Loss of hnRNP A1 in murine skeletal muscle exacerbates high-fat diet-induced onset of insulin resistance and hepatic steatosis
Loss of hnRNP A1 in murine skeletal muscle exacerbates high-fat diet-induced onset of insulin resistance and hepatic steatosis
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小鼠骨骼肌中 hnRNP A1 的缺失会加剧高脂饮食引起的胰岛素抵抗和肝脂肪变性
DOI：
10.1093/jmcb/mjz050
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发表时间：
2019-06
影响因子：
5.5
通讯作者：
Yang Sun
中科院分区：
文献类型：
--
作者：
Mingxia Zhao;Lihong Shen;Zijun Ouyang;Manru Li;Guoliang Deng;Chenxi Yang;Wei Zheng;Lingdong Kong;Xuefeng Wu;Xudong Wu;Wenjie Guo;Ye Yin;Qiang Xu;Yang Sun
摘要骨骼肌对葡萄糖(Glu)的摄取和储存障碍是代谢性疾病发生的主要危险因素。异质性核糖核蛋白A1(HnRNP A1)是一种高度丰富的RNA结合蛋白，参与多种细胞功能。本研究的目的是探讨hnRNP A1在肌肉组织胰岛素敏感性和全身谷氨酸稳态中的作用。我们的结果表明，肌肉中hnRNP A1的有条件缺失导致高脂饮食(HFD)小鼠出现严重的胰岛素抵抗表型。喂食高脂饮食的条件性基因敲除小鼠表现出加重的肥胖、胰岛素抵抗和肝脏脂肪变性。体外干扰C2C12肌管的hnRNP A1可抑制胰岛素信号转导和谷氨酸摄取，而C2C12肌管中hnRNP A1的过表达对超生理浓度胰岛素诱导的胰岛素抵抗有保护作用。在没有hnRNP A1的情况下，糖原合成酶(Gys1)mRNA的表达和稳定性也降低。从机制上讲，hnRNP A1与gys1相互作用并稳定其mRNA，从而促进肌肉组织中糖原的合成并维持胰岛素敏感性。综上所述，我们的研究结果首次表明，hnRNP A1在骨骼肌中的表达减少通过抑制糖原合成来影响代谢特性和全身胰岛素敏感性。
Abstract Impairment of glucose (Glu) uptake and storage by skeletal muscle is a prime risk factor for the development of metabolic diseases. Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a highly abundant RNA-binding protein that has been implicated in diverse cellular functions. The aim of this study was to investigate the function of hnRNP A1 on muscle tissue insulin sensitivity and systemic Glu homeostasis. Our results showed that conditional deletion of hnRNP A1 in the muscle gave rise to a severe insulin resistance phenotype in mice fed a high-fat diet (HFD). Conditional knockout mice fed a HFD showed exacerbated obesity, insulin resistance, and hepatic steatosis. In vitro interference of hnRNP A1 in C2C12 myotubes impaired insulin signal transduction and inhibited Glu uptake, whereas hnRNP A1 overexpression in C2C12 myotubes protected against insulin resistance induced by supraphysiological concentrations of insulin. The expression and stability of glycogen synthase (gys1) mRNA were also decreased in the absence of hnRNP A1. Mechanistically, hnRNP A1 interacted with gys1 and stabilized its mRNA, thereby promoting glycogen synthesis and maintaining the insulin sensitivity in muscle tissue. Taken together, our findings are the first to show that reduced expression of hnRNP A1 in skeletal muscle affects the metabolic properties and systemic insulin sensitivity by inhibiting glycogen synthesis.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
15.8
作者：
Savage DB;Zhai L;Ravikumar B;Choi CS;Snaar JE;McGuire AC;Wou SE;Medina-Gomez G;Kim S;Bock CB;Segvich DM;Solanky B;Deelchand D;Vidal-Puig A;Wareham NJ;Shulman GI;Karpe F;Taylor R;Pederson BA;Roach PJ;O'Rahilly S;DePaoli-Roach AA
通讯作者：
DePaoli-Roach AA
影响因子：
8.2
作者：
Turner, N.;Kowalski, G. M.;Bruce, C. R.
通讯作者：
Bruce, C. R.
影响因子：
1.6
作者：
K. Højlund
通讯作者：
K. Højlund
CILP-2 是一种新型分泌蛋白，与胰岛素抵抗相关
影响因子：
5.5
作者：
Wu, Tong;Zhang, Qin;Yang, Gangyi
通讯作者：
Yang, Gangyi