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

The Wnt/beta-catenin pathway confers a chain of molecular events in livers affected by non-alcoholic steato-hepatitis (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/beta-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 steato-hepatitis 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 signifi-cantly improved liver inflammation and fibrosis, as well as the adiponectin and leptin levels. Namodenoson de-regulated the Wnt/beta-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 kappa-light-chain-enhancer of activated B cells (NF-kappa B), beta-catenin, lymphoid enhancer-binding factor 1 (Lef-1) and cyclin D1, and an increase in the expression level of glycogen synthase kinase 3 beta (GSK-3 beta). The fibrosis marker, alpha-smooth muscle actin (alpha-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-kappa B/Wnt/beta-catenin signaling pathway. Thus, targeting A3AR may prove to be a novel direction in the pharmacotherapy of NAFLD/NASH.