| | Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease☆Received 31 March 2009; received in revised form 30 April 2009; accepted 8 May 2009. published online 08 June 2009. Background/AimsNon-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome that is closely associated with multiple factors such as obesity, hyperlipidemia, type 2 diabetes mellitus and hypertension, making it difficult to treat NAFLD effectively using any monotherapy available to date. In this study, we propose a novel combination therapy for NAFLD comprising ezetimibe (EZ), a cholesterol absorption inhibitor, and acarbose (AC), an α-glucosidase inhibitor. MethodsC57BL/6J mice were divided into five treatment groups as follows: basal diet (BD), high-fat diet (HFD) only, HFD with EZ (5 mg/kg/day), HFD with AC (100mg/kg/day), and HFD with both EZ and AC for 24 weeks. ResultsLong-term combination therapy with EZ and AC significantly reduced steatosis, inflammation and fibrosis in the liver, compared with long-term monotherapy with either drug, in an HFD-induced NAFLD mouse model; the combination therapy also significantly increased the expression of microsomal triglyceride transfer protein (MTP) and peroxisome proliferators-activated receptor-α1 (PPAR-α1) in the liver, compared with either monotherapy, which may have led to the improvement in lipid metabolic disorder seen in this model. ConclusionsCombination therapy with EZ and AC for 24 weeks improved the histopathological findings in a mouse model of NAFLD. Associate Editor: C.P. Day Abbreviations: NAFLD, non-alcoholic fatty liver disease, EZ, ezetimibe, AC, acarbose, BD, basal diet, HFD, high-fat diet, NASH, non-alcoholic steatohepatitis, ALT, alanine aminotransferase, HPLC, high-performance liquid chromatography, Chol, cholesterol, TG, triglyceride, CM, chylomicron, VLDL, very low-density lipoprotein, LDL, low-density lipoprotein, HDL, high-density lipoprotein, HOMA-IR, homeostasis model assessment for insulin resistance, SREBP-1c, sterol regulatory element-binding protein-1c, SREBP-2, sterol regulatory element-binding protein-2, PPAR-α1, peroxisome proliferators-activated receptor-α1, MTP, microsomal triglyceride transfer protein, LDLR, low-density lipoprotein receptor, HMG CoA, 3-hydroxy-3-methylguataryl CoA 1 Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan 2 Department of Pharmacology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan 3 Department of Epidemiology and International Health, Research Institute, International Medical Center of Japan, Tokyo, Japan 4 Department of Gastroenterology, International Medical Center of Japan, Tokyo, Japan 5 Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan 6 Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan  Corresponding author. Tel.: +81 45 7872640; fax: +81 45 7878988.
☆ The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industry or conflict of interest with respect to this manuscript. PII: S0168-8278(09)00384-5 doi:10.1016/j.jhep.2009.05.017 © 2009 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved. | |
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