4‐Aminoethylamino‐emodin – a novel potent inhibitor of GSK‐3β– acts as an insulin‐sensitizer avoiding downstream effects of activated β‐catenin

Abstract

Glycogen synthase kinase-3β (GSK-3β) is a key target and effector of downstream insulin signalling. Using comparative protein kinase assays and molecular docking studies we characterize the emodin-derivative 4-[N-2-(aminoethyl)-amino]-emodin (L4) as a sensitive and potent inhibitor of GSK-3β with peculiar features. Compound L4 shows a low cytotoxic potential compared to other GSK-3β inhibitors determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and cellular ATP levels. Physiologically, L4 acts as an insulin-sensitizing agent that is able to enhance hepatocellular glycogen and fatty acid biosynthesis. These functions are particularly stimulated in the presence of elevated concentrations of glucose and in synergy with the hormone action at moderate but not high insulin levels. In contrast to other low molecular weight GSK-3β inhibitors (SB216763 and LiCl) or Wnt-3α-conditioned medium, however, L4 does not induce reporter and target genes of activated β-catenin such as TOPflash, Axin2 and glutamine synthetase. Moreover, when present together with SB216763 or LiCl, L4 counteracts expression of TOPflash or induction of glutamine synthetase by these inhibitors. Because L4 slightly activates β-catenin on its own, these results suggest that a downstream molecular step essential for activation of gene transcription by β-catenin is also inhibited by L4. It is concluded that L4 represents a potent insulin-sensitizing agent favouring physiological effects of insulin mediated by GSK-3β inhibition but avoiding hazardous effects such as activation of β-catenin-dependent gene expression which may lead to aberrant induction of cell proliferation and cancer.

Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis

“…Primary hepatocytes were isolated from male transgenic and C57BL/6N mice using collagenase perfusion of the liver, as previously described ( Gebhardt et al, 2010 ; Matz-Soja et al, 2014 ). The cell suspension was cleared of the non-parenchymal cells by differential centrifugation.…”

Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging

“…Gebhardt et al 83 showed application of emodin ( 82 ) and its ethylenediamine analog 83 as non-ATP competitive inhibitors of GSK-3 (Table 11 ). Addition of the ethylenediamine group on the emodin nucleus increased potency of inhibition (IC 50 0.56±0.02 µM, 83 ), reduced cytotoxicity and generated an insulin sensitizing effect mediated by increasing hepatocellular glycogen and fatty acid biosynthesis.…”

Antidiabetic potential of anthraquinones: A review

“…In another study, emodin inhibited 11β‐HSD1, with an IC 50 values of 186 and 86 nM for human and mouse 11β‐HSD1, respectively (Feng et al, ). Similarly, 4‐aminoethylamino‐emodin, another emodin derivative, inhibited glycogen synthase kinase‐3β (IC 50 : 16.5 μM) activity (Gebhardt, Lerche, Götschel, Günther, & Kolander, ). The above studies highlighted the potential of emodin, 2‐hydroxyemodin‐1 methylether, alaternin, 4‐aminoethylamino‐emodin, and questin in improving insulin sensitivity in diabetes.…”