Search

Obesity is often associated with dyslipidemia, insulin resistance, and hypertension. Together, these metabolic perturbations greatly increase the risk of developing cardiovascular disease and diabetes. Although fish oil is a well-established hypolipidemic agent, the mechanisms by which it mediates its lipid-lowering effects are not clear. In addition, it has not been established whether dietary fish oil has different effects in lean and obese mice. LDL receptor deficient (LDLR-/-) and leptin deficient mice on a LDLR-/- background (ob/ob; LDLR-/-) were fed a high fat diet (39% total fat) supplemented with 6% olive oil or fish oil for 6 wk. Fish oil supplementation resulted in lower concentrations of plasma total cholesterol (P < 0.01), triglycerides (P< 0.01), and free fatty acids (P< 0.001) in lean LDLR-/- mice, but not in ob/ob; LDLR-/- mice. In contrast, a fish oil diet did not modulate insulin sensitivity in lean LDLR-/- mice, but it improved insulin sensitivity in ob/ob; LDLR-/- mice (P < 0.05) compared with olive oil fed ob/ob; LDLR-/- mice. Interestingly, plasma adiponectin concentrations were significantly higher and hepatic steatosis was reduced in both mouse models upon fish oil feeding. Finally, fish oil fed LDLR-/- mice exhibited higher hepatic AMP activated protein kinase (AMPK) phosphorylation (P < 0.05), whereas AMPK phosphorylation was not elevated by fish oil feeding in ob/ob; LDLR-/- mice. Taken together, our data suggest that fish oil reduces hepatic steatosis in both lean and obese mice, has potent plasma lipid lowering effects in lean mice, and exerts insulin sensitizing effects in obese mice. J. Nutr. 139: 2380-2386, 2009. Manuscript received June 12, 2009. Initial review completed July 17, 2009. Revision accepted October 15, 2009. First published online October 28, 2009; doi: 10.3945/jn.109.111567.

Cytosolic phospholipase [A.sub.2[alpha]] ([cPLA.sub.2[alpha]]) hydrolyzes arachidonic acid from cellular membrane phospholipids, thereby providing enzymatic substrates for the synthesis of eicosanoids, such as prostaglandins and leukotrienes. Considerable understanding of [cPLA.sub.2[alpha]] function has been derived from investigations of the enzyme and from [cPLA.sub.2[alpha]]-null mice, but knowledge of discrete roles for this enzyme in humans is limited. We investigated a patient hypothesized to have an inherited prostanoid biosynthesis deficiency due to his multiple, complicated small intestinal ulcers despite no use of cyclooxygenase inhibitors. Levels of thromboxane [B.sub.2] and 12-hydroxyeicosatetraenoic acid produced by platelets and leukotriene [B.sub.4] released from calcium ionophore--activated blood were markedly reduced, indicating defective enzymatic release of the arachidonic acid substrate for the corresponding cyclooxygenase and lipoxygenases. Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid. Two heterozygous single base pair mutations and a known SNP were found in the coding regions of the patient&apos;s [cPLA.sub.2[alpha]] genes (p.[Ser111Pro]+[Arg485His; Lys651Arg]). The total [PLA.sub.2] activity in sonicated platelets was diminished, and the urinary metabolites of prostacyclin, prostaglandin [E.sub.2], prostaglandin [D.sub.2], and thromboxane [A.sub.2] were also reduced. These findings characterize what we believe is a novel inherited deficiency of [cPLA.sub.2]., Introduction These investigations addressed the problem of a patient with multiple small intestinal ulcers that were not associated with use of NSAIDs. The patient had chronic gastrointestinal blood loss from [...]

Although fish oil has hypolipidemic and antiatherosclerotic properties, the potential for white adipose tissue (WAT) to mediate these effects has not been studied. LDL-receptor deficient (LDLR-/-) mice were fed high fat, olive oil-containing diets supplemented with additional olive oil or with fish oil for 12 wk. Fish oil feeding significantly reduced plasma lipid levels. In contrast, lipid storage in WAT was increased in fish oil-fed mice as evidenced by increased total fat (P < 0.05) and perigonadal WAT mass (P < 0.05), increased cholesterol storage (P < 0.001), and adipocyte hypertrophy. Despite increased adipose tissue mass, WAT-specific inflammation and insulin sensitivity were improved (P < 0.05), concomitant with reduced macrophage infiltration. Furthermore, fish oil increased WAT and plasma levels of adiponectin. In addition, fish oil feeding decreased the formation of proinflammatory F2- isoprostanes, markers of oxidative stress (P < 0.05). The increased WAT lipid storage in fish oil-fed mice was associated with reduced lipid accumulation in liver (P < 0.05) and decreased atherosclerotic lesion area (P < 0.05). Taken together, these data highlight the specific role of WAT in regulating dietary fish oil-mediated improvement in systemic lipid homeostasis and atherosclerosis.

