Celastrol Reverses Palmitic Acid-Induced Insulin Resistance in HepG2 Cells via Restoring the miR-223 and GLUT4 pathway.

In this study, we investigated how celastrol regulates IR. The HepG2 cellular IR model was initially established with palmitic acid (PA). The expression and activity of glucose transporter 4 (GLUT4), insulin receptor substrate-1 (IRS1), and 9 microRNAs (miRNAs) (miR-7, -34a, -96, -113, -126, -145, -150, -223, and -370) were detected before and after celastrol treatment using the PA-induced HepG2 IR model. The results showed that 250 μM PA for ≥ 2 d was optimal for inducing IR in HepG2 cells; 600 nM celastrol significantly attenuated the PA-induced IR in HepG2 cells. The PA-induced GLUT4 and IRS1 down-regulation and Ser307 phosphorylation on IRS1 was reversed by subsequent treatment with 600 nM celastrol for 6 h. We next investigated which IR-related miRNAs were possible up-stream regulators of celastrol mediated reversal of PA-induced HepG2 IR. Two miRNAs, miR-150 and -223, were significantly down-regulated by PA while re-raised by subsequent celastrol treatment, and that miR-223 were up-streaming of miR-150.. Moreover, knocking down miR-223 abolished celastrol's anti-IR effects in the PA-induced model. Collectively, our results demonstrate that celastrol reverses PA-induced IR-related alterations in part via miR-223 in HepG2 cells. Further investigation is warranted for establishing the clinical potential of celastrol in treating IR-related disorders.
Source: Canadian Journal of Diabetes - Category: Endocrinology Source Type: research