Long noncoding RNA (lncRNA) are regulatory RNAs >200 nt. We previously showed that lncRNA GAS5 decreases significantly in serum of type 2 diabetes mellitus (T2DM) patients. Hence, we sought to decipher the molecular mechanisms underlying the role of GAS5 in T2DM in adipose tissue. Using CHIP-RIP, we demonstrate that GAS5 binds to promoter of insulin receptor to regulate its expression, and its depletion inhibits glucose uptake and insulin signaling. Toward stabilizing GAS5 levels in T2DM, we incorporated a strategy to limit the degradation of GAS5 by blocking the interaction of GAS5 and UPF1 with a small molecule identified using OBTC screening strategy. NP-C86 binds to GAS5 with high affinity, and increases GAS5 levels and glucose uptake in diabetic patient adipocytes. As a broader impact, NP-C86 may be used as a molecular probe to investigate the intricacies of GAS5 in relevant biological systems as it offers specificity, efficient cellular uptake and is non-cytotoxic.
Keywords: S-bridged cyclic γ-AApeptide library; adipocytes; adipose tissue; insulin receptor; insulin signaling; lncRNA GAS5; type 2 diabetes mellitus.
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