The effect of lipid composition on the distribution of free radical oxidation products derived from arachidonic acid (20:4) esters is studied in vitro and in vivo. The results have described that dietary [omega]-3 polyunsaturated fatty acids (PUFAs) might influence the formation of bioactive peroxidation products derived from [omega]-6 PUFAs by channeling the free radical pathway away from the pro-inflammatory prostaglandin (PG) [F.sub.2]-like compounds, termed as [F.sub.2]-isoprostanes ([F.sub.2]IsoPs).

Tight regulation of COX-2 expression is a key feature controlling eicosanoid production in atherosclerosis and other inflammatory syndromes. Adhesive interactions between platelets and monocytes occur in these conditions and deliver [...]

The relationships between oxidant stress and nucleoside reverse transcriptase inhibitor (NRTI)-induced peripheral neuropathy were explored by quantifying plasma [F.sub.2]-Isoprostanes among AIDs Clinical Trials Group (ACTG) 384 participants. The findings suggest that symptomatic NRTI-associated peripheral neuropathy was not associated with increased plasma [F.sub.2]-Isoprostanes among ACTG 384 participants.

Electrophilic lipids, such as 4-hydroxynonenal (HNE), and the cyclopentenones 15-deoxy-[[DELTA].sup.12,14]-prostaglandin [J.sub.2] (15d-[PGJ.sub.2]) and 15-[J.sub.2]-isoprostane induce both reactive oxygen species (ROS) formation and cellular antioxidant defenses, such as heme oxygenase-1 (HO-1) and glutathione (GSH). When we compared the ability of these distinct electrophiles to stimulate GSH and HO-1 production, the cyclopentenone electrophiles were somewhat more potent than HNE. Over the concentration range required to observe equivalent induction of GSH, dichlorofluorescein fluorescence was used to determine both the location and amounts of electrophilic lipid-dependent ROS formation in endothelial cells. The origin of the ROS on exposure to these compounds was largely mitochondrial. To investigate the possibility that the increased ROS formation was due to mitochondrial localization of the lipids, we prepared a novel fluorescently labeled form of the electrophilic lipid 15d-[PGJ.sub.2]. The lipid demonstrated strong colocalization with the mitochondria, an effect which was not observed by using a fluorescently labeled nonelectrophilic lipid. The role of mitochondria was confirmed by using cells deficient in functional mitochondria. On the basis of these data, we propose that ROS formation in endothelial cells is due to the direct interaction of these lipids with the organelle. 15-deoxy-[[DELTA].sup.12,14]-prostaglandin [J.sub.2]; isoprostane; cyclopentenone; 4-hydroxynonenal; atherosclerosis; rho0

Glyceryl prostaglandins (PG-Gs) are generated by the oxygenation of the endocannabinoid, 2-arachidonylglycerol, by cyclooxygenase 2. The biological consequences of this selective oxygenation are uncertain because the cellular activities of PG-Gs have yet to be defined. We report that the glyceryl ester of [PGE.sub.2], PG[E.sub.2]-G, triggers rapid, concentration-dependent [Ca.sup.2+] accumulation in a murine macrophage-like cell line, RAW264.7. [Ca.sup.2+] mobilization is not observed after addition of [PGE.sub.2], [PGD.sub.2]-G, or [PGF.sub.2[alpha]]-G but is observed after addition of [PGF.sub.2[alpha]]. Moreover, PG[E.sub.2]-G, but not [PGE.sub.2], stimulates a rapid but transient increase in the levels of inositol 1,4,5-trisphosphate ([IP.sub.3]) as well as the membrane association and activation of PKC. [PGE.sub.2]-G induces a concentration-dependent increase in the levels of phospborylated extracellular signal regulated kinases 1 and 2 through a pathway that requires the activities of PKC, [IP.sub.3] receptor, and phospholipase C [beta]. The results indicate that [PGE.sub.2]-G triggers [Ca.sup.2+] mobilization, [IP.sub.3] synthesis, and activation of PKC in RAW264.7 macrophage cells at low concentrations. These responses are independent of the hydrolysis of [PGE.sub.2]-G to [PGE.sub.2].