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.

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 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: 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
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 28 Issue 11 Pg. 2023-9 (Nov 2008) ISSN: 1524-4636 [Electronic] United States
• PMID: 18757293 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticoagulants
• Apolipoprotein E2
• Blood Coagulation Factors
• Fatty Acids, Omega-3
• Fatty Acids, Omega-6
• Plant Oils
• RNA, Messenger
• Sunflower Oil
• Triglycerides

Topics

• Animals
• Anticoagulants (administration & dosage, pharmacology)
• Apolipoprotein E2 (genetics, metabolism)
• Blood Coagulation (drug effects, genetics)
• Blood Coagulation Factors (metabolism)
• Diet
• Disease Models, Animal
• Fatty Acids, Omega-3 (administration & dosage, pharmacology)
• Fatty Acids, Omega-6 (pharmacology)
• Gene Expression Profiling (methods)
• Gene Expression Regulation (drug effects)
• Humans
• Hyperlipidemias (blood, genetics, metabolism)
• Lipid Metabolism (drug effects, genetics)
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Oligonucleotide Array Sequence Analysis
• Plant Oils (pharmacology)
• Protein Processing, Post-Translational (drug effects)
• RNA, Messenger (metabolism)
• Sunflower Oil
• Time Factors
• Transcription, Genetic (drug effects)
• Triglycerides (blood)