Therapeutic effects of ezetimibe for non-alcoholic steatohepatitis in fatty liver shionogi-ob/ob mice

Aim: An effective therapy for non‐alcoholic steatohepatitis has yet to be defined. This study examined the therapeutic effects of ezetimibe, a lipid‐lowering medication, on steatosis and hepatic fibrosis in fatty liver Shionogi ob/ob (FLS‐ob) mice. Methods: Low‐dose (0.2 mg/kg body weight) and high‐dose (1.0 mg/kg body weight) of ezetimibe were administered to FLS‐ob mice orally for 12 weeks. Results: Administration of ezetimibe significantly and dose‐dependently decreased liver cholesterol content. The area of hepatic fibrosis and hepatic hydroxyproline content in the low‐ and high‐dose groups were significantly decreased compared with controls. Areas of α‐smooth muscle actin positivity and F4/80 positivity were significantly decreased in a dose‐dependent manner. Percentages of 8‐hydroxy‐2‐deoxyguanosine‐positive cells in low‐ and high‐dose groups were significantly decreased compared with those in controls, and 8‐hydroxy‐2‐deoxyguanosine DNA content and thiobarbituric acid reactive substances in the high‐dose group was also significantly decreased compared to controls. Gene expression levels of procollagen I and transforming growth factor β1 mRNA levels were lower in the low‐ and high‐dose groups than in controls. Tumor necrosis factor‐α and sterol regulatory element‐binding protein 1c mRNA levels were also lower in the low‐ and high‐dose groups than in controls. Conclusions: Ezetimibe attenuated steatosis and liver fibrosis by reducing oxidative stress and lipid peroxidation and suppressing activated hepatic stellate cells and Kupffer cells.