Abnormal lipoprotein oxylipins in metabolic syndrome and partial correction by omega-3 fatty acids.

Metabolic syndrome (MetSyn) is characterized by chronic inflammation which mediates the associated high risk for cardiovascular and other diseases. Oxylipins are a superclass of lipid mediators with potent bioactivities in inflammation, vascular biology, and more. While their role as locally produced agents is appreciated, most oxylipins in plasma are found in lipoproteins suggesting defective regulation of inflammation could be mediated by the elevated VLDL and low HDL levels characteristic of MetSyn. Our objective was to compare the oxylipin composition of VLDL, LDL, and HDL in 14 optimally healthy individuals and 31 MetSyn patients, and then to determine the effects of treating MetSyn subjects with 4g/day of prescription omega-3 fatty acids (P-OM3) on lipoprotein oxylipin profiles. We compared oxylipin compositions of healthy (14) and MetSyn (31) subjects followed by randomization and assignment to 4g/d P-OM3 for 16 weeks using LC/MS/MS. Compared to healthy subjects, MetSyn is characterized by abnormalities of (1) pro-inflammatory, arachidonate-derived oxylipins from the lipoxygenase pathway in HDL; and (2) oxylipins mostly not derived from arachidonate in VLDL. P-OM3 treatment corrected many components of these abnormalities, reducing the burden of inflammatory mediators within peripherally circulating lipoproteins that could interfere with, or enhance, local effectors of inflammatory stress. We conclude that MetSyn is associated with a disruption of lipoprotein oxylipin patterns consistent with greater inflammatory stress, and the partial correction of these dysoxylipinemias by treatment with omega-3 fatty acids could explain some of their beneficial effects.

Cross-sectional and longitudinal associations of circulating omega-3 and omega-6 fatty acids with lipoprotein particle concentrations and sizes: population-based cohort study with 6-year follow-up.

BACKGROUND: Cross-sectional studies have suggested that serum omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are related to favorable lipoprotein particle concentrations. We explored the associations of serum n-3 and n-6 PUFAs with lipoprotein particle concentrations and sizes in a general population cohort at baseline and after 6 years. FINDINGS: The cohort included 665 adults (274 men) with a 6-year follow-up. Nutritional counseling was given at baseline. Serum n-3 and n-6 PUFAs and lipoprotein particle concentrations and the mean particle sizes of VLDL, LDL, and HDL were quantified by nuclear magnetic resonance (NMR) spectroscopy for all baseline and follow-up samples at the same time. Concentrations of n-3 and n-6 PUFAs were expressed relative to total fatty acids. At baseline, n-3 PUFAs were not associated with lipoprotein particle concentrations. A weak negative association was observed for VLDL (P = 0.021) and positive for HDL (P = 0.011) particle size. n-6 PUFA was negatively associated with VLDL particle concentration and positively with LDL (P < 0.001) and HDL particle size (P < 0.001). The 6-year change in n-3 PUFA correlated positively with the change in particle size for HDL and LDL lipoproteins but negatively with VLDL particle size. An increase in 6-year levels of n-6 PUFAs was negatively correlated with the change in VLDL particle concentration and size, and positively with LDL particle size. CONCLUSION: Change in circulating levels of both n-3 and n-6 PUFAs, relative to total fatty acids, during 6 years of follow-up are associated with changes in lipoprotein particle size and concentrations at the population level.

The two faces of α- and γ-tocopherols: an in vitro and ex vivo investigation into VLDL, LDL and HDL oxidation.

