Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver disease.
OBJECTIVE
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 alpha-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-alpha1 (PPAR-alpha1) 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.
Nozaki
Yuichi
Y
Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Fujita
Koji
K
Yoneda
Masato
M
Wada
Koichiro
K
Shinohara
Yoshiyasu
Y
Takahashi
Hirokazu
H
Kirikoshi
Hiroyuki
H
Inamori
Masahiko
M
Kubota
Kensuke
K
Saito
Satoru
S
Mizoue
Tetsuya
T
Masaki
Naohiko
N
Nagashima
Yoji
Y
Terauchi
Yasuo
Y
Nakajima
Atsushi
A
D020909:Acarbose / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000069438:Ezetimibe; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D000924:Anticholesteremic Agents; D001384:Azetidines; D002352:Carrier Proteins; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D047493:PPAR alpha; D011973:Receptors, LDL; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol; D000069438:Ezetimibe; D020909:Acarbose