Plasma HDL Concentrations Research Articles

A novel role for ABCA1-generated large pre- migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion

In Tangier disease, absence of ATP binding cassette transporter A1 (ABCA1) results in reduced plasma HDL and elevated triglyceride (TG) levels. We hypothesized that hepatocyte ABCA1 regulates VLDL TG secretion through nascent HDL production. Silencing of ABCA1 expression in oleate-stimulated rat hepatoma cells resulted in: 1) decreased large nascent HDL (>10 nm diameter) and increased small nascent HDL (<10 nm) formation, 2) increased large buoyant VLDL1 particle secretion, and 3) decreased phosphatidylinositol-3 (PI3) kinase activation. Nascent HDL-containing conditioned medium from rat hepatoma cells or HEK293 cells transfected with ABCA1 was effective in increasing PI3 kinase activation and reducing VLDL TG secretion in ABCA1-silenced hepatoma cells. Addition of isolated large nascent HDL particles to ABCA1-silenced hepatoma cells inhibited VLDL TG secretion to a greater extent than small nascent HDL. Similarly, addition of recombinant HDL, but not human plasma HDL, was effective in attenuating TG secretion and increasing PI3 kinase activation in ABCA1-silenced cells. Collectively, these data suggest that large nascent HDL particles, assembled by hepatic ABCA1, generate a PI3 kinase-mediated autocrine signal that attenuates VLDL maturation and TG secretion. This pathway may explain the elevated plasma TG concentration that occurs in most Tangier subjects and may also account, in part, for the inverse relationship between plasma HDL and TG concentrations in individuals with compromised ABCA1 function.

Interrelationships Among HDL Metabolism, Aging, and Atherosclerosis

HDL plasma concentrations decline with age in prospective studies. Decline in HDL concentration and function may occur secondary because of hormonal changes, inflammatory processes, and diabetes mellitus. Beyond these effects specific aging processes may be involved. Replicative aging, the telomere-driven loss of divisional capacity, is a species-specific aging mechanism that may decrease HDL concentration and function. Cross-sectionally, by contrast, HDL levels do not change much or even slightly increase with age, suggesting that only people with still high HDL concentrations survive. A selection bias by HDL lowering genetic variation may explain why HDL deficiency is extremely rare among centenarians. Vice versa, HDL may modulate the aging process, not only by its well-known antiatherogenic effects, eg, its ability to remove cellular lipids and by antiatherogenic pleiotropic effects on cell survival, but possibly also by direct interfering with aging signaling or survival factor KLOTHO. Most of the current findings, however, are based on cell culture and selected animal experiments and await further confirmation by appropriate in vivo models.

Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice

High density lipoprotein cholesterol is thought to represent a preferred source of sterols secreted into bile following hepatic uptake by scavenger receptor class B type I (SR-BI). The present study aimed to determine the metabolic effects of an endothelial lipase (EL)-mediated stimulation of HDL cholesterol uptake on liver lipid metabolism and biliary cholesterol secretion in wild-type, SR-BI knockout, and SR-BI overexpressing mice. In each model, injection of an EL expressing adenovirus decreased plasma HDL cholesterol (P < 0.001) whereas hepatic cholesterol content increased (P < 0.05), translating into decreased expression of sterol-regulatory element binding protein 2 (SREBP2) and its target genes HMG-CoA reductase and LDL receptor (each P < 0.01). Biliary cholesterol secretion was dependent on hepatic SR-BI expression, being decreased in SR-BI knockouts (P < 0.001) and increased following hepatic SR-BI overexpression (P < 0.001). However, in each model, biliary secretion of cholesterol, bile acids, and phospholipids as well as fecal bile acid and neutral sterol content, remained unchanged in response to EL overexpression. Importantly, hepatic ABCG5/G8 expression did not correlate with biliary cholesterol secretion rates under these conditions. These results demonstrate that an acute decrease of plasma HDL cholesterol levels by overexpressing EL increases hepatic cholesterol content but leaves biliary sterol secretion unaltered. Instead, biliary cholesterol secretion rates are related to the hepatic expression level of SR-BI. These data stress the importance of SR-BI for biliary cholesterol secretion and might have relevance for concepts of reverse cholesterol transport.