BACKGROUND: Vitamin E and its derivatives, namely, the tocopherols, are known antioxidants, and numerous clinical trials have investigated their role in preventing cardiovascular disease; however, evidence to date remains inconclusive. Much of the in vitro research has focused on tocopherol's effects during low-density lipoprotein (LDL) oxidation, with little attention being paid to very LDL (VLDL) and high-density lipoprotein (HDL). Also, it is now becoming apparent that γ-tocopherol may potentially be more beneficial in relation to cardiovascular health. OBJECTIVES: Do α- and γ-tocopherols become incorporated into VLDL, LDL and HDL and influence their oxidation potential in an in vitro and ex vivo situation? DESIGN: Following (i) an in vitro investigation, where plasma was preincubated with increasing concentrations of either α- or γ-tocopherol and (ii) an in vivo 4-week placebo-controlled intervention with α- or γ-tocopherol. Tocopherol incorporation into VLDL, LDL and HDL was measured via high-pressure liquid chromatography, followed by an assessment of their oxidation potential by monitoring conjugated diene formation. RESULTS: In vitro: Both tocopherols became incorporated into VLDL, LDL and HDL, which protected VLDL and LDL against oxidation. However and surprisingly, the incorporation into HDL demonstrated pro-oxidant properties. Ex vivo: Both tocopherols were incorporated into all three lipoproteins, protecting VLDL and LDL against oxidation; however, they enhanced the oxidation of HDL. CONCLUSIONS: These results suggest that α- and γ-tocopherols display conflicting oxidant activities dependent on the lipoprotein being oxidized. Their pro-oxidant activity toward HDL may go some way to explain why supplementation studies with vitamin E have not been able to display cardioprotective effects.

Effects of moderate exercise on VLDL1 and Intralipid kinetics in overweight/obese middle-aged men.

Prior moderate exercise reduces plasma triglyceride (TG)-rich lipoprotein concentrations, mainly in the large very low-density lipoprotein (VLDL1) fraction, but the mechanism responsible is unclear. We investigated the effects of brisk walking on TG-rich lipoprotein kinetics using a novel method. Twelve overweight/obese middle-aged men underwent two kinetic studies, involving infusion of Intralipid to block VLDL1 catabolism, in random order. On the afternoon prior to infusion, subjects either walked on a treadmill for 2 h at ∼50% maximal oxygen uptake or performed no exercise. Multiple blood samples were taken during and after infusion for separation of Intralipid (S(f) 400) and VLDL1 (S(f) 60-400). VLDL1-TG and -apoB production rates were calculated from their linear rises during infusion; fractional catabolic rates (FCR) were calculated by dividing linear rises by fasting concentrations. Intralipid-TG FCR was determined from the postinfusion exponential decay. Exercise reduced fasting VLDL1-TG concentration by 30% (P = 0.007) and increased TG enrichment of VLDL1 particles [30% decrease in cholesteryl ester (CE)/TG ratio (P = 0.007); 26% increase in TG/apoB ratio (P = 0.059)]. Exercise also increased VLDL1-TG, VLDL1-apoB, and Intralipid-TG FCRs by 82, 146, and 43%, respectively (all P < 0.05), but had no significant effect on VLDL1-TG or -apoB production rates. The exercise-induced increase in VLDL1-apoB FCR correlated strongly with the exercise-induced changes in VLDL1 CE/TG (r = -0.659, r = 0.020) and TG/apoB (r = 0.785, P = 0.002) ratios. Thus, exercise-induced reductions in VLDL1 concentrations are mediated by increased catabolism, rather than reduced production, which may be facilitated by compositional changes to VLDL1 particles that increase their affinity for clearance from the circulation.

The lipid-lowering effect of dietary proanthocyanidins in rats involves both chylomicron-rich and VLDL-rich fractions.

Proanthocyanidins have been shown to improve postprandial hypertriacylglycerolaemia. The present study aims to determine the actual contribution of chylomicrons (CM) and VLDL in the hypotriacylglycerolaemic action of grape seed proanthocyanidin extract (GSPE) in the postprandial state and to characterise the mechanisms by which the GSPE treatment reduces TAG-rich lipoproteins in vivo. A plasma lipid tolerance test was performed on rats fasted for 14 h and orally loaded with lard containing either GSPE or not. GSPE (250 mg/kg body weight) markedly blocked the increase in plasma TAG induced by lard, with a statistically significant reduction of 22 % in the area under the curve. The VLDL-rich fraction was the major contributor (72 %) after 1 h, whereas the CM-rich fraction was the major contributor (85 %) after 3 h. At 5 and 7 h after treatment, CM-rich and VLDL-rich fractions showed a similar influence. Plasma post-heparin lipoprotein lipase (LPL) activity and LPL mRNA levels in white adipose tissue and muscle were not affected by GSPE. On the contrary, GSPE treatment significantly repressed (30 %) the secretion of VLDL-TAG. In the liver, GSPE treatment induced different effects on the expression of acyl-coenzyme A synthetase long-chain family member 1, Apoc3 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase at 1 h and Cd36 at 5 h, compared to those induced by lard. Furthermore, GSPE treatment significantly increased the activity of carnitine palmitoyltransferase 1a at 1 h. In conclusion, both CM-rich and VLDL-rich fractions contributed to the hypotriacylglycerolaemic action of GSPE, but their influence depended on time. GSPE induces hypotriacylglycerolaemic actions by repressing lipoprotein secretion and not by increasing LPL activity.

