Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review.

BACKGROUND: Epidemiological and genetic studies suggest that elevated triglyceride (TG)-rich lipoprotein levels in the circulation increase the risk of cardiovascular disease. Prescription formulations of omega-3 fatty acids (OM3FAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce plasma TG levels and are approved for the treatment of patients with severe hypertriglyceridemia. Many preclinical studies have investigated the TG-lowering mechanisms of action of OM3FAs, but less is known from clinical studies. METHODS: We conducted a review, using systematic methodology, of studies in humans assessing the mechanisms of action of EPA and DHA on apolipoprotein B-containing lipoproteins, including TG-rich lipoproteins and low-density lipoproteins (LDLs). A systematic search of PubMed retrieved 55 articles, of which 30 were used in the review; 35 additional arrticles were also included. RESULTS: In humans, dietary DHA is retroconverted to EPA, while production of DHA from EPA is not observed. Dietary DHA is preferentially esterified into TGs, while EPA is more evenly esterified into TGs, cholesterol esters and phospholipids. The preferential esterification of DHA into TGs likely explains the higher turnover of DHA than EPA in plasma. The main effects of both EPA and DHA are decreased fasting and postprandial serum TG levels, through reduction of hepatic very-low-density lipoprotein (VLDL)-TG production. The exact mechanism for reduced VLDL production is not clear but does not include retention of lipids in the liver; rather, increased hepatic fatty acid oxidation is likely. The postprandial reduction in TG levels is caused by increased lipoprotein lipase activity and reduced serum VLDL-TG concentrations, resulting in enhanced chylomicron clearance. Overall, no clear differences between the effects of EPA and DHA on TG levels, or on turnover of TG-rich lipoproteins, have been observed. Effects on LDL are complex and may be influenced by genetics, such as APOE genotype. CONCLUSIONS: EPA and DHA diminish fasting circulating TG levels via reduced production of VLDL. The mechanism of reduced VLDL production does not involve hepatic retention of lipids. Lowered postprandial TG levels are also explained by increased chylomicron clearance. Little is known about the specific cellular and biochemical mechanisms underlying the TG-lowering effects of EPA and DHA in humans.

Dietary fat and physiological determinants of plasma chylomicron remnant homoeostasis in normolipidaemic subjects: insight into atherogenic risk.

TAG depleted remnants of postprandial chylomicrons are a risk factor for atherosclerosis. Recent studies have demonstrated that in the fasted state, the majority of chylomicrons are small enough for transcytosis to arterial subendothelial space and accelerate atherogenesis. However, the size distribution of chylomicrons in the absorptive state is unclear. This study explored in normolipidaemic subjects the postprandial distribution of the chylomicron marker, apoB-48, in a TAG-rich lipoprotein plasma fraction (Svedberg flotation rate (Sf>400), in partially hydrolysed remnants (Sf 20-400) and in a TAG-deplete fraction (Sf<20), following ingestion of isoenergetic meals with either palm oil (PO), rice bran or coconut oil. Results from this study show that the majority of fasting chylomicrons are within the potentially pro-atherogenic Sf<20 fraction (70-75 %). Following the ingestion of test meals, chylomicronaemia was also principally distributed within the Sf<20 fraction. However, approximately 40 % of subjects demonstrated exaggerated postprandial lipaemia specifically in response to the SFA-rich PO meal, with a transient shift to more buoyant chylomicron fractions. The latter demonstrates that heterogeneity in the magnitude and duration of hyper-remnantaemia is dependent on both the nature of the meal fatty acids ingested and possible metabolic determinants that influence chylomicron metabolism. The study findings reiterate that fasting plasma TAG is a poor indicator of atherogenic chylomicron remnant homoeostasis and emphasises the merits of considering specifically, chylomicron remnant abundance and kinetics in the context of atherogenic risk. Few studies address the latter, despite the majority of life being spent in the postprandial and absorptive state.

Twice weekly intake of farmed Atlantic salmon (Salmo salar) positively influences lipoprotein concentration and particle size in overweight men and women.

