Anticoagulant effect of dietary fish oil in hyperlipidemia: a study of hepatic gene expression in APOE2 knock-in mice.

K. Vanschoonbeek, Kristiaan Wouters, P.E. van der Meijden, P.J.J. van Gorp, M.A. Feijge, M. Herfs, L.J. Schurgers, M.H. Hofker, M.P. de Maat, J.W. Heemskerk*

*Corresponding author for this work

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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 gamma-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.
Original languageEnglish
Pages (from-to)2023-2029
JournalArteriosclerosis Thrombosis and Vascular Biology
Issue number11
Publication statusPublished - 1 Jan 2008


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