Department of Endocrinology, the Affiliated Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang, China.
Cell Commun Signal. 2020 Oct 28;18(1):173. doi: 10.1186/s12964-020-00654-2.
Skeletal muscle is essential for glucose and lipid metabolism. Growing evidence reveals the importance of long non-coding RNAs (LncRNAs) in metabolism. This study aimed to investigate the function of LncRNA H19 (H19) in lipid metabolism of skeletal muscle and its potential mechanisms.
Glucose tolerance, serum insulin and lipid content in serum and skeletal muscle were determined in control and H19-overexpressed db/db mice. Lipid metabolism was evaluated in H19-overexpressed or H19-silencing muscle cells by detecting lipid contents and mitochondria related functions. The underlying mechanisms were explored by RNA pull-down, mass spectrometry and RNA immunoprecipitation (RIP).
H19 was downregulated in skeletal muscle of db/db mice. H19 overexpression in db/db mice inhibited lipid ectopic deposition in skeletal muscle, meanwhile improved glucose intolerance and insulin resistance as compared with control db/db mice treated with ad-GFP. Furthermore, overexpression of H19 reversed FFA-induced lipid accumulation and increased cellular respiration in muscle cells, while H19 knockdown exhibited opposite effects in muscle cells. Mechanistically, H19 interacted with heterogeneous nuclear ribonucleoprotein (hnRNPA1) which was validated by RNA pulldown and RIP analysis, which increased translation of fatty acid oxidation closely related genes PGC1a and CPT1b.
Our data suggest that overexpression of H19 ameliorates insulin resistance by reducing ectopic lipid accumulation in skeletal muscle. The possible underlying mechanisms are that overexpression of lncRNAH19 promotes fatty acids oxidation via targeting of hnRNPA1. Video abstract.
骨骼肌对于葡萄糖和脂质代谢至关重要。越来越多的证据表明长非编码 RNA（lncRNA）在代谢中具有重要作用。本研究旨在探讨 lncRNA H19（H19）在骨骼肌脂质代谢中的作用及其潜在机制。
在对照和 H19 过表达 db/db 小鼠中测定葡萄糖耐量、血清胰岛素和血清及骨骼肌中的脂质含量。通过检测脂质含量和与线粒体相关的功能来评估 H19 过表达或 H19 沉默的肌肉细胞中的脂质代谢。通过 RNA 下拉、质谱和 RNA 免疫沉淀（RIP）探索潜在机制。
db/db 小鼠骨骼肌中 H19 下调。与对照 db/db 小鼠用 ad-GFP 处理相比，H19 在 db/db 小鼠中的过表达抑制了骨骼肌中的脂质异位沉积，同时改善了葡萄糖耐量和胰岛素抵抗。此外，H19 的过表达逆转了 FFA 诱导的肌肉细胞脂质积累和细胞呼吸增加，而 H19 的敲低在肌肉细胞中则表现出相反的效果。在机制上，H19 与异质核核糖核蛋白 A1（hnRNPA1）相互作用，这通过 RNA 下拉和 RIP 分析得到验证，这增加了与脂肪酸氧化密切相关的基因 PGC1a 和 CPT1b 的翻译。
我们的数据表明，通过减少骨骼肌中异位脂质积累，H19 的过表达改善了胰岛素抵抗。潜在的机制可能是 lncRNAH19 通过靶向 hnRNPA1 促进脂肪酸氧化。视频摘要。