The US Dietary Guidelines for Americans recommend twice weekly fish intake. Farmed Atlantic salmon is a good source of omega-3 (n-3) fatty acids which have positive lipid modifying effects; however, it is unknown whether these responses are dose-dependent. Our primary research objective was to determine the effect of dose-dependent intake of farmed Atlantic salmon on lipoprotein particle (P) size and concentration. We hypothesized that low-density lipoprotein (LDL)-P and high-density lipoprotein (HDL)-P size and concentration would increase with salmon intake in a dose-dependent manner. Overweight, adult participants (n = 19) were enrolled in a cross-over designed clinical trial evaluating intake of farmed Atlantic salmon. In random order, participants were assigned to 90, 180, or 270 g of salmon twice weekly for 4-week dietary treatments. Following a 4- to 8-week washout, participants crossed over to another dose of fish intake until all treatments were completed. Plasma lipid concentrations were determined and serum lipoprotein concentrations and particle size were determined by nuclear magnetic resonance. Intake of salmon reduced plasma and serum triglyceride (TG) concentrations and increased plasma HDL-C concentrations. The concentrations of large very low-density lipoprotein (VLDL)-P and chylomicron (CM)-P were reduced. Large LDL-P concentrations were increased in a dose-dependent manner. The mean size of VLDL-P was reduced and that of LDL was increased. Total TG was reduced as was the TG content of VLDL-P and CM-P. Twice weekly intake of farmed Atlantic salmon portions influences lipoprotein particle size and concentration in a manner associated with cardiovascular disease risk reduction.

Vitamin A Supplementation Increases the Uptake of Chylomicron Retinyl Esters into the Brain of Neonatal Rats Raised under Vitamin A-Marginal Conditions.

BACKGROUND: The most rapid phase of brain development occurs during the neonatal period. Vitamin A (VA; retinol) is critical for many aspects of this process, including neurogenesis, synaptic plasticity, learning, and memory formation. However, the metabolism of retinol in the neonatal brain has not been extensively explored. OBJECTIVE: We examined the uptake of VA into the brain in neonatal rats raised under VA-marginal conditions (control group) and assessed the effect of VA supplementation on the uptake of VA into the brain. METHODS: Sprague-Dawley neonatal rats (n = 104) nursed by mothers fed a VA-marginal diet were randomly assigned and treated on postnatal day 4 with an oral dose of either VA (6 µg retinyl palmitate/g body weight) or canola oil as the control, both of which contained 1.8 µCi [(3)H]retinol. Pups (n = 4/group at a time) were killed at 13 sampling times from 30 min to 24 d after dosing. The uptake of total retinol, chylomicron-associated retinyl esters (REs), and retinol bound to retinol-binding protein (RBP) was estimated with the use of WinSAAM version 3.0.8. RESULTS: Total retinol mass in the brain was closely dependent on its mass in plasma over time (r = 0.91; P < 0.001). The uptake of retinol into the brain involved both postprandial chylomicrons and RBP, with RBP delivering most of the retinol in the control group [0.27 nmol/d (RBP) compared with 0.01 nmol/d (chylomicrons)]. VA supplementation increased the fractional uptake of chylomicron REs from 0.3% to 1.2% of plasma pool/d, decreased that of RBP retinol from 0.5% to 0.2% of plasma pool/d, and increased the transfer rate of chylomicron REs from nearly zero to 0.7 nmol/d, causing a day-long elevation in the brain mass of total retinol. CONCLUSION: Postprandial chylomicrons may be a primary mechanism for delivering a recently ingested large dose of VA to the brain of neonatal rats raised under VA-marginal conditions.

Enhanced Bioavailability of EPA From Emulsified Fish Oil Preparations Versus Capsular Triacylglycerol.