Reduction of HDL levels lowers plasma PLTP and affects its distribution among lipoproteins in mice

Phospholipid transfer protein (PLTP) is associated with HDL particles in plasma, where it transfers phospholipids between lipoproteins and remodels HDL particles. Tangier disease patients, with a mutated ABCA1 transporter, have extremely low plasma HDL concentration and reduced PLTP activity levels, a phenotype that is also observed in mice lacking ABCA1. We investigated whether low HDL levels and low PLTP activity are mechanistically related. Firstly, we studied PLTP expression and distribution among lipoproteins in mice lacking ABCA1 (ABCA1 −/−). Parallel to the strong reduction in PLTP activity in plasma of ABCA1 −/− mice, decreased PLTP protein levels were observed. Neither PLTP synthesis in liver or macrophages nor the ability of the macrophages to secrete PLTP were impaired in ABCA1 −/− mice. However, the PLTP activity level in the medium of cultured macrophages was determined by HDL levels in the medium. PLTP was associated with HDL particles in wild type mice, whereas in ABCA1 −/− mice, PLTP was associated with VLDL and LDL particles. Secondly, we treated different mouse models with varying plasma HDL and PLTP levels (wild type, ABCA1 −/−, apoE −/− and PLTPtg mice, overexpressing human PLTP) with a synthetic LXR ligand, and investigated the relationship between LXR-mediated PLTP induction and HDL levels in plasma. Plasma PLTP activity in wild type mice was induced 5.6-fold after LXR activation, whereas in ABCA1 −/−, apoE −/− and PLTPtg mice, all having reduced HDL levels, induction of PLTP activity was 2.4- , 3.2- and 2.0-fold, respectively. The less pronounced PLTP induction in these mice compared to wild type mice was not caused by a decreased PLTP gene expression in the liver or macrophages. Our findings indicate that the extent of LXR-mediated PLTP induction depends on plasma HDL levels. In conclusion, we demonstrate that ABCA1 deficiency in mice affects plasma PLTP level and distribution through an indirect effect on HDL metabolism. In addition, we show that the extent of LXR-mediated PLTP induction is HDL-dependent. These findings indicate that plasma HDL level is an important regulator of plasma PLTP and might play a role in the stabilization of PLTP in plasma.

Effects of hamburger patties with bamboo leaf (Sasa borealis) extract or sea tangle (Laminaria japonica) powder on plasma glucose and lipid profiles

This study was performed to determine the effects of hamburger patties with water extract of bamboo leaf (Sasa borealis) or powder of dried sea tangle (Laminaria japonica) on plasma glucose and lipid profiles. Three kinds of patties were prepared; one was a control patty (C), S was the patty with 2.5% of the bamboo leaf extract substituted for the meat, and L was the patty with sea tangle substituted for 2.5% of the meat. A total of ten healthy adult women voluntarily participated in the study. Plasma glucose concentrations and lipid profiles were measured at 0, 30, 60, 90, 120, 180, and 240 minutes after consuming each patty. Δ‐AUCs (Change in area under the curve) of plasma glucose concentrations when consuming S or L were significantly lower than that when consuming C. Δ‐AUCs of plasma concentrations of triglyceride and total cholesterol consuming L were significantly less than those when consuming C or S, respectively. However, Δ‐AUCs of plasma concentrations of HDL‐ and LDL‐cholesterol were not significantly different among the three patties. These results indicate that the patties with 2.5% of the meat with water extract of the bamboo leaf or powder of dried sea tangle may improve blood glucose and, in addition, the patty with sea tangle powder may also improve plasma lipid profiles.

