Abstract

VERAPAMIL MITIGATES LIPID ACCUMULATION, OXIDATIVE STRESS AND REGULATES AUTOPHAGY AND APOPTOSIS IN METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE IN RATS

Sally M. Ezzat*, Maha H. Sharawy and Ghada M. Suddek

ABSTRACT

Aim: Non-alcoholic fatty liver disease (NAFLD) is a category of liver diseases that range from simple steatosis to inflammation and fibrosis. Metabolic associated fatty liver disease (MAFLD) is a more appropriate term for steatosis associated with metabolic dysfunction. It takes into account the more general environmental, metabolic and genetic aspects that influence each patient. Autophagy is a conserved quality-control mechanism in lysosomes that destroys cytoplasmic contents. Lipophagy is the process through which autophagy destroys lipid droplets. This study investigates the effects of verapamil on MAFLD induced by high fat diet (HFD) in rats by autophagy induction. Materials and Methods: Sprague Dawley rats were fed 60 % HFD for 8 weeks, and verapamil (10 and 25 mg/kg/day) was given intraperitoneally. Results: Liver integrity markers and antioxidant biomarkers were improved by verapamil and lipid profile was rectified. AMPK as a positive regulator of autophagy was increased. Autophagic markers (Beclin 1, ULK1, LC3) were elevated compared to HFD group. Protein expression of p62 was decreased by verapamil when assessed immunohistochemically. In addition, it decreased apoptosis by decreasing capase-3 and increasing Bcl-2 protein expression. Histopathological examination revealed a decrease of the degree of steatosis. In conclusion: verapamil was found to induce autophagy in MAFLD in a dose dependent manner, inhibit apoptosis and improve liver functions and degree of steatosis. Verapamil, therefore, may show a potential adjunctive therapeutic option in clinical settings for treating MAFLD.

Keywords: Verapamil; MAFLD; HFD; autophagy; apoptosis.