For those individuals who are unable to consume adequate long chain omega-3 fatty acids (LCn3) from dietary sources, fish oil supplementation is an attractive alternative Pre-emulsified fish oil supplements, an alternative to capsular triacylglycerol, may enhance the uptake of LCn3 fatty acids it contains. A randomized, Latin-square crossover design was used to compare the effects of four fish oil supplement preparations (Emulsions S, B and N) on phospholipid fatty acid (PLFA) concentrations in ten healthy volunteers compared to oil capsules over 48 h after a single dose and chylomicron fatty acid (CMFA) was evaluated over 8 h. Blood samples were collected at 0, 2, 4, 8, 24 and 48 h and fatty acid concentrations of PLFA and CMFA were determined by gas chromatography and the integrated area under the curve over 40 h (iAUC0-48) was determined. Emulsion S and Emulsion N promoted increased uptake of EPA into PLFA over 48 h when evaluating by iAUC0-48 or individual time points of assessment. No differences were observed between supplements in the CMFA concentrations.

Krill oil reduces plasma triacylglycerol level and improves related lipoprotein particle concentration, fatty acid composition and redox status in healthy young adults - a pilot study.

BACKGROUND: Lipid abnormalities, enhanced inflammation and oxidative stress seem to represent a vicious circle in atherogenesis, and therapeutic options directed against these processes seems like a reasonable approach in the management of atherosclerotic disorders. Krill oil (RIMFROST Sublime®) is a phospholipid-rich oil with eicosapentaenoic acid (EPA): docosahexaenoic acid (DHA) ratio of 1.8:1. In this pilot study we determined if krill oil could favourable affect plasma lipid parameters and parameters involved in the initiation and progression of atherosclerosis. METHODS: The study was conducted as a 28 days intervention study examining effect-parameters of dietary supplementation with krill oil (832.5 mg EPA and DHA per day). 17 healthy volunteers in the age group 18-36 (mean age 23 ± 4 years) participated. Plasma lipids, lipoprotein particle sizes, fatty acid composition in plasma and red blood cells (RBCs), plasma cytokines, antioxidant capacity, acylcarntines, carnitine, choline, betaine, and trimethylamine-N-oxide (TMAO) were measured before and after supplementation. RESULTS: Plasma triacylglycerol (TAG) and large very-low density lipoprotein (VLDL) & chylomicron particle concentrations decreased after 28 days of krill oil intake. A significant reduction in the TAG/HDL cholesterol resulted. Krill oil supplementation decreased n-6/n-3 polyunsaturated fatty acids (PUFA) ratio both in plasma and RBCs. This was due to increased EPA, DHA and docosapentaenoic acid (DPA) and reduced amount of arachidonic acid (AA). The increase of n-3 fatty acids and wt % of EPA and DHA in RBC was of smaller magnitude than found in plasma. Krill oil intake increased the antioxidant capacity, double bond index (DBI) and the fatty acid anti-inflammatory index. The plasma atherogenicity index remained constant whereas the thrombogenicity index decreased. Plasma choline, betaine and the carnitine precursor, γ-butyrobetaine were increased after krill oil supplementation whereas the TMAO and carnitine concentrations remained unchanged. CONCLUSION: Krill oil consumption is considered health beneficial as it decreases cardiovascular disease risk parameters through effects on plasma TAGs, lipoprotein particles, fatty acid profile, redox status and possible inflammation. Noteworthy, no adverse effects on plasma levels of TMAO and carnitine were found.

Lean-seafood intake reduces cardiovascular lipid risk factors in healthy subjects: results from a randomized controlled trial with a crossover design.

