过氧化物酶体增殖物激活受体γ共激活因子1α在高脂饮食导致的大鼠骨骼肌线粒体功能紊乱中的作用机制  

Mechanisms of peroxisome proliferator-activated receptor gamma coactivator 1α in high-fat diet-induced skeletal muscle mitochondrial dysfunction in rats

作　　者：马欢[1] 张冬会[1] 王杏[1] 王子猜 宋光耀[1,2] 马慧娟[1,2] Ma Huan;Zhang Donghui;Wang Xing;Wang Zijing;Song Guangyao;Ma Huijuan(Hebei Key Laboratory of Metabolic Disease, Hebei General Hospital, Shijiazhuang 050000, China;Department of Endocrinology and Metabolism, Hebei General Hospital, Shijiazhuang 050000, China)

机构地区：[1]河北省人民医院河北省代谢病重点实验室,石家庄050000 [2]河北省人民医院内分泌科,石家庄050000

出　　处：《中华老年医学杂志》2019年第4期439-443,共5页Chinese Journal of Geriatrics

基　　金：国家自然科学基金(61200638);河北省国际合作项目( 15397750D).

摘　　要：目的研究过氧化物酶体增殖物激活受体γ共激活因子1α(PGC1α)在高脂饮食诱导的胰岛素抵抗、线粒体损伤过程中的作用。 方法将Wistar大鼠数字抽签分为对照组和高脂饮食组(各10只),高脂喂养8周后,测定空腹血糖、胰岛素水平和葡萄糖输注率,留取大鼠骨骼肌;将分化好的L6细胞分为对照组、软脂酸干预组(PA组)、空质粒转染组(pcDNA3组)和PGC1α过表达质粒转染组(pcDNA3-PGC1α组),收集细胞(n=3)。实时荧光定量聚合酶链反应(RtPCR)和免疫印迹(Westernblotting)法测定骨骼肌和肌细胞的PGC1α、核呼吸因子(NRF1)、解偶联蛋白3(UCP3)、细胞色素C氧化酶1(COX1)的表达变化。 结果与对照组比较,高脂饮食组大鼠的空腹血糖、胰岛素水平升高,葡萄糖输注率降低,(6.0±0.7)mmol/L比(5.0±0.4)mmol/L、(23.3±3.0)mU/L比(12.9±1.8)mU/L、(14.2±1.8)%比(22.6±2.4)%(t值分别为-3.578、-6.679、6.265,均P<0.05),其骨骼肌PGC1α、NRF1、UCP3、COX1表达降低(P<0.05)。在软脂酸干预的L6肌细胞,PGC1α、NRF1、UCP3、COX1表达降低(P<0.05)。PGC1α过表达后,逆转了软脂酸诱导的NRF1、UCP3、COX1表达的下降(F值分别为30.079、96.883、226.772,均P<0.001)。 结论高脂饮食造成胰岛素抵抗和骨骼肌线粒体代谢相关基因表达下降,PGC1α表达增加可改善上述基因的表达。PGC-1α表达降低可能介导了高脂诱导的线粒体功能异常和胰岛素抵抗。Objective To investigate the role of peroxisome proliferator-activated receptor gamma coactivator 1α(PGC1α)in high-fat diet-induced insulin resistance(IR)and mitochondrial degeneration in skeletal muscle. Methods Wistar rats were randomly divided into a normal chow(NC)group (n=10) and a high-fat diet(HFD)group (n=10). After eight weeks, fasting plasma glucose(FBG)levels, fasting insulin(FINS)levels and glucose infusion rates(GIR)in each group were measured (n=3). Samples of rat skeletal muscle were harvested.L6 myoblasts were divided into a control group, a PA group(cells were cultured in palmitic acid), a pcDNA3 group(cells were transfected by the plasmid pcDNA3)and a pcDNA3-PGC1α group(cells were transfected by the PGC1α-overexpression plasmid). Expression levels of PGC1α, nuclear respiratory factor 1(NRF1), uncoupling protein 3(UCP3), and cytochrome C oxidase 1(COX1)in skeletal muscle and L6 myoblasts were measured by real-time PCR and Western blotting. Results Levels of FBG and insulin were higher and those of GIR were lower in the HFD group than in the NC group,(6.0±0.7)mmol/L vs.(5.0±0.4)mmol/L、(23.3±3.0)mU/L vs.(12.9±1.8)mU/L、(14.2±1.8)% vs.(22.6±2.4)%(t=-3.578,-6.679, 6.265, respectively, P<0.05). Expression levels of PGC1α, NRF1, UCP3, and COX1 were down in skeletal muscle in the HFD group compared with those in the NC group(P<0.05). In L6 myoblasts cultured with palmitic acid, the expression of PGC1α, NRF1, UCP3, and COX1 were down compared with their expression in the NC group(P<0.05). However, the altered expression of PGC1α, NRF1, UCP3, and COX1 was reversed by transfecting with PGC1α-overexpression plasmids(F=30.079, 96.883, 226.772, respectively, P<0.001). Conclusions High-fat diets can lead to insulin resistance and decreased expression of mitochondrial energy metabolism-related genes, which can be reversed by PGC1α.The decreased expression of PGC1α may mediate the high-fat diet-induced mitochondrial dysfunction and IR.

关 键 词：过氧化物酶体增殖物激活受体 胰岛素抗药性 线粒体 髙脂血症 

分 类 号：R587.1[医药卫生—内分泌]