Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice.
Ezetimibe is a novel cholesterol and plant sterol absorption inhibitor that reduces plasma low-density lipoprotein-cholesterol by selectively binding to the intestinal cholesterol transporter, Niemann-Pick C1-Like 1. Mice deficient in Niemann-Pick C1-Like 1 are protected from high fat/cholesterol diet-induced fatty liver as well as hypercholesterolemia. The object of the present study was to determine whether ezetimibe treatment could reduce hepatic steatosis in diet-induced obese mice. C57BL/6J mice were fed a high fat/cholesterol containing semi-purified diet (45% Kcal fat and 0.12% cholesterol) for 7 months after weaning. These mice were not only obese, but also developed hepatomegaly and hepatic steatosis, with varying degrees of liver fibrosis and steatohepatitis. About 87% of the mice on the high fat/cholesterol diet for 7 months had elevated plasma alanine aminotransferase activity, a biomarker for non-alcoholic fatty liver disease. Chronic administration of ezetimibe for 4 weeks significantly reduced hepatomegaly by decreasing hepatic triglyceride, cholesteryl ester and free cholesterol in diet-induced obese mice fed high fat/cholesterol diet for 7 months. Chronic ezetimibe treatment also significantly decreased plasma alanine aminotransferase activity. These results suggest that ezetimibe may be a novel treatment for high fat/cholesterol-induced non-alcoholic fatty liver disease.
Zheng
Shuqin
S
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Hoos
Lizbeth
L
Cook
John
J
Tetzloff
Glen
G
Davis
Harry
H
van Heek
Margaret
M
Hwa
Joyce J
JJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001384:Azetidines / Q000494:pharmacology* / Q000627:therapeutic use; D002788:Cholesterol Esters / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000069438:Ezetimibe; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006529:Hepatomegaly; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D000924:Anticholesteremic Agents; D001384:Azetidines; D002788:Cholesterol Esters; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D014280:Triglycerides; D000410:Alanine Transaminase; D000069438:Ezetimibe