BACKGROUND: Observational studies have strongly indicated an association between fish consumption and reduced risk of cardiovascular disease, but data from randomized controlled trials have been inconclusive. OBJECTIVE: Our primary outcome in this study was to elucidate the potentials of the 2 main dietary protein sources lean seafood and nonseafood to modulate fasting and postprandial lipids in healthy subjects. We hypothesized that lean-seafood intake would reduce cardiovascular lipid risk factors in healthy subjects more than would the intake of nonseafood protein sources. DESIGN: This study was a randomized controlled trial with a crossover design. After 3-wk run-in periods and separated by a 5-wk washout period, 20 healthy subjects (7 men and 13 women) consumed 2 balanced diets that varied in main protein sources (60% of total dietary proteins from lean-seafood or nonseafood sources for 4 wk). At days 1 and 28 of each intervention, fasting and postprandial blood samples were collected before and after consumption, respectively, of test meals with cod or lean beef. RESULTS: Relative to the nonseafood intervention, the lean-seafood intervention reduced fasting (relative difference by diets: 0.31 mmol/L; P = 0.03) and postprandial (P = 0.01) serum triacylglycerol concentrations. The lower serum triacylglycerol concentration was associated with reduced fasting triacylglycerol in chylomicrons and very-low-density lipoproteins (VLDLs) (P = 0.004), reduced fasting VLDL particle size (P = 0.04), and a reduced postprandial concentration of medium-sized VLDL particles (P = 0.02). The lean-seafood intervention prevented the elevated ratio of total cholesterol to HDL cholesterol in the fasted serum (P = 0.03) and postprandial serum (P = 0.01) that was observed after the nonseafood intervention. CONCLUSION: The dietary protein source determines fasting and postprandial lipids in healthy individuals in a manner that may have an effect on the long-term development of cardiovascular disease. This study was registered at clinicaltrials.gov as NCT01708681.

New Insights into the Regulation of Chylomicron Production.

Dietary lipids are efficiently absorbed by the small intestine, incorporated into triglyceride-rich lipoproteins (chylomicrons), and transported in the circulation to various tissues. Intestinal lipid absorption and mobilization and chylomicron synthesis and secretion are highly regulated processes. Elevated chylomicron production rate contributes to the dyslipidemia seen in common metabolic disorders such as insulin-resistant states and type 2 diabetes and likely increases the risk for atherosclerosis seen in these conditions. An in-depth understanding of the regulation of chylomicron production may provide leads for the development of drugs that could be of therapeutic utility in the prevention of dyslipidemia and atherosclerosis. Chylomicron secretion is subject to regulation by various factors, including diet, body weight, genetic variants, hormones, nutraceuticals, medications, and emerging interventions such as bariatric surgical procedures. In this review we discuss the regulation of chylomicron production, mechanisms that underlie chylomicron dysregulation, and potential avenues for future research.

Dairy proteins, dairy lipids, and postprandial lipemia in persons with abdominal obesity (DairyHealth): a 12-wk, randomized, parallel-controlled, double-blinded, diet intervention study.

BACKGROUND: Abdominal obesity and exaggerated postprandial lipemia are independent risk factors for cardiovascular disease (CVD) and mortality, and both are affected by dietary behavior. OBJECTIVE: We investigated whether dietary supplementation with whey protein and medium-chain saturated fatty acids (MC-SFAs) improved postprandial lipid metabolism in humans with abdominal obesity. DESIGN: We conducted a 12-wk, randomized, double-blinded, diet intervention study. Sixty-three adults were randomly allocated to one of 4 diets in a 2 × 2 factorial design. Participants consumed 60 g milk protein (whey or casein) and 63 g milk fat (with high or low MC-SFA content) daily. Before and after the intervention, a high-fat meal test was performed. We measured changes from baseline in fasting and postprandial triacylglycerol, apolipoprotein B-48 (apoB-48; reflecting chylomicrons of intestinal origin), free fatty acids (FFAs), insulin, glucose, glucagon, glucagon-like peptide 1 (GLP-1), and gastric inhibitory polypeptide (GIP). Furthermore, changes in the expression of adipose tissue genes involved in lipid metabolism were investigated. Two-factor ANOVA was used to examine the difference between protein types and fatty acid compositions, as well as any interaction between the two. RESULTS: Fifty-two participants completed the study. We found that the postprandial apoB-48 response decreased significantly after whey compared with casein (P = 0.025) independently of fatty acid composition. Furthermore, supplementation with casein resulted in a significant increase in the postprandial GLP-1 response compared with whey (P = 0.003). We found no difference in postprandial triacylglycerol, FFA, insulin, glucose, glucagon, or GIP related to protein type or MC-SFA content. We observed no interaction between milk protein and milk fat on postprandial lipemia. CONCLUSION: We found that a whey protein supplement decreased the postprandial chylomicron response compared with casein in persons with abdominal obesity, thereby indicating a beneficial impact on CVD risk. This trial was registered at clinicaltrials.gov as NCT01472666.