Folate: in vitro and in vivo effects on VLDL and LDL oxidation.

Raised total homocysteine (tHcy) levels may be involved in the etiology of cardiovascular disease and can lead to damage of vascular endothelial cells and arterial wall matrix. Folic acid supplementation can help negate these detrimental effects by reducing tHcy. Recent evidence has suggested an additional anti-atherogenic property of folate in protecting lipoproteins against oxidation. This study utilized both an in vitro and in vivo approach. In vitro: Very-low-density lipoprotein (VLDL) and low density lipoprotein (LDL) were isolated by rapid ultracentrifugation and then oxidized in the presence of increasing concentrations (0-->10 micromol/L) of either folic acid or 5-methyltetrahydrofolate (5-MTHF). In vivo: Twelve female subjects were supplemented with folic acid (1 mg/day), and the pre- and post-VLDL and LDL isolates subjected to oxidation. In vitro: 5-MTHF, but not folic acid, significantly increased the resistance of VLDL and LDL to oxidation. In vivo: Following folic acid supplementation, tHcy decreased, serum folate increased, and both VLDL and LDL displayed a significant increase in their resistance to oxidation. These results indicated that in vitro, only the active form of folate, 5-MTHF, had antioxidant properties. In vivo results demonstrated that folic acid supplementation reduced tHcy and protected both VLDL and LDL against oxidation. These findings provide further support for the use of folic acid supplements to aid in the prevention of atherosclerosis.

Effect of a high-fat meal on absorption and disposition of lipophilic compounds: the importance of degree of association with triglyceride-rich lipoproteins.

Following a high-fat meal, triglyceride-rich lipoproteins (TRL) are assembled in the gut and absorbed via the lymph into the blood circulation, producing a temporal hyperlipidemia. The purpose of this study is to verify the hypothesis that this transient acute postprandial hyperlipidemia affects the pharmacokinetics of lipophilic drugs on both absorption and disposition levels by the same underlying mechanism, namely the association of active lipophilic compounds with TRL in the plasma (disposition) or within the enterocyte (lymphatic transport). This concept was assessed in rats using two model compounds, DDT with high affinity to chylomicrons and diazepam which does not bind to chylomicrons. Oral administration of peanut oil significantly increased the AUC of plasma DDT concentrations following its IV bolus administration in comparison to a water treated group. On the other hand, the AUC of diazepam following IV bolus administration was the same in oil and water treated rats. While DDT is known to have significant lymphatic bioavailability, diazepam has negligible intestinal lymphatic transport (0.014+/-0.004% of a given dose). In conclusion, lipophilic molecules that bind extensively to TRL will be prone to both intestinal lymphatic transport and to post-absorptive changes in disposition (decrease in clearance and volume of distribution) following a high-fat meal.

Characterization of very-low density lipoprotein particle diameter dynamics in relation to egg production in a passerine bird.

