Model of intestinal chylomicron over-production and Ezetimibe treatment: Impact on the retention of cholesterol in arterial vessels

The metabolic syndrome (MetS) and conditions of insulin resistance are often characterized by an increase in cardiovascular disease (CVD) risk without a concomitant increase in low-density lipoprotein cholesterol (LDL-C), suggesting that other atherogenic pathways maybe involved. Intestinally derived chylomicron remnants (CM-r) are also thought to contribute to atherogenic dyslipidemia during insulin resistance. Recent animal and human studies suggest that insulin resistance leads to an over-production of intestinal chylomicrons (CM), which can contribute to fasting and post-prandial dyslipidemia during these conditions. We and others have contributed new insights into the mucosal absorption, efflux and secretion of cholesterol and triglyceride (TG) in intestinal CM during conditions of insulin resistance. One of the pertinent discoveries has been that the intestine has the capacity to increase the secretion of CM during conditions of hyper-insulinemia (observed in the JCR: LA-cp rat model). Advances to identify cholesterol-transporter targets have highlighted the contribution of the intestine to whole body cholesterol metabolism. Ezetimibe (EZ) is a novel pharmaceutical compound that reduces intestinal cholesterol absorption. We know that Ezetimibe either alone, or in combination with a HMG-CoA reductase inhibitor (such as Simvastatin [SV]) can decrease both plasma LDL-C and CM-r concentrations. However, the combined effects of these compounds (EZ + SV) on post-prandial dyslipidemia and/or impact on arterial deposition of cholesterol during MetS have not been studied. The focus of this review is to highlight studies using an animal model of MetS and CM over-production (the JCR: LA-cp rat), and to summarize the effects of Ezetimibe on intestinal cholesterol flux, CM metabolism and uptake of cholesterol into arterial vessels. (C) 2010 Elsevier Ireland Ltd. All rights reserved.