Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease☆

Background/Aims

Non-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.

Methods

C57BL/6J mice were divided into five treatment groups as follows: basal diet (BD), high-fat diet (HFD) only, HFD with EZ (5mg/kg/day), HFD with AC (100mg/kg/day), and HFD with both EZ and AC for 24 weeks.

Results

Long-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.

Conclusions

Combination therapy with EZ and AC for 24 weeks improved the histopathological findings in a mouse model of NAFLD.

Keywords: Ezetimibe, Acarbose, Combination therapy, Non-alcoholic fatty liver disease (NAFLD)

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