During avian egg production, oestrogen mediates marked increases in hepatic lipid production and changes in the diameter of assembled very-low density lipoprotein (VLDL). A nearly complete shift from generic VLDL ( approximately 70 nm in diameter), which transports lipids to peripheral tissues, to yolk-targeted VLDL (VLDLy) ( approximately 30 nm), which supplies the yolk with energy-rich lipid, has been observed in the plasma of laying domestic fowl. We validated an established dynamic laser scattering technique for a passerine songbird Taeniopygia guttata, the zebra finch, to characterize the dynamics of VLDL particle diameter distribution in relation to egg production. We predicted that non-gallinaceous avian species that have not been selected for maximum egg production would exhibit less dramatic shifts in lipid metabolism during egg production. As predicted, there was considerable overlap between the VLDL particle diameter distributions of laying and non-laying zebra finches. But unexpectedly, non-laying zebra finches had VLDL diameter distributions that peaked at small particles and had relatively few large VLDL particles. As a result, laying zebra finches, in comparison, had diameter distributions that were shifted towards larger VLDL particles. Nevertheless, laying zebra finches, like laying chickens, had larger proportions of particles within proposed VLDLy particle diameter ranges than non-laying zebra finches (e.g. sVLDLy: 50% vs 37%). Furthermore, zebra finches and chickens had similar modal (29.7 nm in both species) and median (32.7 nm vs 29.6 nm) VLDL particle diameters during egg production. Therefore, although zebra finches and chickens exhibited opposing directional shifts in VLDL particle diameter distribution during egg production, the modifications to VLDL particle structure in both species resulted in the realization of a common goal, i.e. to produce and maintain a large proportion of small VLDL particles of specific diameters that are capable of being incorporated into newly forming egg yolks.

Vegetable oils affect the composition of lipoproteins in sea bream (Sparus aurata).

The aim of the present study was to determine the influence of the dietary fatty acid profile on the lipoprotein composition in sea bream fed different vegetable oils. Six experimental diets were formulated combining fish oil with three vegetable oils (soybean, rapeseed, linseed) in order to obtain 60-80 % (w/w) fish-oil replacement. VLDL, LDL and HDL in plasma samples were obtained by sequential centrifugal flotation. The lipid class, protein content and fatty acid composition of each lipoprotein fraction were analysed. HDL was the predominant lipoprotein in sea bream plasma containing the highest proportion of protein (34 %) and phosphatidylcholine. LDL presented a high content of cholesterol, whereas triacylglycerol comprised a larger proportion of VLDL. The lipid class of the lipoprotein fractions was affected by the dietary vegetable oils. Thus, a high dietary inclusion of soyabean and linseed oil (80 %) increased the cholesterol in HDL and LDL in comparison to fish oil. Similarly, the triacylglycerol concentration of VLDL was increased in fish fed 80 % soyabean and linseed oils owing to the low n-3 highly unsaturated fatty acid content of these diets. Lipoprotein fatty acid composition easily responded to dietary fatty acid composition. VLDL was the fraction more affected by dietary fatty acid, followed by LDL and HDL. The n-3 highly unsaturated fatty acid content increased in the order VLDL less than LDL and less than HDL, regardless of dietary vegetable oils.

Alpha-tocopherol distribution in lipoproteins and anti-inflammatory effects differ between CHD-patients and healthy subjects.

OBJECTIVE: The purpose of this study was to investigate the dose-dependent effects of RRR-alpha-tocopherol supplementation in coronary heart disease (CHD) patients and healthy subjects on plasma alpha-tocopherol levels, plasma lipoprotein distribution, LDL oxidation, and inflammatory plasma markers. METHODS: 12 patients with coronary heart disease and 12 healthy subjects were supplemented with increasing dosages of RRR-alpha-tocopherol at 100, 200 and 400 mg/day for a period of 3 weeks per dose. Lipoproteins were separated by FPLC and ultracentrifugation. Alpha-tocopherol was measured by HPLC. Resistance of LDL to oxidation was determined by reading the absorption at 234 nm after CuCl2-induced oxidation. Clinical chemistry and inflammatory markers were measured on automated analysis systems. RESULTS: Plasma alpha-tocopherol concentrations at baseline were comparable between CHD-patients and healthy subjects (21.7 +/- 4.7 micromol/L and 25.8 +/- 7.6 micromol/L, respectively). CHD-patients showed a significant increase (59%) of plasma alpha-tocopherol concentrations to 34.6 +/- 9.8 micromol/L at a dosage of 100 mg/day RRR-alpha-tocopherol, whereas healthy subjects showed a significant (54%) increase to 39.7 +/- 6.1 micromol/L only with 400 mg/day RRR-alpha-tocopherol. In addition, CHD-patients showed a significantly increased enrichment of alpha-tocopherol in VLDL. Supplementation (200 mg/day) caused a significant decrease of the acute phase plasma proteins C-reactive protein (CRP) (-65%) and fibrinogen (-24%). CONCLUSION: Our data demonstrate that CHD-patients require lower dosages of alpha-tocopherol supplementation than healthy subjects to exert biological effects on plasma lipoproteins and acute phase response.