Lycopene bioavailability is associated with a combination of genetic variants.

The intake of tomatoes and tomato products, which constitute the main dietary source of the red pigment lycopene (LYC), has been associated with a reduced risk of prostate cancer and cardiovascular disease, suggesting a protective role of this carotenoid. However, LYC bioavailability displays high interindividual variability. This variability may lead to varying biological effects following LYC consumption. Based on recent results obtained with two other carotenoids, we assumed that this variability was due, at least in part, to several single nucleotide polymorphisms (SNPs) in genes involved in LYC and lipid metabolism. Thus, we aimed at identifying a combination of SNPs significantly associated with the variability in LYC bioavailability. In a postprandial study, 33 healthy male volunteers consumed a test meal containing 100g tomato puree, which provided 9.7 mg all-trans LYC. LYC concentrations were measured in plasma chylomicrons (CM) isolated at regular time intervals over 8 h postprandially. For the study 1885 SNPs in 49 candidate genes, i.e., genes assumed to play a role in LYC bioavailability, were selected. Multivariate statistical analysis (partial least squares regression) was used to identify and validate the combination of SNPs most closely associated with postprandial CM LYC response. The postprandial CM LYC response to the meal was notably variable with a CV of 70%. A significant (P=0.037) and validated partial least squares regression model, which included 28 SNPs in 16 genes, explained 72% of the variance in the postprandial CM LYC response. The postprandial CM LYC response was also positively correlated to fasting plasma LYC concentrations (r=0.37, P<0.05). The ability to respond to LYC is explained, at least partly, by a combination of 28 SNPs in 16 genes. Interindividual variability in bioavailability apparently affects the long-term blood LYC status, which could ultimately modulate the biological response following LYC supplementation.

Serum TG-lowering properties of plant sterols and stanols are associated with decreased hepatic VLDL secretion.

Plant sterols and stanols are structurally similar to cholesterol and when added to the diet they are able to reduce serum total- and LDL-cholesterol concentrations. They also lower serum triglyceride concentrations in humans, particularly under conditions of hypertriglyceridemia. The aim of this study was to unravel the mechanism by which plant sterols and stanols reduce serum triglyceride concentrations in high-fat diet (HFD) fed mice. Male C57BL/6J mice were fed HFD for 4 weeks. Subsequently, they received HFD, HFD supplemented with 3.1% plant sterol ester (PSE) or HFD supplemented with 3.1% plant stanol ester (PSA) for another three weeks. Both PSE and PSA feeding resulted in decreased plasma triglyceride concentrations compared with HFD, while plasma cholesterol levels were unchanged. Interestingly, hepatic cholesterol levels were decreased in the PSE/PSA groups compared with HFD and no differences were found in hepatic triglyceride levels between groups. To investigate the mechanism underlying the hypotriglyceridemic effects from PSE/PSA feeding, we measured chylomicron and VLDL secretion. PSE and PSA feeding resulted in reduced VLDL secretion, while no differences were found between groups in chylomicron secretion. In conclusion, our data indicate that plasma triglyceride-lowering resulting from PSE and PSA feeding is associated with decreased hepatic VLDL secretion.

Interindividual variability of lutein bioavailability in healthy men: characterization, genetic variants involved, and relation with fasting plasma lutein concentration.

