Background and Aims:
Icosabutate is a structurally engineered fatty acid derived from eicosapentaenoic acid (EPA) which decreases plasma triglycerides (TG) and non-HDL lipoprotein cholesterol (VLDL-C and LDL-C) in hyperlipidemic patients. We examined the mechanism by which icosabutate decreases plasma lipids and affects atherosclerotic lesion formation.
Methods:
APOE*3Leiden.CETP mice received a semi-synthetic Western-type diet (WTD) supplemented with icosabutate, high-dose omega-3 ethyl esters (Omacor®) or vehicle for up to 6 weeks. Plasma total cholesterol (TC), TG and lipoprotein profiles were determined in time. VLDL production, clearance, and tissue uptake were measured. To examine atherosclerosis, mice received a WTD for 17 weeks with icosabutate or vehicle. A low cholesterol WTD group was included as control. Plaque formation and severity were scored by image analysis and histopathological scoring.
Results
Icosabutate treatment for 4 weeks reduced TC (-69% vs controls, p<0.001; -43% vs omega-3, p<0.01) and TG (-75% vs controls, p<0.001; -57% vs omega-3, p<0.001). Lipoprotein profile analysis showed that icosabutate reduced non-HDL-cholesterol and TG compared to controls, but not the HDL fraction. Icosabutate had no effect on VLDL-TG or ApoB production, but significantly increased hepatic VLDL-TG uptake compared to control (87%, p<0.01) and omega-3 (53%, p<0.05); hepatic VLDL-C uptake was significantly increased compared to controls (73%, p<0.01). Treatment with icosabutate reduced atherosclerotic lesion development compared to the control WTD group. Icosabutate, but not low cholesterol WTD, reduced lesion severity compared to controls.
Conclusions:
Treatment with icosabutate has improved lipid-lowering capacity compared to omega-3. Icosabutate promotes hepatic clearance of VLDL and reduces atherosclerotic lesion development in a translational mouse model.

07 - THE STRUCTURALLY ENGINEERED FATTY ACID ICOSABUTATE IMPROVES LIPID METABOLISM AND REDUCES SEVERITY OF ATHEROGENESIS IN MICE