Saturated fat-induced changes in Sf 60-400 particle composition reduces uptake of LDL by HepG2 cells.

The ability of human postprandial triacylglycerol-rich lipoproteins (TRLs), isolated after meals enriched in saturated fatty acids (SFAs), n-6 PUFAs, and MUFAs, to inhibit the uptake of 125I-labeled LDL by the LDL receptor was investigated in HepG2 cells. Addition of TRLs resulted in a dose-dependent inhibition of heparin-releasable binding, cell-associated radioactivity, and degradation products of 125I-labeled LDL (P < 0.001). SFA-rich Svedberg flotation rate (Sf) 60-400 resulted in significantly greater inhibition of cell-associated radioactivity than PUFA-rich particles (P = 0.016) and total uptake of 125I-labeled LDL compared with PUFA- and MUFA-rich particles (P < 0.02). Normalization of the apolipoprotein (apo)E but not apoC-III content of the TRLs removed the effect of meal fatty acid composition, and addition of an anti-apoE antibody reversed the inhibitory effect of TRLs on the total uptake of 125I-labeled LDL. Real time RT-PCR showed that the SFA-rich Sf 60-400 increased the expression of genes involved in hepatic lipid synthesis (P < 0.05) and decreased the expression of the LDL receptor-related protein 1 compared with MUFAs (P = 0.008). In conclusion, these findings suggest an alternative or additional mechanism whereby acute fat ingestion can influence LDL clearance via competitive apoE-dependent effects of TRL on the LDL receptor.

Triacylglycerol oxidation in pig lipoproteins after a diet rich in oxidized sunflower seed oil.

The effects of two sunflower seed oil diets differing in oxidation levels (PV in oils 1 and 190 mequiv O2/kg) on lipoprotein TAG and total lipid oxidation were investigated in growing pigs. For 2 wk, two groups of 10 pigs were fed either of the diets, after which blood samples were collected. A method based on RP-HPLC and electrospray ionization-MS was used for the analysis of oxidized TAG molecules in chylomicrons and VLDL. The baseline diene conjugation method was used for the estimation of in vivo levels of lipoprotein lipid oxidation. TAG molecules with a hydroxy, an epoxy, or a keto group attached to a FA, as well as TAG core aldehydes were detected in the samples. Typically, lipoprotein TAG and total lipids were more oxidized in the pigs fed on the oxidized oil compared with those fed on nonoxidized oil. Oxidation of dietary fat was thus reflected in the lipoprotein oxidation, which confirmed our earlier findings.

Eicosapentaenoic acid improves endothelial function in hypertriglyceridemic subjects despite increased lipid oxidizability.

BACKGROUND: Epidemiologic investigations suggest that fish oil, which contains eicosapentaenoic acid (EPA), has favorable cardiovascular effects. Fish oil improves endothelial function in subjects with hypercholesterolemia or diabetes. However, controversy persists regarding relationships between primary hypertriglyceridemia and endothelial dysfunction. Moreover, lipoproteins are more susceptible to oxidation in vitro after incorporation of fish oil. METHODS: We determined the effects of EPA on serum lipids, susceptibility of low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) to oxidation, and endothelial function in hypertriglyceridemic (HTG) subjects. In 8 men with untreated primary hypertriglyceridemia (plasma triglyceride between 150 and 500 mg/dL) and 7 control subjects (triglyceride below 150 mg/dL), forearm blood flow (FBF) responses were tested. In HTG subjects, this was repeated 3 months after initiation of EPA (1800 mg/day). Cu2+-induced oxidation of VLDL and LDL was determined by serial measurement of conjugated dienes. We used lag time, which corresponded to the period when the lipoproteins were resistant to oxidation, as a parameter of oxidizability. FBF responses to acetylcholine and sodium nitroprusside were determined by strain-gauge plethysmography. RESULTS: Plasma triglyceride in HTG subjects fell 31% with EPA supplementation. Before EPA, VLDL and LDL lag times in HTG subjects were shorter than in control subjects. EPA further reduced lag time for VLDL but not LDL. The FBF response to acetylcholine (but not to nitroprusside) was significantly less in HTG subjects before EPA than in control subjects. EPA normalized the FBF response to acetylcholine. CONCLUSIONS: EPA improves endothelial function in HTG subjects despite increasing in VLDL oxidizability.