BACKGROUND: Lutein accumulates in the macula and brain, where it is assumed to play physiologic roles. The bioavailability of lutein is assumed to display a high interindividual variability that has been hypothesized to be attributable, at least partly, to genetic polymorphisms. OBJECTIVES: We characterized the interindividual variability in lutein bioavailability in humans, assessed the relation between this variability and the fasting blood lutein concentration, and identified single nucleotide polymorphisms (SNPs) involved in this phenomenon. DESIGN: In a randomized, 2-way crossover study, 39 healthy men consumed a meal that contained a lutein supplement or the same meal for which lutein was provided through a tomato puree. The lutein concentration was measured in plasma chylomicrons isolated at regular time intervals over 8 h postprandially. Multivariate statistical analyses were used to identify a combination of SNPs associated with the postprandial chylomicron lutein response (0-8-h area under the curve). A total of 1785 SNPs in 51 candidate genes were selected. RESULTS: Postprandial chylomicron lutein responses to meals were very variable (CV of 75% and 137% for the lutein-supplement meal and the meal with tomato-sourced lutein, respectively). Postprandial chylomicron lutein responses measured after the 2 meals were positively correlated (r = 0.68, P < 0.0001) and positively correlated to the fasting plasma lutein concentration (r = 0.51, P < 0.005 for the lutein-supplement-containing meal). A significant (P = 1.9 × 10(-4)) and validated partial least-squares regression model, which included 29 SNPs in 15 genes, explained most of the variance in the postprandial chylomicron lutein response. CONCLUSIONS: The ability to respond to lutein appears to be, at least in part, genetically determined. The ability is explained, in large part, by a combination of SNPs in 15 genes related to both lutein and chylomicron metabolism. Finally, our results suggest that the ability to respond to lutein and blood lutein status are related. This trial was registered at clinicaltrials.gov as NCT02100774.

Modulation of human postprandial lipemia by changing ratios of polyunsaturated to saturated (P/S) fatty acid content of blended dietary fats: a cross-over design with repeated measures.

BACKGROUND: Postprandial lipemia (PL) contributes to coronary artery disease. The fatty acid composition of dietary fats is potentially a modifiable factor in modulating PL response. METHODS: This human postprandial study evaluated 3 edible fat blends with differing polyunsaturated to saturated fatty acids (P/S) ratios (POL = 0.27, AHA = 1.00, PCAN = 1.32). A cross-over design included mildly hypercholestrolemic subjects (9 men and 6 women) preconditioned on test diets fats at 31% energy for 7 days prior to the postprandial challenge on the 8th day with 50 g test fat. Plasma lipids and lipoproteins were monitored at 0, 1.5, 3.5, 5.5 and 7 hr. RESULTS: Plasma triacylglycerol (TAG) concentrations in response to POL, AHA or PCAN meals were not significant for time x test meal interactions (P > 0.05) despite an observed trend (POL > AHA > PCAN). TAG area-under-the-curve (AUC) increased by 22.58% after POL and 7.63% after PCAN compared to AHA treatments (P > 0.05). Plasma total cholesterol (TC) response was not significant between meals (P > 0.05). Varying P/S ratios of test meals significantly altered prandial high density lipoprotein-cholesterol (HDL-C) concentrations (P < 0.001) which increased with decreasing P/S ratio (POL > AHA > PCAN). Paired comparisons was significant between POL vs PCAN (P = 0.009) but not with AHA or between AHA vs PCAN (P > 0.05). A significantly higher HDL-C AUC for POL vs AHA (P = 0.015) and PCAN (P = 0.001) was observed. HDL-C AUC increased for POL by 25.38% and 16.0% compared to PCAN and AHA respectively. Plasma low density lipoprotein-cholesterol (LDL-C) concentrations was significant (P = 0.005) between meals and significantly lowest after POL meal compared to PCAN (P = 0.004) and AHA (P > 0.05) but not between AHA vs PCAN (P > 0.05). AUC for LDL-C was not significant between diets (P > 0.05). Palmitic (C16:0), oleic (C18:1), linoleic (C18:2) and linolenic (C18:3) acids in TAGs and cholesteryl esters were significantly modulated by meal source (P < 0.05). CONCLUSIONS: P/S ratio of dietary fats significantly affected prandial HDL-C levels without affecting lipemia.

Lipidomic profiling of chylomicron triacylglycerols in response to high fat meals.

