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 Physiology3.73
· 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)
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)
  • Citations (33)
#1Tomonori Muraoka (YCU: Yokohama City University)H-Index: 4
#2Kazutaka Aoki (YCU: Yokohama City University)H-Index: 15
Last.Yasuo Terauchi (YCU: Yokohama City University)H-Index: 58
view all 11 authors...
#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
view all 14 authors...
#1Shusuke Yagi (University of Tokushima)H-Index: 23
#2Masashi Akaike (University of Tokushima)H-Index: 32
Last.Masataka Sata (University of Tokushima)H-Index: 59
view all 20 authors...
Cited By33
#1Amy P. Ross (GSU: Georgia State University)H-Index: 6
#2Alisa Norvelle (GSU: Georgia State University)H-Index: 7
Last.Kim L. Huhman (GSU: Georgia State University)H-Index: 32
view all 6 authors...
#1Davood Mehrabani (Shiraz University of Medical Sciences)H-Index: 23
#2N. Booyash (Shiraz University of Medical Sciences)H-Index: 1
Last.Mehdi Dianatpour (Shiraz University of Medical Sciences)H-Index: 7
view all 6 authors...
#1Changting Xiao (U of T: University of Toronto)H-Index: 25
#2Satya Dash (U of T: University of Toronto)H-Index: 10
Last.Gary F. Lewis (U of T: University of Toronto)H-Index: 46
view all 4 authors...
#1Yunan Wang (PKU: Peking University)H-Index: 10
#2Abudurexiti Kayoumu (PKU: Peking University)H-Index: 4
Last.George Liu (PKU: Peking University)H-Index: 25
view all 11 authors...
View next paperEffect of Ezetimibe on Hepatic Fat, Inflammatory Markers, and Apolipoprotein B-100 Kinetics in Insulin-Resistant Obese Subjects on a Weight Loss Diet