Abstract 18507: Icosabutate, a Novel Structurally Enhanced Fatty-acid Increases Hepatic Uptake of Cholesterol and Triglycerides in Conjunction With Increased Hepatic LDL Receptor Expression
Background: At a tenth of the dose of unmodified omega-3 fatty acids, Icosabutate (a structurally modified omega-3 fatty acid) achieves potent lowering of both plasma triglycerides (TG) and non-HDL cholesterol (C) in APOE*3Leiden.CETP transgenic mice. The mechanism/s by which Icosabutate exerts its hypolipidemic effect was investigated.
Methods: Male APOE*3Leiden.CETP mice were fed a semi-synthetic Western-type diet (WTD, 15% cocoa butter, 40% sucrose and 0.25% cholesterol; all w/w) without or with Icosabutate (112 mg/kg bw/day). Hepatic production and clearance of lipids/lipoproteins, lipolytic activity, hepatic lipids and expression of LDL receptor protein (LDLr) were assessed.
Results: After 4 to 6 weeks of treatment Icosabutate lowered both plasma TG and C, confined to the non-HDL particles, by 68% (p<0.001 vs. control). No significant effects were seen in lipoprotein lipase and hepatic lipase activity. However, hepatic uptake of VLDL-like 14C-cholesteryl oleate particles (as marker for VLDL-CE) and 3H-triolein (as marker for VLDL-TG) were significantly increased vs. control by 72% and 87%, respectively (both p<0.001). Icosabutate tended to decrease hepatic TG (38%, p=0.083) and significantly decreased CE (25%, p<0.05). Hepatic expression of LDLr was increased 1.9 fold (p<0.05). In contrast to fenofibrate, there was no increase in hepatic VLDL-TG production rate with Icosabutate.
Conclusion: Icosabutate lowers plasma lipids primarily via a markedly increased hepatic uptake and is associated with a significant increase in hepatic LDLr expression. Despite the increased hepatic TG uptake, no compensatory increase in hepatic lipid storage or TG production was observed. Icosabutate thus offers a promising new approach to lowering plasma TG and non-HDL cholesterol.
Author Disclosures: D.A. Fraser: Employment; Significant; Pronova BioPharma Norge AS - part of BASF. T. Skjaeret: Employment; Significant; Pronova BioPharma Norge AS - part of BASF. Y. Qin: Employment; Significant; Pronova BioPharma Norge AS - part of BASF. L.N. Larsen: Employment; Significant; Pronova BioPharma Norge AS - part of BASF. C. Husberg: Employment; Significant; Pronova BioPharma Norge AS - part of BASF. R. Hovland: None. E.J. Pieterman: None. A.M. van den Hoek: None. H.M. Princen: None. S. Hustvedt: Employment; Significant; Pronova BioPharma Norge AS - part of BASF.
- © 2014 by American Heart Association, Inc.