LncRNAH19 improves insulin resistance in skeletal muscle by regulating heterogeneous nuclear ribonucleoprotein A1

Abstract

Background 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. Methods 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). Results 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. Conclusion 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.

Trends in insulin resistance: insights into mechanisms and therapeutic strategy

“…These processes are closely related to the genes PGC1a and CPT1b that reverse FFA-induced lipid accumulation and improve IR. 263 This suggests the complex effect of lncRNAs on the IR progression.…”

LncRNA-Mediated Adipogenesis in Different Adipocytes

“…Additionally, it negatively regulates PPARγ at the translation and protein levels and inhibits the formation of lipid droplets in liver cells. In addition to regulating the growth and development of adipocytes, H19 improves insulin resistance by promoting fatty acid oxidation and reducing the accumulation of ectopic lipids in skeletal muscle by targeting hnRNPA1 [141].…”

Role of Long Non-Coding RNAs and the Molecular Mechanisms Involved in Insulin Resistance

“…Additionally, the overexpression of H19 in muscle increased acetyl-CoA carboxylase 1 (ACC1) and cAMP-activated protein kinase (AMPK) phosphorylation and increased the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), SIRT1, carnitine palmitoyltransferase 1b, and CD36, which suggests that H19 overexpression ameliorates glucose intolerance, dyslipidemia, and IR ( Figure 2 ). Furthermore, using RNA pull-down and immunoprecipitation assays, the authors identified the interaction of H19 with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which has been reported to play an important role in glucose and lipid metabolism [ 55 ].…”