Using lipidomic methodologies the impact that meal lipid composition and metabolic syndrome (MetS) exerts on the postprandial chylomicron triacylglycerol (TAG) response was examined. Males (9 control; 11 MetS) participated in a randomised crossover trial ingesting two high fat breakfast meals composed of either dairy-based foods or vegetable oil-based foods. The postprandial lipidomic molecular composition of the TAG in the chylomicron-rich (CM) fraction was analysed with tandem mass spectrometry coupled with liquid chromatography to profile CM TAG species and targeted TAG regioisomers. Postprandial CM TAG concentrations were significantly lower after the dairy-based foods compared with the vegetable oil-based foods for both control and MetS subjects. The CM TAG response to the ingested meals involved both significant and differential depletion of TAG species containing shorter- and medium-chain fatty acids (FA) and enrichment of TAG molecular species containing C16 and C18 saturated, monounsaturated and diunsaturated FA. Furthermore, there were significant changes in the TAG species between the food TAG and CM TAG and between the 3- and 5-h postprandial samples for the CM TAG regioisomers. Unexpectedly, the postprandial CM TAG concentration and CM TAG lipidomic responses did not differ between the control and MetS subjects. Lipidomic analysing of CM TAG molecular species revealed dynamic changes in the molecular species of CM TAG during the postprandial phase suggesting either preferential CM TAG species formation and/or clearance.

Absence of acute inhibitory effect of insulin on chylomicron production in type 2 diabetes.

OBJECTIVE: Overproduction of intestinally derived apoB-48-containing triglyceride-rich lipoproteins (TRLs) (chylomicrons) has recently been described in type 2 diabetes, as is known for hepatic TRL-apoB-100 (very-low-density lipoprotein) production. Furthermore, insulin acutely inhibits both intestinal and hepatic TRL production, whereas this acute inhibitory effect on very-low-density lipoprotein production is blunted in type 2 diabetes. It is not currently known whether this acute effect on chylomicron production is similarly blunted in humans with type 2 diabetes. METHODS AND RESULTS: We investigated the effect of acute hyperinsulinemia on TRL metabolism in 18 type 2 diabetic men using stable isotope methodology. Each subject underwent 1 control (saline infusion [SAL]) lipoprotein turnover study followed by a second study, under 1 of the 3 following clamp conditions: (1) hyperinsulinemic-euglycemic, (2) hyperinsulinemic-hyperglycemic, or (3) hyperinsulinemic-euglycemic plus intralipid and heparin. TRL-apoB-48 and TRL-apoB-100 production and clearance rates were not different between SAL and clamp and between the different clamp conditions, except for significantly lower TRL-apoB-100 clearance and production rates in hyperinsulinemic-euglycemic plus intralipid and heparin clamp compared with SAL. CONCLUSIONS: This is the first demonstration in individuals with type 2 diabetes that chylomicron production is resistant to the normal acute suppressive effect of insulin. This phenomenon may contribute to the highly prevalent dyslipidemia of type 2 diabetes and potentially to atherosclerosis. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00950209.

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.

Effects of baked products enriched with n-3 fatty acids, folates, ß-glucans, and tocopherol in patients with mild mixed hyperlipidemia.

OBJECTIVE: To assess whether a diet containing foods enriched with ß-glucans (3.6 g/d), folic acid (1600 µg/d), long-chain (800 mg/d) and short-chain (400 mg/d) n-3 fatty acids, and tocopherols (120 mg/d) is able to modulate positively the cardiovascular risk profile in people at slightly increased cardiovascular risk. METHODS: Sixteen subjects with mild plasma lipid abnormalities were studied according to a randomized crossover design. After a 2-week run-in period, they followed a diet containing baked products enriched with active nutrients (active diet) or a diet containing the same products but without active nutrients (control diet) for 1 month and then crossed over to the other diet. At the end of each period, a test meal of the same composition as the corresponding diet was administered, and plasma samples were obtained before and for 6 hours after the meal. Hunger and satiety were evaluated by the visual analog scale at fasting and after the meal. RESULTS: Fasting plasma triglycerides were significantly lower after the active versus the control diet (1.56 ± 0.18 vs 1.74 ± 0.16 mmol/l, p < 0.05), as was the postprandial level of chylomicron triglycerides and the insulin peak (p < 0.05). The active diet also reduced fasting homocysteine (8 ± 0.6 vs 10 ± 0.8 µmol/l, p < 0.05) and the feeling of hunger at the fifth and sixth hour (p < 0.05). CONCLUSIONS: Baked functional products enriched with n-3 fatty acids, folates, ß-glucans, and tocopherols within the context of a balanced diet lower fasting and postprandial plasma triglycerides, fasting homocysteinemia, and the postprandial insulin peak. They induce a greater feeling of satiety with possible beneficial implications on energy intake.