Effects of dietary fish oil on the fatty acid composition of the main lipid classes of chick plasma lipoproteins.

We have studied the effects of diet supplementation with 10% fish oil on fatty acid composition of the main lipid classes of chick plasma lipoproteins bearing in mind the relationship between platelet aggregation and eicosanoid production from arachidonic acid. Fish oil drastically increased the percentages of 20:5 n-3 and 22:6 n-3 acids in the high density lipoprotein lipids. The 20:5/22:6 ratio increased in triacylglycerol fraction whereas in phospholipids and cholesterol esters both 20:5 and 22:6 acids increased in a similar proportion. The percentage of arachidonic acid was higher in phospholipids than in the other lipid classes from this lipoprotein fraction and was significantly reduced by fish oil feeding. Linoleic acid, which was the most abundant fatty acid in cholesterol esters, strongly decreased after fish oil consumption. Changes induced in low- and very low density lipoproteins were similar to that observed in the high density lipoproteins. However, in the very low density lipoproteins, the 20:5/22:6 ratio was not increased in triacylglycerols, in contrast to that found in the high- and low density fractions. Our results suggest that decreases observed by fish oil feeding in the percentages of arachidonic acid in phospholipids and linoleic acid in cholesterol esters in the three lipoprotein fractions may be of importance to explain some pharmacological effects of n-3 PUFA with regard to vascular diseases.

A novel series of 2,6,7-substituted 2,3-dihydro-1,4-benzodioxin and 2,6,7-substituted 1,4-benzodioxin derivatives as lipid peroxidation inhibitors. Structure-activity relationships for high inhibition of human low-density lipoprotein peroxidation.

A series of 6- or 7-substituted 2-carboxamido- or 2-(aminomethyl)-1,4-benzodioxin and -2,3-dihydro-1,4-benzodioxin derivatives were synthesized and evaluated to determine the necessary structural requirements for a high inhibition of human low-density lipoprotein copper-induced peroxidation. The most active compounds (21, 25, 28, 36, and 37) were found between 5 and >45 times more active than probucol itself. Due to both their potency and their structural features, compounds 25 and 36 were selected with others for complementary in vitro and in vivo investigations. Both of them exhibit calcium antagonist properties in the same range of potency as flunarizine itself. Compound 36 was also found to have significant hypolipaemic activity in mice at 100 and 300 mg/kg po, while compound 25 proved to be clearly active in a normobar hypoxia test.

Effects of palm oil and transesterified palm oil on chylomicron and VLDL triacylglycerol structures and postprandial lipid response.

The effects of positional distribution of triacylglycerol (TAG) fatty acids to TAG structures in chylomicrons and VLDL, and to postprandial lipemia, were studied in 10 healthy premenopausal women using a 6-h oral fat load test and a randomized, double-blind cross-over design. Molecular level information of TAG regioisomerism was obtained with a tandem mass spectrometric method. The positional distribution of fatty acids in chylomicron TAGs was similar to the respective dietary fat; 79% of the analyzed regioisomers in palm oil and 84% of the analyzed regioisomers in transesterified oil were found in chylomicron TAGs 3 h after the oral fat loads. VLDL TAGs were equal after the two fat loads in all but one regioisomer. Similarities in the fatty acid compositions of chylomicron TAGs suggest that palmitic acid was absorbed equally from both test fats. The proportion of palmitoleic acid in the chylomicrons was increased. Fat with palmitic acid predominantly in the sn-1 and sn-3 positions caused a larger incremental area of total TAGs in plasma and reduced plasma insulin values at the beginning of the postprandial response (0-90 min) compared with fat with palmitic acid randomly distributed. The relationship between TAG molecular structures in dietary fats and in lipoproteins provides new means for understanding the effects of fatty acid positional distribution on human lipid metabolism.

