MiR-301a mediates the effect of IL-6 on the AKT/GSK pathway and hepatic glycogenesis by regulating PTEN expression.

BACKGROUND/AIMS: IL-6 has been implicated in the pathogenesis of insulin resistance. MiR-301a plays an important role in various biological and pathological processes, including cellular development and differentiation, inflammation, apoptosis and cancer. However, whether miR-301a mediates IL-6-induced insulin resistance in hepatocytes remains unknown.

METHODS

The activation of AKT/GSK pathway and the level of glycogenesis were examed in NCTC 1469 cells transfected miR-301a mimics and inhibitor. Using computational miRNA target prediction database, PTEN was a target of miR-301a. The effect of miR-301a on PTEN expression was evaluated using Luciferase assay and western blot. A PTEN-specific siRNA was used to further determine the effect of PTEN on IL-6-induced insulin resistance.

RESULTS

In vivo and in vitro treatment with IL-6 was led to down-regulation of miR-301a, accompanied by impairment of theAKT/GSK pathway and glycogenesis. Importantly, over-expression of miR-301a rescued IL-6-induced decreased activation of the AKT/GSK pathway and hepatic glycogenesis. In contrast, down-regulation of miR-301a induced impaired phosphorylation of AKT and GSK, accompanied by reduced glycogenesis in hepatocytes. Moreover, our results indicate that suppression of PTEN, a target of miR-301a, diminished the effect of IL-6 on the AKT/GSK pathway and hepatic glycogenesis.

CONCLUSION

We present novel evidence of the contribution of miR-301a to IL-6-induced insulin resistance by direct regulation of PTEN expression.