Abstract 13867: Molecular Mechanisms of Ezetimibe-Induced Attenuation of Postprandial Hypertriglyceridemia
Background: Postprandial hypertriglyceridemia (PHTG) is caused by the accumulation of chylomicron and chylomicron remnants and has been shown to be associated with metabolic syndrome and the development of atherosclerotic cardiovascular diseases. In our previous studies, we showed that the intestinal cholesterol transporter inhibitor, ezetimibe, attenuates PHTG and postprandial elevation of FFAs in patients with type IIb hyperlipidemia (Eur J Clin Invest 2009), however the mechanisms for this have not been elucidated yet.
Methods and Results: We investigated the effect of ezetimibe on PHTG in wild-type (WT) mice fed a western diet and CD36KO mice fed a normal chow diet, which is an animal model of PHTG which was due to the intestinal over-production of chylomicrons. Ezetimibe significantly reduced TG levels at 3 hours after oral fat load using olive oil in both WT and CD36KO mice (from 375±41 to 252±19 mg/dl. 457±114 to 383±93 mg/dl, respectively). The analysis of lipoprotein profiles by HPLC analysis showed that ezetimibe decreased TG concentrations in chylomicrons and VLDL-sized lipoproteins (mainly small sized chylomicrons) and apoB-48 mass in postprandial plasma in both mice. Intestinal lymph was collected after oral fat loading in ezetimibe-treated and non-treated mice. HPLC analysis of the postprandial intestinal lymph showed that TG content in chylomicrons and apolipoprotein (apo) B-48 mass were decreased in ezetimibe-treated mice. Quantitative RT-PCR analysis of enzymes and transporters in the small intestines showed an inhibition of expression of genes involved in fatty acid transport (fatty acid transport protein 4, FATP4) and apoB-48, but not microsomal triglyceride transfer protein (MTP) gene. Moreover, ezetimibe decreased the intestinal absorption of oleic acid-radiolabeled 3H-triolein in both groups. Taken together, ezetimibe reduces PHTG by blocking the absorption of cholesterol and FATP4-mediated intracellular trafficking and metabolism of long-chain fatty acids in enterocytes, thereby reducing the formation of apoB-48 which is necessary for chylomicron production in the small intestines.
- © 2010 by American Heart Association, Inc.