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

Abstract : OBJECTIVES: The natural triterpenoid compound celastrol ameliorates insulin resistance (IR) in animal models, but the underlying molecular mechanism is unclear. In this study, we investigated how celastrol regulates IR. METHODS: 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. RESULTS: The results showed that 250 µM PA for ≥2 days 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 downregulation 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 upstream regulators of celastrol-mediated reversal of PA-induced HepG2 IR. Two miRNAs, miR-150 and -223, were significantly downregulated by PA and were re-raised by subsequent celastrol treatment; and miR-223 was upstream of miR-150. Moreover, knocking down miR-223 abolished celastrol's anti-IR effects in the PA-induced model. CONCLUSIONS: Collectively, our results demonstrated 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.
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Submitted on : Tuesday, December 10, 2019 - 11:58:48 AM
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Xue Zhang, Xiao-Cheng Xue, Ying Wang, Fan-Fan Cao, Jun You, et al.. Celastrol Reverses Palmitic Acid-Induced Insulin Resistance in HepG2 Cells via Restoring the miR-223 and GLUT4 Pathway. Canadian Journal of Diabetes, Canadian Diabetes Association, 2019, 43 (3), pp.165-172. ⟨10.1016/j.jcjd.2018.07.002⟩. ⟨inserm-02402019⟩



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