Plasma factors controlling atrial natriuretic peptide (ANP) aggregation: role of lipoproteins.

We have previously shown that human plasma atrial alpha-natriuretic peptide (alpha-hANP) sequestering is a protective phenomenon against amyloid aggregation. In the present work, the possible role of lipoproteins as alpha-hANP binding factors has been investigated in vitro using an experimental model, developed in our laboratory, that allows to work at physiological concentrations. This approach consists of gel filtration on Sephacryl S-300 HR of big alpha-[(125)I]hANP generated in phosphate buffered saline or in human normal plasma supplemented or not with lipoproteins. The results of these experiments indicate that high density lipoproteins (HDL) are responsible for the ANP binding phenomenon observed in vitro, while low density lipoproteins and very low density lipoproteins do not directly interact with ANP. Moreover, the HDL remodeling process occurring in vitro has been analyzed during plasma incubation by monitoring the redistribution of lipids and apolipoproteins among the HDL subclasses. The changes in HDL size and composition observed in incubated plasma were compared with the redistribution of endogenous and labeled big ANP. The obtained results revealed that both tend to follow the molecular rearrangement in plasma of apolipoprotein A-I containing particles and suggested that, among HDL species, the small particles are mainly involved in the ANP binding phenomenon. This hypothesis was further demonstrated by ligand blotting experiments that confirmed the existence of differences in the ability of HDL particles to bind alpha-[(125)I]hANP.

The coffee diterpene cafestol increases plasma triacylglycerol by increasing the production rate of large VLDL apolipoprotein B in healthy normolipidemic subjects.

BACKGROUND: Cafestol is a diterpene in unfiltered coffee that raises plasma triacylglycerol in humans. OBJECTIVE: We studied whether cafestol increases plasma triacylglycerol by increasing the production rate or by decreasing the fractional catabolic rate of VLDL(1) [Svedberg flotation unit (S(f)) 60-400] apolipoprotein (apo) B. In addition, we studied the effect of cafestol on the composition of VLDL(1) and VLDL(2) (S(f) 20-60). DESIGN: Eight healthy normolipidemic men were administered a daily dose of 75 mg cafestol for 2 wk. A bolus injection of 7 mg L-[5,5,5-(2)H(3)]leucine/kg body wt was given after a baseline period with no cafestol and again after treatment with cafestol. We derived kinetic constants to describe the metabolism of VLDL(1) apo B by using a multicompartmental model. RESULTS: Cafestol significantly increased plasma triacylglycerol by 31% or 0.32 mmol/L (95% CI: 0.03, 0.61); the increase was due mainly to a nonsignificant rise in VLDL(1) triacylglycerol of 57% or 0.23 mmol/L (95% CI: -0.02, 0.48). Cafestol significantly increased the mean rate of VLDL(1) apo B production by 80% or 755 mg/d (95% CI: 0.2, 5353), whereas it did not significantly change the mean fractional catabolic rate of VLDL(1) apo B (mean increase of 3 pools/d; 95% CI: -4, 10]). Cafestol did not change the composition of VLDL(1). A significant increase in the ratio of VLDL(2) cholesteryl ester to triacylglycerol indicates that VLDL(2) became enriched with cholesteryl esters at the cost of triacylglycerol. CONCLUSION: Cafestol increases plasma triacylglycerol by increasing the production rate of VLDL(1) apo B, probably via increased assembly of VLDL(1) in the liver.

Comparison of maritime pine oil and fish oil effects on plasma lipoproteins in apolipoprotein E-deficient mice.

The goal of this study was to compare the lipid lowering properties of maritime pine and fish oils in apolipoprotein E-deficient (KOE) mice, an animal model of hyperlipidemia. KOE mice were supplemented with either lard, fish or maritime pine oil (10% w/w) for one month. Compared to lard, fish and maritime pine oils decreased cholesterol (-31% and -52% respectively) and phospholipid (-41 and -52%) levels and increased triglyceride (+182% and +123%) levels. These lipid changes resulted in an enrichment in triglycerides and a depletion in cholesterol of VLDL+IDL plasma fraction as compared to lard-fed mice. These findings suggest that VLDL-triglyceride lipolysis is impaired in KOE mice fed fish or maritime pine oil.