This Article Full Text Full Text (PDF) All Versions of this Article: 28/11/2023    most recent ATVBAHA.107.156992v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Vanschoonbeek, K. Articles by Heemskerk, J. W.M. Search for Related Content PubMed PubMed Citation Articles by Vanschoonbeek, K. Articles by Heemskerk, J. W.M.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2023.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Anticoagulant Effect of Dietary Fish Oil in Hyperlipidemia

A Study of Hepatic Gene Expression in APOE2 Knock-in Mice

Kristof Vanschoonbeek; Kristiaan Wouters; Paola E.J. van der Meijden; Patrick J. van Gorp; Marion A.H. Feijge; Marjolein Herfs; Leon J. Schurgers; Marten H. Hofker; Moniek P.M. de Maat; Johan W.M. Heemskerk

From the Departments of Biochemistry (K.V., P.E.J.v.M., M.A.H.F., L.J.S., J.W.M.H.), Human Biology (K.V.), and Molecular Genetics (K.W., P.J.v.G., M.H.H.), CARIM and NUTRIM, and VitaK (M.H., L.J.S.), Maastricht University, The Netherlands; the Department of Pathology and Laboratory Medicine (M.H.H.), University Medical Center Groningen, The Netherlands; and the Department of Hematology (M.d.M.), Erasmus Medical Centre Rotterdam, The Netherlands.

Correspondence to Dr J.W.M. Heemskerk, Department of Biochemistry, CARIM, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. E-mail jwm.heemskerk{at}bioch.unimaas.nl

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 -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.

In hyperlipidemic APOE2 knock-in mice, dietary fish oil containing n-3 polyunsaturated fatty acids (PUFA) provokes plasma triacylglycerol lowering and hypocoagulant activity. The hypocoagulant effect results from retention of uncarboxylated coagulation factors, whereas the lipid-lowering effect links to altered expression of genes that regulate fatty acid metabolism.

Key Words: APOE2 mice • coagulation • fish oil • gene expression profiles • thrombin