Objective - In hyperlipidemia, dietary fish oil containing n-3 polyunsaturated fatty acids (PUFA) provokes plasma triacylglycerol lowering and hypocoagulant activity. Using APOE2 knock-in mice, the relation of these fish-oil effects with altered gene expression was investigated. Methods and Results - Male APOE2 knock-in mice, fed regular low-fat diet, had elevated plasma levels of triacylglycerol and coagulation factors. Plasma lipids and (anti)coagulant factors reduced on feeding the mice with fish oil (n-3 PUFA) or, to a lesser degree, with sunflowerseed oil (n-6 PUFA). The fish-oil diet provoked a 40% reduction in thrombin generation. Microarray (Affymetrix) and single-gene expression analysis of mouse livers showed that fish oil induced: (1) upregulation of genes contributing to lipid degradation and oxidation; (2) downregulation of genes of γ-glutamyl carboxylase and of transcription factors implicated in lipid synthesis; (3) unchanged expression of coagulation factor genes. After fish-oil diet, vitamin K-dependent coagulation factors accumulated in periportal areas of the liver; prothrombin was partly retained in uncarboxylated form. Only part of the changes in gene expression were different from the effects of sunflowerseed oil diet. Conclusions - The hypocoagulant effect of n-3 PUFA is not caused by reduced hepatic synthesis of coagulation factors, but rather results from retention of uncarboxylated coagulation factors. In contrast, the lipid-lowering effect of n-3 PUFA links to altered expression of genes that regulate transcription and fatty acid metabolism.

APOE2 mice, Coagulation, Fish oil, Gene expression profiles, Thrombin
dx.doi.org/10.1161/ATVBAHA.107.156992, hdl.handle.net/1765/30190
Arteriosclerosis, Thrombosis, and Vascular Biology
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Erasmus MC: University Medical Center Rotterdam

Vanschoonbeek, K, Wouters, K, van der Meijden, P.E.J, van Gorp, P.J, Feijge, M.A.H, Herfs, M, … Heemskerk, J.W.M. (2008). Anticoagulant effect of dietary fish oil in hyperlipidemia. A study of hepatic gene expression in APOE2 knock-in mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(11), 2023–2029. doi:10.1161/ATVBAHA.107.156992