The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis

Reverse cholesterol transport (RCT) is a term used to describe the efflux of excess cellular cholesterol from peripheral tissues and its return to the liver for excretion in the bile and ultimately the feces. It is believed to be a critical mechanism by which HDL exert a protective effect on the development of atherosclerosis. In this paradigm, cholesterol is effluxed from arterial macrophages to extracellular HDL-based acceptors through the action of transporters such as ABCA1 and ABCG1. After efflux to HDL, cholesterol may be esterified in the plasma by the enzyme lecithin:cholesterol acyltransferase and is ultimately transported from HDL to the liver, either directly via the scavenger receptor BI or after transfer to apolipoprotein B-containing lipoproteins by the cholesteryl ester transfer protein. Methods for assessing the integrated rate of macrophage RCT in animals have provided insights into the molecular regulation of the process and suggest that the dynamic rate of macrophage RCT is more strongly associated with atherosclerosis than the steady-state plasma concentration of HDL cholesterol. Promotion of macrophage RCT is a potential therapeutic approach to preventing or regressing atherosclerotic vascular disease, but robust measures of RCT in humans will be needed in order to confidently advance RCT-promoting therapies in clinical development.

Long term effects on human plasma lipoproteins of a formulation enriched in butter milk polar lipid

BackgroundSphingolipids (SL), in particular sphingomyelin (SM) are important components of milk fat polar lipids. Dietary SM inhibits cholesterol absorption in rats (Nyberg et al. J Nutr Biochem. 2000) and SLs decrease both cholesterol and TG concentrations in lipid- and cholesterol fed APOE*3Leiden mice (Duivenvoorden et al. Am J Clin Nutr. 2006). This human study examines effects of a butter milk formulation enriched in milk fat globule membrane material, and thereby in SLs, on blood lipids in healthy volunteers. In a four week parallel group study with 33 men and 15 women we examined the effects of an SL-enriched butter milk formulation (A) and an equivalent control formulation (B) on plasma lipid levels. Plasma concentrations of HDL and LDL cholesterol, triacylglycerols (TG), apolipoproteins AI and B, and lipoprotein (a) were measured. The daily dose of SL in A was 975 mg of which 700 mg was SM. The participants registered food and drink intake four days before introducing the test formula and the last four days of the test period.ResultsA daily increase of SL intake did not significantly influence fasting plasma lipids or lipoproteins. In group B TG, cholesterol, LDL, HDL and apolipoprotein B concentrations increased, however, but not in group A after four weeks. The difference in LDL cholesterol was seen primarily in women and difference in TG primarily in men. No significant side effects were observed.ConclusionThe study did not show any significant decrease on plasma lipids or lipoprotein levels of an SL-enriched formulation containing 2-3 times more SL than the normal dietary intake on cholesterol, other plasma lipids or on energy intake. The formulation A may, however, have counteracted the trend towards increased blood lipid concentrations caused by increased energy intake that was seen with the B formulation.

Macrophage cholesterol efflux correlates with lipoprotein subclass distribution and risk of obstructive coronary artery disease in patients undergoing coronary angiography

BackgroundStudies in patients with low HDL have suggested that impaired cellular cholesterol efflux is a heritable phenotype increasing atherosclerosis risk. Less is known about the association of macrophage cholesterol efflux with lipid profiles and CAD risk in normolipidemic subjects. We have therefore measured macrophage cholesterol efflux in142 normolipidemic subjects undergoing coronary angiography.MethodsMonocytes isolated from blood samples of patients scheduled for cardiac catheterization were differentiated into macrophages over seven days. Isotopic cholesterol efflux to exogenously added apolipoprotein A-I and HDL2 was measured. Quantitative cholesterol efflux from macrophages was correlated with lipoprotein subclass distribution in plasma from the same individuals measured by NMR-spectroscopy of lipids and with the extent of coronary artery disease seen on coronary angiography.ResultsMacrophage cholesterol efflux was positively correlated with particle concentration of smaller HDL and LDL particles but not with total plasma concentrations of HDL or LDL-cholesterol. We observed an inverse relationship between macrophage cholesterol efflux and the concntration of larger and triglyceride rich particles (VLDL, chylomicrons). Subjects with significant stenosis on coronary angiography had lower cholesterol efflux from macrophages compared to individuals without significant stenosis (adjusted p = 0.02).ConclusionMacrophage cholesterol efflux is inversely correlated with lipoprotein particle size and risk of CAD.

