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Novel effect of ezetimibe to inhibit the development of non‐alcoholic fatty liver disease in F atty L iver S hionogi mouse
Author(s) -
Wang Xiang,
Sugimoto Ken,
Fujisawa Tomomi,
Shindo Nobuyasu,
Minato Satomi,
Kamada Yoshihiro,
Hamano Mina,
Ohishi Mitsuru,
Ikegami Hiroshi,
Rakugi Hiromi
Publication year - 2014
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/hepr.12092
Subject(s) - ezetimibe , steatohepatitis , fatty liver , steatosis , microsomal triglyceride transfer protein , hyperlipidemia , chemistry , triglyceride , medicine , endocrinology , nonalcoholic fatty liver disease , lipoprotein , pharmacology , cholesterol , very low density lipoprotein , disease , diabetes mellitus
Aim Several studies using experimental non‐alcoholic fatty liver disease ( NAFLD ) models have shown that ezetimibe, an inhibitor of cholesterol absorption mainly in the intestine, not only protects against diet‐induced hyperlipidemia, but also attenuates liver steatosis. The aim of this study was to clarify whether ezetimibe inhibits the development of NAFLD and to elaborate the mechanism of ezetimibe to inhibit the development of NAFLD using F atty L iver S hionogi ( FLS ) mice, a spontaneous model of NAFLD /non‐alcoholic steatohepatitis.Methods Male FLS mice at 20 weeks of age were divided into two groups ( n = 7 in each group). Mice fed a normal laboratory chow, CRF ‐1 or CRF ‐1 containing 0.005% w/w ezetimibe (7 mg/kg per day) for 4 weeks. After 4‐week treatment with ezetimibe, the livers of each group of mice were subjected to histological as well as molecular evaluation. Results Ezetimibe administration for 4 weeks was associated with improvement of steatosis and fibrosis of the liver in normal diet‐fed FLS mice. Ezetimibe reduced hepatic reactive oxygen species generation and prevented ubiquitination and protein degradation of microsomal triglyceride transfer protein ( MTP ), a key molecule for very low‐density lipoprotein assembly and export, via downregulation of the protein expression of S kp2 and CDC20 . Conclusion Ezetimibe not only reduced lipid synthesis in the liver, but also promoted lipid discharge from the liver by preventing post‐translational degradation of MTP via a reduction of hepatic reactive oxygen species generation, leading to inhibition of the development of NAFLD .