APOE*3Leiden.CETP transgenic mice as model for pharmaceutical treatment of the metabolic syndrome

Aims: This study aimed to investigate systematically (i) the appropriate dietary conditions to induce the features of the MetS in APOE*3Leiden.humanCholesteryl Ester Transfer Protein (E3L.CETP) mice and (ii) whether the response of this model to different antidiabetic and hypolipidemic drugs is similar as in humans. Methods: Male obese, IR and...

Combined analysis of pharmacokinetic and efficacy data of preclinical studies with statins markedly improves translation of drug efficacy to human trialss

Correct prediction of human pharmacokinetics (PK) and the safety and efficacy of novel compounds based on preclinical data, is essential but often fails. In the current study, we aimed to improve the predictive value of ApoE*3Leiden (E3L) trans-genic mice regarding the cholesterol-lowering efficacy of various statins in humans by combining...

Apolipoprotein CI aggravates atherosclerosis development in ApoE-knockout mice despite mediating cholesterol efflux from macrophages

Objective: Apolipoprotein CI (apoCI) is expressed in the liver and in macrophages, and has several roles in lipid metabolism. Since macrophage apoCI expression might affect macrophage lipid homeostasis and atherosclerotic lesion development locally in the arterial wall, we investigated the effect of both systemic and macrophage apoCI on...

Apolipoprotein C-I binds free fatty acids and reduces their intracellular esterification

Mice that overexpress human apolipoprotein C-I (apoC-I) homozygously (APOC1+/+ mice) are protected against obesity and show cutaneous abnormalities. Although these effects can result from our previous observation that apoC-I inhibits FFA generation by LPL, we have also found that apoC-I impairs the uptake of a FFA analog in adipose tissue. In...

Cholesteryl ester transfer protein decreases high-density lipoprotein and severely aggravates atherosclerosis in APOE*3-Leiden mice

OBJECTIVE - The role of cholesteryl ester transfer protein (CETP) in the development of atherosclerosis is still undergoing debate. Therefore, we evaluated the effect of human CETP expression on atherosclerosis in APOE*3-Leiden (E3L) mice with a humanized lipoprotein profile. METHODS AND RESULTS - E3L mice were crossbred with human CETP...

No effect of C-reactive protein on early atherosclerosis development in apolipoprotein E*3-Leiden/human C-reactive protein transgenic mice

Objective - C-reactive protein (CRP) has been associated with risk of cardiovascular disease. It is not clear whether CRP is causally involved in the development of atherosclerosis. Mouse CRP is not expressed at high levels under normal conditions and increases in concentration only several-fold during an acute phase response. Because the...

Effect of low dose atorvastatin versus diet-induced cholesterol lowering on atherosclerotic lesion progression and inflammation in apolipoprotein E*3-Leiden transgenic mice

Objective - To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)-Leiden mice beyond its cholesterol-lowering effect. Methods and Results - ApoE*3-Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet...

Acyl-CoA:Cholesterol acyltransferase inhibitor avasimibe reduces atherosclerosis in addition to its cholesterol-lowering effect in ApoE*3-leiden mice

Background - The present study investigated whether the ACAT inhibitor avasimibe can reduce atherogenesis independently of its cholesterol-lowering effect in ApoE*3-Leiden mice. Methods and Results - Two groups of 15 female ApoE*3-Leiden mice were put on a high-cholesterol (HC) diet; 1 group received 0.01% (wt/wt) avasimibe mixed into the diet....