Increased lipid availability for three days reduces whole body glucose uptake, impairs muscle mitochondrial function and initiates opposing effects on PGC-1α promoter methylation in healthy subjects.
Increased lipid availability for three days reduces whole body glucose uptake, impairs muscle mitochondrial function and initiates opposing effects on PGC-1α promoter methylation in healthy subjects.
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DOI：
10.1371/journal.pone.0188208
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Abdul-Ghani M
中科院分区：
文献类型：
--
作者：
Eldor R;Norton L;Fourcaudot M;Galindo C;DeFronzo RA;Abdul-Ghani M
FFA和FFA代谢物导致胰岛素抵抗并损害β细胞功能。本研究的目的是检测血浆FFA升高是否损害线粒体功能并改变PGC-1α启动子甲基化。在这项非对照的、较基线变化的研究设计中，在3天脂质输注以升高血浆FFA浓度之前和之后，测量了9名正常葡萄糖耐受受试者的胰岛素敏感性和葡萄糖刺激的胰岛素分泌。获得股外侧肌活检组织，并定量线粒体功能、PGC-1α表达和PGC-1α启动子甲基化。血浆FFA升高（440±93 μmol/L至997±242 μM，p<0.001）使胰岛素刺激的总葡萄糖处置（TGD）减少25%（p = 0.008），内源性葡萄糖生成抑制受损（p = 0.01），并且用复合物1（34%，p<0.05）和复合物2（30%，p<0.05）底物减少线粒体ATP合成。脂质输注对肌肉PGC-1α RNA表达、总甲基化或非CpG甲基化没有影响，但替代PGC-1α启动子的甲基化降低（1.30±0.30至0.84±0.15%甲基化残基/患者·链，p = 0.055）。PGC-1α启动子区CpT残基存在去甲基化（0.72±0.16 vs. 0.28±0.10甲基化残基/患者·链）（p = 0.002），与PGC-1α mRNA表达呈负相关（r =-0.94，p<0.0001）和用复合物1（r =-0.80，p<0.01）和复合物2（r =-0.69，p<0.05）底物的ATP合成。脂质输注增加了DNMT-3B（与PGC-1α启动子非CpG甲基化相关的甲基转移酶）mRNA表达（0.87 ± 0.09至1.62 ± 0.22任意单位，p = 0.005），其与CpT去甲基化呈负相关（r = 0.67，p<0.05）。NGT个体生理性血浆FFA升高对PGC-1α非CpG残基甲基化（CpT去甲基化和DNMT-3B表达增加）有相反的影响，这与PGC-1α表达和骨骼肌线粒体功能的变化相关。
FFA and FFA metabolites cause insulin resistance and impair beta cell function. The goal of our research was to examine whether elevation of plasma FFA impairs mitochondrial function and alters PGC-1α promoter methylation. In this uncontrolled, change from baseline study design, insulin sensitivity and glucose-stimulated insulin secretion were measured in 9 normal glucose tolerant subjects before and after 3 day lipid infusion to elevate plasma FFA concentration. Vastus lateralis muscle biopsies were obtained and mitochondrial function, PGC-1α expression, and PGC-1α promoter methylation were quantitated. Increased plasma FFA (440±93 μmol/Lto 997±242 μM, p<0.001) decreased insulin-stimulated total glucose disposal (TGD) by 25% (p = 0.008), impaired suppression of endogenous glucose production (p = 0.01), and reduced mitochondrial ATP synthesis with complex 1 (34%, p<0.05) and complex 2 (30%, p<0.05) substrates. Lipid infusion had no effect on muscle PGC-1α RNA expression, total methylation or non-CpG methylation, but methylation of the alternative PGC-1α promoter decreased (1.30±0.30 to 0.84±0.15% methylated residues/patient•strand, p = 0.055). Within PGC-1α promoter there was demethylation of CpT residues (0.72±0.16 vs. 0.28±0.10 methylated residues/patient•strand) (p = 0.002), which was inversely correlated with PGC-1α mRNA expression (r = -0.94, p<0.0001) and ATP synthesis with complex 1 (r = -0.80, p<0.01) and complex 2 (r = -0.69, p<0.05) substrates. Lipid infusion increased DNMT-3B (methyltransferase associated with PGC-1α promoter non-CpG methylation) mRNA expression (0.87 ± 0.09 to 1.62 ± 0.22 arbitrary units, p = 0.005), which correlated inversely with CpT demethylation (r = 0.67, p<0.05). Physiologic plasma FFA elevation in NGT individuals has opposing effects on PGC-1α non-CpG residue methylation (CpT demethylation and increased DNMT-3B expression), which is correlated with changes in PGC-1α expression and skeletal muscle mitochondrial function.
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影响因子：
15.9
作者：
Cusi, K;Maezono, K;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
25
作者：
Guo, Junjie U.;Su, Yijing;Shin, Joo Heon;Shin, Jaehoon;Li, Hongda;Xie, Bin;Zhong, Chun;Hu, Shaohui;Le, Thuc;Fan, Guoping;Zhu, Heng;Chang, Qiang;Gao, Yuan;Ming, Guo-li;Song, Hongjun
通讯作者：
Song, Hongjun
影响因子：
29
作者：
Barres, Romain;Yan, Jie;Zierath, Juleen R.
通讯作者：
Zierath, Juleen R.
影响因子：
15.9
作者：
FERRANNINI, E;BARRETT, EJ;DEFRONZO, RA
通讯作者：
DEFRONZO, RA
影响因子：
7.1
作者：
Fernandez-Marcos, Pablo J.;Auwerx, Johan
通讯作者：
Auwerx, Johan