胰岛素抵抗
内科学
骨骼肌
内分泌学
胰岛素
肌发生
下调和上调
泛素连接酶
心肌细胞
C2C12型
基因敲除
生物
泛素
细胞凋亡
医学
生物化学
基因
作者
Bo Li,Jingjing Ye,Ruxia Liu,Lin Weng,Yangpo Cao,Shi Jia,Chun-Ling Xu,Ying-Ying Liu,Saifang Yan,Ming Zheng
出处
期刊:Life Sciences
[Elsevier]
日期:2021-11-15
卷期号:285: 119918-119918
标识
DOI:10.1016/j.lfs.2021.119918
摘要
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.
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