Pyrvinium pamoate attenuates non-alcoholic steatohepatitis: Insight on hedgehog/Gli and Wnt/β-catenin signaling crosstalk

Abstract

Non‐alcoholic steatohepatitis (NASH) is a devastating form of non‐alcoholic fatty liver disease (NAFLD). Pyrvinium pamoate (PP) has been recently introduced as anti-adipogenic compound. We aimed to investigate the effects of PP on high fat diet (HFD)-induced NASH in rats and examine the underlying mechanisms. NASH was induced by exposing rats to HFD for 16 weeks and a single dose of streptozotocin (STZ) 35 mg/kg at the fifth week. At the tenth week, PP was given orally at a dose of 60 µg/kg, day after day for 6 weeks. HFD/STZ induced significant steatohepatitis and insulin resistance as was evident by the elevated transaminases activity, NAFLD activity score and HOMA-IR level. Also, HFD induced serum hyperlipidemia and hepatic lipid accumulation. In addition, HFD induced an imbalance in the oxidative status of the liver via upregulating lipid peroxides and mitochondrial oxidative stress markers (MnSOD, UCP-2), together with marked decrease in anti-oxidant glutathione level, glutathione peroxidase activity and expression of mitophagy related markers (PINK1, Parkin, ULK1) and increase in SQSTM1/p62 and LC3II/LC3I. Upregulation of inflammatory mediators (TNF-α, IL-6, IL-1β) and apoptotic marker (caspase 3) were observed. Those events all together precipitated in initiation of liver fibrosis as confirmed by elevation of transforming growth factor-β1 (TGF-β1), alpha-smooth muscle actin (α-SMA) and liver collagen content. Co-treatment with PP protected against HFD-induced NASH and liver fibrosis via downregulating the expression of key factors in Hedgehog and Wnt/ β-catenin signaling pathway. These findings imply that PP can attenuate the progression of NASH and its associated sequela of liver fibrosis.