Aerobic exercise training improves the role of high‐density lipoprotein antioxidant and reduces plasma lipid peroxidation in type 2 diabetes mellitus

In this study, we analyzed the effect of aerobic exercise training (AET) and of a single bout of exercise on plasma oxidative stress and on antioxidant defenses in type 2 diabetes mellitus (DM) and in healthy control subjects (C). DM and C did not differ regarding triglycerides, high-density lipoprotein cholesterol (HDL-c), insulin, and HOMA index at baseline and after AET. To measure the lag time for low-density lipoprotein (LDL) oxidation (LAG) and the maximal rate of conjugated diene formation (MCD), participants' plasma HDL(2) and HDL(3) were incubated with LDL from pooled healthy donors' plasma. In the presence of HDL(3), both LAG and MCD were similar in C and DM, but only in DM did AET improve LAG and reduce MCD. In the presence of HDL(2), the lower baseline LAG in DM equaled C after AET. MCD was unchanged in DM after AET, but was lower than C only after AET. Furthermore, after AET plasma thiobarbituric acid-reactive substances were reduced only in DM subjects. Despite not modifying the total plasma antioxidant status and serum paraoxonase-1 activity in both groups, AET lowered the plasma lipid peroxides, corrected the HDL(2), and improved the HDL(3) antioxidant efficiency in DM independent of the changes in blood glucose, insulin, and plasma HDL concentration and composition.

The Antiatherogenic Function of HDL Is Impaired in Hyperhomocysteinemic Subjects

High plasma homocysteine concentrations have been associated with increased risk of cardiovascular disease, whereas plasma HDL concentration is inversely correlated to such disorders. We hypothesized that hyperhomocysteinemic subjects may have dysfunctional HDL. We therefore investigated the ability of serum from hyperhomocysteinemic male and female subjects (n = 10) and control subjects (n = 10) to induce cholesterol efflux and to inhibit release of inflammatory mediators from human umbilical vein endothelial cell. We found that serum from hyperhomocysteinemic subjects had impaired ability to induce cholesterol efflux from lipid-loaded macrophages compared with healthy controls. HDL from those with markedly raised homocysteine concentrations had a reduced antiinflammatory effect in tumor necrosis factor-α–activated endothelial cells with an attenuated suppressive effect on interleukin-6 growth-related oncogene-α release. Also, the activity of paraoxonase in serum, a multifunctional enzyme with antioxidative effects in relation to the function of HDL, was significantly reduced in hyperhomocysteinemic subjects, in particular those with markedly raised homocysteine concentration. Our findings suggest that hyperhomocysteinemic individuals have dysfunctional HDL particles with attenuated antiatherogenic activity and may represent a novel explanation for the increased risk of cardiovascular events in these individuals.

Interaction between dietary fat intake and the cholesterol ester transfer protein TaqIB polymorphism in relation to HDL-cholesterol concentrations among US diabetic men

Background: A low plasma HDL-cholesterol concentration is a major characteristic of diabetic dyslipidemia. HDL concentrations are determined by both environmental factors and genetic factors. Cholesterol ester transfer protein (CETP) plays an important role in the regulation of HDL metabolism, and the TaqIB polymorphism of the CETP gene has been associated with elevated HDL concentrations.Objective: We examined the association between the CETP TaqIB polymorphism and plasma HDL concentrations and evaluated whether this association was modified by dietary fat intake.Design: We followed 780 diabetic men aged 40–75 y who participated in the Health Professionals Follow-Up Study since its initiation in 1986. The participants had confirmed type 2 diabetes and were free of cardiovascular disease at the time blood was drawn.Results: After adjustment for age, smoking, alcohol consumption, fasting status, hemoglobin A1c, physical activity, total energy intake, and body mass index, HDL concentrations were significantly higher in men with the B2B2 or B1B2 genotype than in those with the B1B1 genotype (adjusted x̄ ± SE: 37.9 ± 0.02, 40.3 ± 0.01, and 42.6 ± 0.02 mg/dL for B1B1, B1B2, and B2B2, respectively; P for trend = 0.0004). This inverse association of the B1 allele with plasma HDL concentrations existed for those with a high consumption of animal fat (P for interaction = 0.02), saturated fat (P for interaction = 0.02), and monounsaturated fat (P for interaction = 0.04).Conclusion: These data confirmed a significant effect of the CETP Taq1 gene on HDL concentrations and suggested a potential interaction between the CETP TaqIB polymorphism and intake of dietary fat on plasma HDL concentration.

