Purpose
Non-alcoholic fatty liver disease is the most prevalent metabolic disorder that can lead to the development of non-alcoholic steatohepatitis (NASH) and, eventually, result in hepatocellular carcinoma. This study evaluated the therapeutic potential of berberine-loaded bovine serum albumin nanoparticles (BBR-BSA NPs) toward the induced NASH physical, biochemical, and ultrastructural changes.
Methods
NASH was induced in male rats by an high-fat high-sucrose diet (HFHSD) and repeated carbon tetrachloride (CCl4) injections. The treated groups received HFHSD/CCl4 and were then administered BBR, BBR-BSA NPs, BSA NPs, and Atorvastatin for four weeks. Finally, physical, liver function, lipid profile, hepatic oxidative stress, and inflammatory biomarkers were determined. Furthermore, hepatic sigma 1 receptor (SIGMAR1) and autophagy signaling proteins were evaluated. The hepatic transmission electron microscopic and histopathological examinations were also assessed. Finally, the chemical- and protein–protein interaction networks were presented using the visualization tools STITCH 5.0 and STRING databases. In addition, molecular docking analyses were conducted to illustrate the binding of BBR and Atorvastatin toward SREBP-2 and mTOR targets.
Results
The long-term administration of HFHSD/CCl4 had the potential to develop a NASH model. This model is characterized by hepatic steatosis, necro-inflammation, and impaired endoplasmic reticulum-mitochondrial signaling. The results revealed an impaired SIGMAR1 and autophagy flux signaling pathways. In contrast, the administration of BBR-BSA NP improved the therapeutic properties of entrapped BBR on the alterations associated with NASH. The BBR-BSA NPs enhanced the autophagic flux and SIGMAR1 signaling modulators compared to BBR and Atorvastatin. The in-silico bioinformatics analysis demonstrated that BBR exhibited a more robust interaction with SREBP-2 and mTOR compared to Atorvastatin, which supports the in vivo results.
Conclusion
BBR-BSA NPs restored hepatic homeostasis and enhanced the free BBR’s hepatoprotection against the induced NASH via the upregulation of SIGMAR1 and autophagy flux signaling.
