スギモト　ケン   Ken Sugimoto   杉本　研    所属   川崎医科大学  医学部 臨床医学　総合老年医学    職種   教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Novel effect of ezetimibe to inhibit the development of non-alcoholic fatty liver disease in Fatty Liver Shionogi mouse.
掲載誌名	正式名：Hepatology research : the official journal of the Japan Society of Hepatology 略　 称：Hepatol Res ISSNコード：13866346/13866346
掲載区分	国外
巻・号・頁	44(1),pp.102-113
著者・共著者	Wang Xiang, Sugimoto Ken, Fujisawa Tomomi, Shindo Nobuyasu, Minato Satomi, Kamada Yoshihiro, Hamano Mina, Ohishi Mitsuru, Ikegami Hiroshi, Rakugi Hiromi
発行年月	2014/01
概要	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 Fatty Liver Shionogi (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 Skp2 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.
DOI	10.1111/hepr.12092
PMID	23510093