[30] In the present study, ezetimibe not only decreased CCL4-induced

ROS production, but also increased protein expression of MTP check details and decreased ubiquitination of MTP and protein expression of Skp2. These in vitro findings suggest that the inhibition of ubiquitination and degradation of MTP protein via reduced hepatic protein levels of Skp2 and CDC20 observed in vivo was induced by a reduction of hepatic ROS by administration of ezetimibe. The limitation of our study is that the administration of ezetimibe was assessed only for 4 weeks, not for a longer or shorter period. Based on previous studies,[13, 14, 20] however, 4 weeks may be an optimal time to investigate the effect of ezetimibe to inhibit the development of NAFLD in FLS mice; thus, 4-week administration of ezetimibe was chosen in the current study. Further study will be considered to confirm the best period of ezetimibe administration. In conclusion, ezetimibe administration in a spontaneous model of NAFLD resulted in amelioration of histological lesions, hepatic ROS level and hepatic expression of lipogenesis-related genes. In addition, the FLS mice receiving ezetimibe showed reduced ubiquitinated MTP protein level together with lower protein levels of Skp2 and CDC20 in the liver. Ezetimibe treatment decreased intracellular ROS and ubiquitinated MTP protein

levels together with a lower protein level of Skp2, suggesting that ezetimibe suppressed post-translational degradation of MTP via a reduction of hepatic ROS generation in CCL4-induced MCA-RH7777 cells. These findings point to a beneficial effect of ezetimibe against NAFLD, possibly through DNA/RNA Synthesis inhibitor targeting hepatic ROS generation,

suggesting its potential Sclareol benefits in patients with NAFLD/NASH having low expression of MTP. WE GRATEFULLY THANK Ms T. Sato for her skillful technical assistance, and Dr T. Hirasawa (Shionogi & Company) for donating FLS mice. Figure S1 Food consumption and bodyweight variation. (a) Bodyweight variation of Fatty Liver Shionogi (FLS) mice fed normal diet. White squares, control group (CT). Black rhombuses, EZ. (b) Food consumption of FLS mice fed normal diet. White squares, CT. Black rhombuses, EZ. Data are expressed as mean ± standard deviation (n = 7). Figure S2 Effect of ezetimibe on glucose metabolism. A Glucose levels during ipGTT in Fatty Liver Shionogi (FLS) mice fed normal diet. White squares, control group. Black rhombuses, EZ. Table S1 The fatty acid content in liver of Fatty Liver Shionogi (FLS) mice fed a normal diet with or without ezetimibe. Data are expressed as mean ± SD; n = 4. CT = FLS mice fed a normal diet, EZ = FLS mice fed a normal diet containing ezetimibe. *P < 0.05 between CT and EZ. "
“Background and Study Aim:  Residual or locally recurrent lesions may occur after endoscopic therapy for epithelial colorectal tumors. Additional endoscopic mucosal resection is difficult for large lesions.