Macrophage cholesterol efflux elicited by human total plasma and by HDL subfractions is not affected by different types of dietary fatty acids

Background: Plasma HDL concentrations and composition, important predictors of coronary heart disease, are modified by fatty acids (FAs) in high-fat diets.Objective: Following the National Cholesterol Education Program Adult Treatment Panel III recommendation that 25%–30% of total calorie intake be in the form of fat, we compared the results of the intake of 30% of energy as fat in diets enriched with trans, polyunsaturated, or saturated FAs. These dietary effects on the composition and ability of HDL2, HDL3, and total plasma to efflux cholesterol from mouse peritoneal macrophages that previously were loaded with LDL-acetylated 14C-cholesteryl ester were evaluated by using ultracentrifugally isolated lipoproteins.Design: After a 2-wk run-in period, 30 healthy persons (9 M, 21 F), were randomly distributed among 3 groups (n = 10/group) and fed for 4 wk with either an 8.3% trans FA, a 14.6% polyunsaturated FA, or a 13.2% saturated FA diet. The 3 diets had similar proportions of monounsaturated FAs.Results: The percentage of radioactive cell cholesterol removal did not vary among these diets, possibly because of the small difference in the composition of the HDL fraction elicited by the different diets. However, the percentage was consistently higher for HDL3 than for HDL2.Conclusion: Differences in the cell cholesterol efflux with these diets were not observed, probably because the changes in the HDL composition were quite modest as a result of the limitation of the fat intake to 30% of total calories and because of the rigorous control of the proportions of FAs in the experimental diets used in this investigation.

Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism

In humans, one of the hallmarks of type 2 diabetes is a reduced plasma concentration of HDL and its major protein component, apolipoprotein A-I (APOA-I). However, it is unknown whether APOA-I directly protects against diabetes. The aim of this study was to characterise the functional role of APOA-I in glucose homeostasis. The effects of APOA-I on phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase (ACC), glucose uptake and endocytosis were analysed in C2C12 myocytes. Glucose metabolism was investigated in Apoa-I knockout (Apoa-I (-/-)) mice. APOA-I was able to stimulate the phosphorylation of AMPK and ACC, and elevated glucose uptake in C2C12 myocytes. APOA-I could be endocytosed into C2C12 myotubes through a clathrin-dependent endocytotic process. Inhibition of endocytosis abrogated APOA-I-stimulated AMPK phosphorylation. In Apoa-I (-/-) mice, AMPK phosphorylation was reduced in skeletal muscle and liver, and expression of gluconeogenic enzymes was increased in liver. In addition, the Apoa-I (-/-) mice had increased fat content and compromised glucose tolerance. Our data indicate that APOA-I has a protective effect against diabetes via activation of AMPK. ApoA-I deletion in the mouse led to increased fat mass and impaired glucose tolerance.

Experimental hyperlipidaemia does not prevent preconditioning and it reduces ischemia-induced apoptosis

Background Although ischemic preconditioning (PC) is known to confer cardioprotection in healthy subjects, it is unclear whether this phenomenon exists in the presence of hyperlipidaemia. The goal of this study was to determine whether the cardioprotective effect of PC is affected by hyperlipidaemia in a guinea pig model. Methods We investigated the influence of preconditioning in normo- and hyperlipidaemic animals on papillary muscle contractility and myocardial damage as expressed by the percentage of apoptotic cells. Guinea pigs were fed a normal diet or a hyperlipidaemic diet for 5 weeks. Experiments were performed on papillary muscles subjected to experimental ischemia-reperfusion with or without prior PC. Results The dietary treatment resulted in significant changes in lipid parameters, which had not affected the functionality of the right ventricle papillary muscle, both at basal conditions and in response to ischemia-reperfusion injury. However, it was found that the hyperlipidaemic diet had an effect on ischemia-induced apoptosis. Papillary muscles of hyperlipidaemic animals with higher HDL plasma concentrations were less susceptible to ischemia-reperfusion injury. Conclusions This study demonstrates that hyperlipidaemia does not alter the benefits of ischemic preconditioning such as a reduction of apoptosis and preservation of myocardial contractility. Additionally, it has been shown that plasma HDL may protect cardiomyocytes against ischemia-induced apoptosis.

