Targeting fibrosis and steatosis: Nebivolol multi-pathway modulator ameliorates experimental non-alcoholic steatohepatitis in rats through AMPK/mTOR and TGF-β1/α-SMA pathways.

Non-alcoholic steatohepatitis (NASH) is a progressive hepatic disease that can advance into hepatocellular fibrosis, cirrhosis, and carcinoma. This study evaluates the therapeutic potential of Nebivolol on a diet-induced NASH rat model. Out of 32 male Wistar albino rats, 24 rats were fed a NASH-inducing diet for 8 weeks. The remaining were kept on a normal diet as healthy controls. After the induction phase, the NASH group was divided into three equal subgroups: an untreated NASH group and two treatment groups receiving 5 or 10 mg/kg/day of Nebivolol orally for six weeks. The NASH model demonstrated significantly higher levels of lipid profile, glucose, hepatic enzymes, Interleukin-1 beta (IL-1β), and malondialdehyde. NASH group also showed downregulation of endothelial nitric oxide synthase (e-NOS), AMP-activated protein kinase (AMPK), Beclin-1, and Peroxisome proliferator-activated receptor alpha (PPAR-α) with upregulation of mammalian target of rapamycin (mTOR) and sterol regulatory element-binding proteins (SREBP). The liver histopathology showed hepatocellular steatosis, fibroblastic proliferation, and inflammation. Immunohistochemical analysis revealed elevated transforming growth factor beta (TGF-β1) and α-smooth muscle actin (α-SMA) compared to normal control. Nebivolol administration dose-dependently reduced oxidative stress, inflammation, lipid profile, glucose, and hepatic enzymes. Besides, nebivolol downregulated mTOR, SREBP, TGF-β1, and α-SMA while inducing e-NOS, AMPK, PPAR-α, and Beclin-1 signaling. The histopathology of Nebivolol-treated rats revealed a noticeable improvement in hepatic architecture, characterized by reduced steatosis, inflammation, and fibrosis. Nebivolol exerts a multi-targeted hepatoprotective effect against NASH, mainly mediated through the modulation of AMPK/mTOR and TGF-β1/α-SMA pathways, besides restoration of NO and eNOS signaling. These findings highlight Nebivolol as a promising candidate for the management of NASH and related liver disorders.