Long non-coding RNA H19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1

Skeletal muscles play a pivotal role in glucose and lipid metabolism, and it has become a consensus that impaired lipid metabolism leads to ectopic lipid accumulation in skeletal muscles, which ultimately causes systematic insulin resistant. Previous reports have shown that down-regulation of long non-coding RNA(lncRNA) H19 in skeletal muscle impairs glucose metabolism. To better understand the impact of H19 on insulin resistance, here we focused on the relationships between H19 and fatty acid metabolism in skeletal muscle. In our research, decreased H19 expression was found in skeletal muscle of db/db mice compared with db/m mice. In vivo overexpression of H19 via injection of recombinant H19-adenovirus by tail-vein in db/db mice significantly improved glucose tolerance, lowered serum insulin, TG and skeletal muscle TG levels, which were consistent with improved skeletal muscle H&E and oil red staining contrast to vehicle-treated db/db mice, indicating that overexpression of H19 in db/db mice ameliorated ectopic lipid accumulation in skeletal muscle. As expected, similar effects were observed in vitro. Overexpression of H19 in muscle cells treated with palmitate acid reduced lipid contents,promoted mitochondrial synthesis and ATP productions,and increased the expression of fatty acid oxidation related genes and mitochondrial respiratory chain complexes.Finally, it was drawn from RNA pull-down and RIP that heterogeneous nuclear ribonucleoprotein A1(hnRNPA1)is the target gene of H19, whose function in mitochondria has not been reported yet. Furthermore, we identified PGC1a and CPT1b were among the target genes of hnRNPA1 by searching widely used bioinformatics databases and preliminary RIP validation. Based on these results, we put forth our hypothesis that lncRNA H19 could improve insulin resistance by promoting mitochondrial biosynthesis and fatty acid oxidation in skeletal muscle, through regulating hnRNPA1. Disclosure X. Lin: None. W. Gui: None. H. Li: None. Funding National Natural Science Foundation of China (81873653)