Thematic review series: Patient-Oriented Research. What have we learned about HDL metabolism from kinetics studies in humans?

Plasma measurements of lipids, lipoproteins, and apolipoproteins provide information on the static levels of these fractions without providing key information on the dynamic fluxes of lipoproteins in the circulation. Kinetics studies, in contrast, provide additional information on the production and clearance rates of lipoproteins and the flow of lipids and apolipoproteins through lipoprotein fractions. This information is crucial in accurately delineating the metabolism of HDL in plasma, because plasma concentrations of HDL are the net result of the de novo production and catabolism of HDL as well as the recycling of HDL particles and the contribution to HDL from components of other lipoproteins. Studies aimed at measuring the metabolism of HDL particles have shown that HDL metabolism in vivo is complex and consists of multiple components. Kinetics studies provide a window into the metabolism of HDL, allowing us to better understand the mechanisms of HDL decrease in human conditions and the functionality of HDL particles. Here, we review the progress in our understanding of HDL metabolism derived from in vivo kinetics studies, focusing primarily on studies in humans but also reviewing key studies in animal models.

Determinants of plasma HDL concentrations and reverse cholesterol transport

One of the major mechanisms whereby HDL particles are felt to protect against atherosclerosis is that of reverse cholesterol transport from atherosclerotic lesion macrophages to the liver, with subsequent excretion of cholesterol in the bile. This review focuses on recent progress in our understanding of reverse cholesterol transport and the factors that determine plasma HDL cholesterol concentrations. The liver and intestine are the major sites of apolipoprotein A-I synthesis and nascent HDL particle secretion. The liver has recently been shown to be a major contributor to the plasma HDL-cholesterol concentration, but the precise site or mechanism whereby hepatically-synthesized HDL acquire the bulk of their lipid content remains to be determined. Contrastingly, macrophages contribute little to the plasma HDL cholesterol pool, whereas the quantitatively small macrophage-specific reverse cholesterol transport contributes disproportionately to protection against atherosclerosis. Studies have highlighted the coordinate action of cell surface lipid transporters, cholesterol esterification enzymes and lipid transfer factors in the early steps of reverse cholesterol transport and the recycling of pre-beta HDL particles to create a ready supply of cholesterol acceptor HDL particles. Most of the variation in plasma HDL-cholesterol levels in human populations is accounted for by variations in HDL clearance rather than production. Our understanding of the in-vivo metabolism of HDL particles and their role in reverse cholesterol transport is rapidly evolving, with long-standing concepts being constantly challenged by emerging evidence. An in-depth understanding of HDL metabolism will guide the rational design of novel pharmacological therapies that effectively protect against atherosclerosis.

Mass kinetics of apolipoprotein A-I in interstitial fluid after administration of intravenous apolipoprotein A-I/lecithin discs in humans

Apolipoprotein kinetics are customarily determined by modeling time curves of specific radioactivity or isotopic enrichment in plasma after intravenous infusion of radiolabeled lipoproteins or stable isotope-enriched amino acids. However, this provides no information on the fractional rate of transfer of the apolipoprotein from plasma to interstitial fluid (k(p-if)) or its mean residence time in interstitial fluid (MRT(if)). To determine these parameters for a pharmacologic dose of exogenous apolipoprotein A-I (apoA-I) given intravenously as apoA-I/lecithin discs, we measured apoA-I in plasma and prenodal leg lymph in five healthy men before, during, and after a 4 h infusion at 10 mg/kg/h. ApoA-I concentrations in plasma and lymph were modeled by linear compartmental models (SAAM II version 1.1), using lymph albumin to adjust for the effects of variations in lymph flow rate. k(p-if) averaged 0.75%/h (range, 0.33-1.32), and MRT(if) averaged 29.1 h (14.1-40.0). Neither parameter was correlated with the distribution volume (57-105 ml/kg) or the fractional elimination rate (1.44-2.91%/h) of apoA-I, determined by modeling plasma apoA-I concentration alone. Although used here to study the mass kinetics of apoA-I, if combined with infusion of a tracer, analysis of lymph could also expand the modeling of endogenous apolipoprotein kinetics.

