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

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

Endotoxin tolerance does not limit mild ischemia-reperfusion injury in humans in vivo.

Contains fulltext : 80768.pdf (publisher's version ) (Closed access)Animal studies have shown that previous exposure to lipopolysaccharide (LPS) can limit ischemia-reperfusion injury. We tested whether pretreatment with LPS also protects against ischemia-reperfusion injury in humans in vivo. Fourteen volunteers received bolus injections of incremental dosages of LPS on 5 consecutive days (LPS group). Before the first and 1 day after the last LPS administration, the forearm circulation of the non-dominant arm was occluded for 10 min, with concomitant intermittent handgripping to induce transient ischemia. After reperfusion, 0.1 mg of ( 99m)Tc-labeled annexin A5 (400 MBq) was injected intravenously to detect phosphatidylserine expression as an early marker of ischemia-reperfusion injury. Similarly, the control group (n = 10) underwent the ischemic exercise twice, but without pretreatment with LPS. Annexin A5 targeting was expressed as the percentage difference in radioactivity in the thenar muscle between both hands. Endotoxin tolerance developed during 5 consecutive days of LPS administration. Annexin A5 targeting was 12.1 +/- 2.2% and 10.4 +/- 2.1% before LPS treatment at 1 h and 4 h after reperfusion, compared to 12.2 +/- 2.4% and 8.9 +/- 2.1% at 1 h and 4 h after reperfusion on day 5 (P = 1.0 and 0.6, respectively). Also, no significant changes in annexin A5 targeting were found in the control group. So, in this model, LPS-tolerance does not protect against ischemia-reperfusion injury in humans in vivo