Lycopene isomerisation takes place within enterocytes during absorption in human subjects.

Lycopene in fruits and vegetables occurs mostly (80-97 %) in the all-E configuration, whereas a considerable proportion of lycopene in the human body is present as Z-isomers. The Z-isomers offer potentially better health benefits and show improved antioxidant activity in vitro when compared with the all-E-isomer. The absorption of dietary lycopene is a complex process involving transfer of the carotenoid from the food matrix into micelles, uptake by enterocytes, packaging into chylomicrons and finally secretion into plasma. Isomerisation could take place at any of these individual steps. By exploiting in vitro and in vivo models, we traced lycopene isomerisation during absorption using various methods to mimic gastric and duodenal conditions, incorporation into mixed micelles, absorption and metabolism by various Caco-2 cell clones, and performed a postprandial study in human subjects to identify the profile of lycopene isomers in plasma chylomicrons. We demonstrate that all-E-lycopene remains unchanged during its passage in the gastrointestinal tract, including its incorporation into mixed micelles. The key site of lycopene isomerisation is inside the intestinal cells resulting in 29 % of lycopene as Z-isomers. Lycopene isomerisation in the various Caco-2 cell clones is consistent with that observed in human chylomicrons formed in a postprandial state. There is no selection in the release of lycopene isomers from enterocytes. Although there is a huge inter-individual variability of total lycopene absorption reported both in in vitro intestinal cell lines as well as in human chylomicrons, the lycopene isomer profile is quite similar.

Role of plasma lipoproteins in the transport of the soyabean isoflavones daidzein and daidzein-7-O-beta-D-glucoside.

Isoflavone intake is associated with various properties beneficial to human health which are related to their antioxidant activity, for example, to their ability to increase LDL oxidation resistance. However, the distribution of isoflavones among plasma lipoproteins has not yet been elucidated in vivo. Therefore, the objective of the present study was to investigate the association between daidzein (DAI) and lipoproteins in human plasma upon administration of the aglycone and glucoside form. Five men aged 22-30 years participated in a randomised, double-blind study in cross-over design. After ingestion of DAI and daidzein-7-O-beta-D-glucoside (DG) (1 mg DAI aglycone equivalents/kg body weight) blood samples were drawn before isoflavone administration as well as 1, 2, 3, 4.5, 6, 8, 10, 12, 24 and 48 h post-dose. Concentrations of DAI in the different lipoprotein fractions (chylomicrons, VLDL, LDL, HDL) and in the non-lipoprotein fraction were analysed using isotope dilution capillary GC/MS. The lipoprotein fraction profiles were similar for all subjects and resembled those obtained for plasma in our previously published study. The lipoprotein distribution based on the area under the concentration-time profiles from 0 h to infinity in the different fractions were irrespective of the administered form: non-lipoprotein fraction (53%) > LDL (20%) > HDL (14%) > VLDL (9.5%) > chylomicrons (2.5%). Of DAI present in plasma, 47 % was associated to lipoproteins. Concentrations in the different lipoprotein fractions as well as in the non-lipoprotein fraction were always higher after the ingestion of DG than of DAI. Taken together, these results demonstrate an association between isoflavones and plasma lipoproteins in vivo.