Regulation of trans fats: The gap, the Polder, and McDonald's French fries

Lowering the intake of trans fatty acids (TFA) probably reduces the incidence of coronary heart disease. Estimates of the reduction vary from 4% based on changes in plasma LDL and HDL concentrations alone, to >20% based on epidemiological associations when TFA intake is lowered by 2% of energy (5 g/day). Even the lowest estimate represents enough cases to justify measures to reduce TFA intake. In The Netherlands, a major reduction in TFA content of retail foods has been achieved in the 1990s through efforts of industry; government intervention has been minimal. Societal pressure is now helping to reduce the TFA content of fast foods. McDonald's French fries in The Netherlands now have less than 4% trans and 24% saturates, as opposed to 21% trans and 21% saturates in the USA. This illustrates the feasibility of reducing TFA in fast foods without increasing saturates. As a result of these developments, dairy and meat have become the major remaining source of TFA in Europe. The question whether these ruminant TFA have the same effect on coronary heart disease risk as industrial TFA has not been settled.

Paraoxonase-1 and serum concentrations of HDL-cholesterol and apoA-I

Paraoxonase-1 (PON1) and HDL are tightly associated in plasma, and this is generally assumed to reflect the need for the enzyme to associate with a hydrophobic complex. The association has been examined in coronary cases and age-matched controls. Highly significant (P < 0.0001), positive associations were observed between PON1 activities and concentrations and HDL-cholesterol and apolipoprotein A-I (apoA-I) concentrations in cases and controls. Corrected slopes were significantly different in cases (cases vs. controls: arylesterase, r = 0.19 vs. 0.38, P < 0.02 for apoA-I and r = 0.15 vs. 0.34, P < 0.02 for HDL-cholesterol) such that if PON1 should influence serum HDL, it would be less effective in coronary cases. When examined as a function of the PON1 gene promoter polymorphism C-107 T, highly significant differences (P < 0.001) in HDL-cholesterol and apoA-I were observed between genotypes for controls, with high expresser alleles having the highest HDL concentrations. This relationship was lost in cases with coronary disease. The coding region polymorphisms Q192R and L55M of the PON1 gene showed no association with HDL. The promoter polymorphism was an independent determinant of HDL concentrations in multivariate analyses. These data are consistent with an impact of PON1 on plasma concentrations of HDL, with detrimental modifications to the relationship in coronary cases.

Association of the T+294C polymorphism in PPAR δ with low HDL cholesterol and coronary heart disease risk in women

The +T294C polymorphism in PPARdelta represents a functional SNP affecting transcriptional activity of the PPARdelta gene. To address whether this polymorphism is associated with the risk for coronary heart disease and/or plasma lipid levels in women, we studied a group of 967 female patients with hyperlipidaemia in the presence (n=453) or absence (n=514) of coronary heart disease. 967 female patients with or without coronary heart disease were genotyped using mutagenically separated polymerase chain reaction (MS-PCR). Statistical analysis was performed according to genotype with parameters of lipid metabolism as dependant variables. A highly significant association between the rare C allele and lower plasma HDL concentrations was found in female subjects. The effect remained significant after correcting for multiparametric testing according to Bonferoni and was seen only in subjects with a BMI below the median. Moreover, a significant association of the C-allele with coronary heart disease and BMI was obtained. Regarding the entire group, trends towards higher VLDL and LDL levels were observed. Our data show for the first time that the PPARdelta +T294C polymorphism is associated with lipid levels and coronary heart disease in women. However, the molecular mechanism of action remains to be elucidated.