Open Access

The A3 adenosine receptor agonist, namodenoson, ameliorates non‑alcoholic steatohepatitis in mice

  • Authors:
    • Pnina Fishman
    • Shira Cohen
    • Inbal Itzhak
    • Johnny Amer
    • Ahmad Salhab
    • Faina Barer
    • Rifaat Safadi
  • View Affiliations

  • Published online on: October 3, 2019     https://doi.org/10.3892/ijmm.2019.4364
  • Pages: 2256-2264
  • Copyright: © Fishman et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The Wnt/β‑catenin pathway confers a chain of molecular events in livers affected by non‑alcoholic steatohepatitis (NASH). Namodenoson, a selective agonist of the A3 adenosine receptor (A3AR), which is highly expressed in pathological liver cells, induces a robust anti‑inflammatory effect in the liver, mediated via the de‑regulation of the Wnt/β‑catenin pathway. Namodenoson also acts as a liver protective agent by inhibiting ischemia/reperfusion injury. Based on these unique characteristics, we investigated the anti‑NASH effect of Namodenoson in murine models of steatohepatitis and in the LX2 human hepatic stellate cell line (HSC). In the STAM model, Namodenoson significantly decreased the non‑alcoholic fatty liver disease (NAFLD) activity score, NAS, demonstrating anti‑inflammatory and anti‑steatotic effects. In the carbon tetrachloride (CCl4) model, Namodenoson reversed alanine aminotransferase (ALT) to normal values and significantly improved liver inflammation and fibrosis, as well as the adiponectin and leptin levels. Namodenoson de‑regulated the Wnt/β‑catenin pathway in the liver extracts of the CCl4 model mice and in the LX2 HSCs, manifested by a decrease in the expression of phosphoinositide 3‑kinase (PI3K), nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB), β‑catenin, lymphoid enhancer‑binding factor 1 (Lef‑1) and cyclin D1, and an increase in the expression level of glycogen synthase kinase 3β (GSK‑3β). The fibrosis marker, α‑smooth muscle actin (α‑SMA) was also de‑regulated, supporting the anti‑fibrotic effect of Namodenoson. On the whole, the findings of this study demonstrate that Namodenoson exerts an anti‑NASH effect mediated via the de‑regulation of the PI3K/NF‑κB/Wnt/β‑catenin signaling pathway. Thus, targeting A3AR may prove to be a novel direction in the pharmacotherapy of NAFLD/NASH.
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December 2019
Volume 44 Issue 6

Print ISSN: 1107-3756
Online ISSN:1791-244X

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APA
Fishman, P., Cohen, S., Itzhak, I., Amer, J., Salhab, A., Barer, F., & Safadi, R. (2019). The A3 adenosine receptor agonist, namodenoson, ameliorates non‑alcoholic steatohepatitis in mice. International Journal of Molecular Medicine, 44, 2256-2264. https://doi.org/10.3892/ijmm.2019.4364
MLA
Fishman, P., Cohen, S., Itzhak, I., Amer, J., Salhab, A., Barer, F., Safadi, R."The A3 adenosine receptor agonist, namodenoson, ameliorates non‑alcoholic steatohepatitis in mice". International Journal of Molecular Medicine 44.6 (2019): 2256-2264.
Chicago
Fishman, P., Cohen, S., Itzhak, I., Amer, J., Salhab, A., Barer, F., Safadi, R."The A3 adenosine receptor agonist, namodenoson, ameliorates non‑alcoholic steatohepatitis in mice". International Journal of Molecular Medicine 44, no. 6 (2019): 2256-2264. https://doi.org/10.3892/ijmm.2019.4364