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Ezetimibe ameliorates intestinal chylomicron overproduction and improves glucose tolerance in a diet-induced hamster model of insulin resistance

Published on May 1, 2012in American Journal of Physiology-gastrointestinal and Liver Physiology3.729
· DOI :10.1152/ajpgi.00250.2011
Mark Naples23
Estimated H-index: 23
(U of T: University of Toronto),
Chris Baker12
Estimated H-index: 12
(U of T: University of Toronto)
+ 3 AuthorsKhosrow Adeli55
Estimated H-index: 55
(U of T: University of Toronto)
Abstract
Ezetimibe is a cholesterol uptake inhibitor that targets the Niemann-Pick C1-like 1 cholesterol transporter. Ezetimibe treatment has been shown to cause significant decreases in plasma cholesterol levels in patients with hypercholesterolemia and familial hypercholesterolemia. A recent study in humans has shown that ezetimibe can decrease the release of atherogenic postprandial intestinal lipoproteins. In the present study, we evaluated the mechanisms by which ezetimibe treatment can lower postprandial apoB48-containing chylomicron particles, using a hyperlipidemic and insulin-resistant hamster model fed a diet rich in fructose and fat (the FF diet) and fructose, fat, and cholesterol (the FFC diet). Male Syrian Golden hamsters were fed either chow or the FF or FFC diet ± ezetimibe for 2 wk. After 2 wk, chylomicron production was assessed following intravenous triton infusion. Tissues were then collected and analyzed for protein and mRNA content. FFC-fed hamsters treated with ezetimibe showed improved glucose tolerance, decreased fasting insulin levels, and markedly reduced circulating levels of TG and cholesterol in both the LDL and VLDL fractions. Examination of triglyceride (TG)-rich lipoprotein (TRL) fractions showed that ezetimibe treatment reduced postprandial cholesterol content in TRL lipoproteins as well as reducing apoB48 content. Although ezetimibe did not decrease TRL-TG levels in FFC hamsters, ezetimibe treatment in FF hamsters resulted in decreases in TRL-TG. Jejunal apoB48 protein expression was lower in ezetimibe-treated hamsters. Reductions in jejunal protein levels of scavenger receptor type B-1 (SRB-1) and fatty acid transport protein 4 were also observed. In addition, ezetimibe-treated hamsters showed significantly lower jejunal mRNA expression of a number of genes involved in lipid synthesis and transport, including srebp-1c, sr-b1, ppar-γ, and abcg1. These data suggest that treatment with ezetimibe not only inhibits cholesterol uptake, but may also alter intestinal function to promote improved handling of dietary lipids and reduced chylomicron production. These, in turn, promote decreases in fasting and postprandial lipid levels and improvements in glucose homeostasis.
  • References (33)
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References33
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#1Lutgarda BozzettoH-Index: 11
#2Giovanni AnnuzziH-Index: 23
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#1Tomonori Muraoka (YCU: Yokohama City University)H-Index: 4
#2Kazutaka Aoki (YCU: Yokohama City University)H-Index: 15
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Ezetimibe inhibits intestinal cholesterol absorption, thereby reducing serum cholesterol. Recent studies suggest that ezetimibe affects liver steatosis and insulin resistance. We investigated the impact of ezetimibe on insulin sensitivity and glucose metabolism in C57BL/6 mice. We analyzed 4 mouse groups fed the following diets: normal chow (4% fat) for 12 weeks, normal chow for 10 weeks followed by normal chow plus ezetimibe for 2 weeks, high-fat chow (32% fat) for 12 weeks, and high-fat chow f...
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#1Hyohun Park (Kyoto Prefectural University of Medicine)H-Index: 10
#2Toshihide ShimaH-Index: 15
Last. Takeshi Okanoue (Kyoto Prefectural University of Medicine)H-Index: 23
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Background Hyperlipidemia, insulin resistance, and oxidative stress can heavily contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD). Currently, there is no established treatment for this disease. Recently, several studies have shown that ezetimibe (EZ), a lipid-lowering drug, attenuates liver steatosis in an experimental NAFLD model. This study was designed to assess the efficacy of long-term EZ monotherapy in patients with NAFLD.
132 CitationsSource
#1Jose C. Sandoval (Osaka University)H-Index: 11
#2Yumiko Nakagawa-Toyama (Osaka University)H-Index: 16
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#1Dick C. ChanH-Index: 39
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Aim: Ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, has been shown to reduce the intestinal absorption of cholesterol. We investigated whether it also has beneficial effects on metabolic disorder and/or renal insufficiency in patients with hypercholesterolemia.Methods: Ezetimibe was administered to 38 Japanese patients with hypercholesterolemia to obtain appropriate low-density lipoprotein cholesterol (LDL-chol) levels. Age- and sex-matched patients with hypercholesterolemia (n=38) w...
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Type 2 diabetes plays a major role in the development of cardiovascular diseases. The present study was undertaken to investigate the effect of ezetimibe, a potent cholesterol absorption inhibitor, on cardiovascular injury of obese and type 2 diabetic db/db mice. Diabetic db/db mice fed western diet were given ezetimibe for 9 weeks and the effects on cardiovascular injury and hepatic steatosis were examined. Ezetimibe treatment of db/db mice significantly improved vascular endothelial function, ...
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#1Daisaku MasudaH-Index: 17
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Background Postprandial hyperlipidaemia is known to be a high-risk factor for atherosclerotic disease because of rapid and lasting accumulations of triglyceride-rich lipoproteins and remnants. The Niemann-Pick C1-Like 1 (NPC1L1) protein acts as an intestinal cholesterol transporter and ezetimibe, which inhibits NPC1L1, has been used in patients with hypercholesterolaemia. We investigated effects of ezetimibe on fasting lipid and lipoprotein profiles and postprandial hyperlipidaemia in patients w...
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Although the atherogenic role of dietary cholesterol has been well established, its diabetogenic potential and associated metabolic disturbances have not been reported. Diet-induced hamster models of insulin resistance and dyslipidemia were employed to determine lipogenic and diabetogenic effects of dietary cholesterol. Metabolic studies were conducted in hamsters fed diets rich in fructose (40%), fat (30%), and cholesterol (0.05–0.25%) (FFC) and other test diets. Short-term feeding of the FFC d...
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Sixteen hyperlipidemic men were enrolled in a randomized, placebo-controlled, double-blind, cross-over study to evaluate the effect of ezetimibe 10 mg and simvastatin 40 mg, coadministered and alone, on the in vivo kinetics of apolipoprotein (apo) B-48 and B-100 in humans. Subjects underwent a primed-constant infusion of a stable isotope in the fed state. The coadministration of simvastatin and ezetimibe significantly reduced plasma concentrations of cholesterol (−43.0%), LDL-C (−53.6%), and tri...
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