥胖模型。C2C12成肌细胞分化为肌管，然后用棕榈酸处理以诱导胰岛素抵抗。通过用含有PDCD5 cDNA或PDCD5 shRNA的腺病毒感染C2C12进行功能获得和功能丧失实验。
在高脂饮食诱导的肥胖小鼠的骨骼肌中，PDCD5蛋白先升高后降低，在棕榈酸诱导的胰岛素抵抗C2C12肌管中也呈现同样变化。在C2C12细胞中过表达PDCD5不影响对胰岛素的敏感性，但可抑制棕榈酸诱导的胰岛素抵抗，而敲低PDCD5则加重胰岛素抵抗。机制上，PDCD5与泛素连接酶MDM2相互作用；过表达PDCD5可降低MDM2蛋白水平，抑制MDM2与胰岛素受体底物1（IRS-1）相互作用的增加以及棕榈酸刺激导致的IRS-1降解。
在骨骼肌胰岛素抵抗的早期阶段，PDCD5表达上调。增加的PDCD5通过与MDM2相互作用并使其降解来抑制IRS-1泛素化，增加IRS-1的稳定性，从而对骨骼肌中的胰岛素抵抗起到保护作用。
