title: Anticoagulant effect of dietary fish oil in hyperlipidemia: a study of hepatic gene expression in APOE2 knock-in mice.
abstract: 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.
  
  
  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 sunflower seed 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 sunflower seed 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.
authors.affiliation: Department of Biochemistry, CARIM and NUTRIM, Maastricht University, Maastricht, The Netherlands.
authors.forename: Kristof
authors.initials: K
authors.lastname: Vanschoonbeek
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.forename: Paola E J
authors.initials: PE
authors.lastname: van der Meijden
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van Gorp
authors.forename: Marion A H
authors.initials: MA
authors.lastname: Feijge
authors.forename: Marjolein
authors.initials: M
authors.lastname: Herfs
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Moniek P M
authors.initials: MP
authors.lastname: de Maat
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk