Plasma High-density Lipoprotein Cholesterol Concentrations Research Articles

Persistence of improvement in insulin sensitivity following a dietary weight loss programme

Short-term dietary weight loss can improve insulin resistance but long-term studies are lacking. We sought to quantify the degree to which maintenance of weight loss after a short-term dietary intervention was associated with persistent metabolic benefits. Fifty-seven insulin-resistant obese subjects had insulin-mediated glucose disposal quantified through the steady-state plasma glucose (SSPG) test, and associated metabolic risk markers quantified at baseline, after a 16-week dietary weight loss intervention, and in 25 subjects, at follow-up of 28.8 +/- 13 months. Changes in metabolic variables over time were analysed and correlation with weight loss ascertained. Those with greatest vs. least long-term SSPG response (responders vs. non-responders) were compared. Multivariate analysis was performed for predictors of persistent SSPG response. At follow-up, the 25 subjects who returned for metabolic testing had, on average, maintained their weight loss. Insulin-mediated glucose disposal remained significantly improved vs. baseline, as did plasma triglyceride and HDL cholesterol (HDL-C) concentrations, and improvement correlated with total amount of weight lost. Comparison of SSPG responders to non-responders showed no difference in amount of weight lost and SSPG change during the 16-week dietary intervention; however, SSPG non-responders regained 2.6% of weight lost, whereas responders lost an additional 1.5% at follow-up (p < 0.05 vs. non-responders). Non-responders had baseline characteristics consistent with more severe insulin resistance, including higher fasting plasma glucose (p = 0.03). Long-term SSPG change was independently predicted by both total weight loss (p = 0.005) and baseline fasting plasma glucose (p = 0.007). Improvement in insulin sensitivity is maintained for 2-3 years following dietary weight loss if weight is not regained. Triglyceride and HDL-C concentrations also remain improved over time, consistent with improvement in insulin sensitivity. Fasting glucose and weight regain predict less long-term response in insulin sensitivity. These results highlight the potential long-term benefits of weight loss and importance of preventing weight regain among high-risk individuals.

Of Mice and Men

IAn increasing body of evidence suggests that disturbed HDL metabolism increases the risk of cardiovascular disease (CVD).1 HDL metabolism is central to reverse cholesterol transport (RCT), in which excess cholesterol from peripheral tissue is returned to the liver for extracorporeal elimination. HDLs also have non-RCT functions including antiinflammatory, antioxidant, and antithrombotic properties. These may relate collectively to the apoA-I content of HDL particles. A number of therapeutic approaches that target HDL metabolism may be useful in preventing and regressing atherosclerosis and coronary disease.2–3 See accompanying article on page 2016 Among lipid-regulators, niacin (nicotinic acid, vitamin B3, pyridine-3-carboxylic acid) is the most effective therapeutic agent presently available for elevating HDL-cholesterol and apoA-I. Notwithstanding issues with tolerability, niacin has long been available for treating atherogenic dyslipidemias. Data from several clinical trials collectively demonstrate that niacin alone or in combination with other agents, including statins, can reduce cardiovascular events and progression of coronary atherosclerosis.4 The precise therapeutic mechanism(s) of action of niacin remains unclear, but may largely involve a favorable regulation of HDL metabolism. But exactly how it mediates this effect has not yet been elucidated. In this issue of Atherosclerosis, Thrombosis and Vascular Biology , van der Hoorn et al present data in a new animal model on the mechanism of the effect of niacin on HDL metabolism.5 First, they demonstrated that niacin increased plasma HDL-cholesterol concentration in the APOE * 3Leiden.CETP ( E3L.CETP ) mouse model (ie, E3L mice crossbred with human CETP-expressing mice) but not in the E3L model alone. Second, in a matched study design they showed in E3L.CETP mice on a Western-type diet that niacin (118 mg/kg/d, 360 mg/kg/d and 1180 mg/kg/d for at least 3 weeks) dose-dependently increased plasma HDL-cholesterol and apoA-I concentrations by several mechanisms involving reductions in plasma VLDL-triglyceride concentrations and in the …

Leukocyte-derived hepatic lipase increases HDL and decreases en face aortic atherosclerosis in LDLr−/− mice expressing CETP

In addition to hepatic expression, cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) are expressed by human macrophages. The combined actions of these proteins have profound effects on HDL structure and function. It is not known how these HDL changes influence atherosclerosis. To elucidate the role of leukocyte-derived HL on atherosclerosis in a background of CETP expression, we studied low density lipoprotein receptor-deficient mice expressing human CETP (CETPtgLDLr -/-) with a leukocyte-derived HL deficiency (HL -/- BM). HL(-/-) bone marrow (BM), CETPtgLDLr(-/-) mice were generated via bone marrow transplantation. Wild-type bone marrow was transplanted into CETPtgLDLr(-/-) mice to generate HL +/+ BM, CETPtgLDLr(-/-) controls. The chimeras were fed a high-fat, high-cholesterol diet for 14 weeks to promote atherosclerosis. In female HL(-/-) BM, CETPtgLDLr(-/-) mice plasma HDL-cholesterol concentration during high-fat feeding was decreased 27% when compared with HL +/+ BM, CETPtgLDLr(-/-) mice (P < 0.05), and this was associated with a 96% increase in en face aortic atherosclerosis (P < 0.05). In male CETPtgLDLr(-/-) mice, leukocyte-derived HL deficiency was associated with a 16% decrease in plasma HDL-cholesterol concentration and a 25% increase in aortic atherosclerosis. Thus, leukocyte-derived HL in CETPtgLDLr(-/-) mice has an atheroprotective role that may involve increased HDL levels.

Effect of obesity on the plasma lipoprotein subclass profile in normoglycemic and normolipidemic men and women.

To determine the effect of obesity without the confounding effect of metabolic complications on the lipoprotein subclass profile in men and women. Cross-sectional study. A total of 40 lean (body mass index (BMI): 18.5-25 kg/m(2)) and 40 obese (BMI: 30-45 kg/m(2)) subjects, with blood pressure <140/90 mm Hg, fasting plasma glucose concentration <100 mg per 100 ml and total triglyceride concentration <150 mg per 100 ml; all obese subjects had normal oral glucose tolerance. Fasting concentrations of very low-, intermediate-, low- and high-density lipoproteins (VLDL, IDL, LDL, and HDL, respectively) and average VLDL, LDL and HDL particle sizes were evaluated by using proton nuclear magnetic resonance spectroscopy. Obese compared with lean individuals of both sexes had increased plasma concentrations of VLDL (by approximately 50%), IDL (by approximately 100%), LDL (by approximately 50%), and to some extent HDL (by approximately 10%) particles (P<0.05). The contribution of large VLDL to total VLDL concentration, small LDL to total LDL concentration, and small HDL to total HDL concentration was greater in obese than lean subjects (P<0.05), resulting in larger average VLDL size but smaller average LDL and HDL sizes (P<0.05). Women, compared with men, had reduced concentrations of total VLDL particles (by approximately 10%) due to lower concentrations of large and medium VLDL and a shift toward large at the expense of small HDL particles (P<0.05), with no difference in total HDL particle concentration. IDL and total LDL concentrations and LDL subclass distribution were not different between men and women. Obesity is associated with pro-atherogenic alterations in the lipoprotein subclass profile, which may increase cardiovascular disease risk even in the absence of classical metabolic risk factors. On the other hand, the female cardiovascular disease risk advantage is probably largely related to differences in traditional lipid risk factors (plasma triglyceride and HDL-cholesterol concentrations) because sex differences in the plasma lipoprotein subclass profile are minimal.

Low HDL cholesterol levels in type I Gaucher disease do not lead to an increased risk of cardiovascular disease

Objective A low plasma high-density lipoprotein cholesterol (HDL-c) concentration is an important risk factor for the development of atherosclerotic cardiovascular disease. HDL-c levels are abnormally low in type I Gaucher disease (GD) patients. The aim of this study was to determine whether GD is associated with premature atherosclerosis. Methods Lipid profiles, apolipoproteins, and carotid artery intima-media thickness (cIMT) were analyzed in 40 type I GD patients, 34 carriers and 41 control subjects. cIMT is a non-invasive validated biomarker for the status of atherosclerosis and present and future cardiovascular disease risk. Results Compared to control subjects, patients showed decreased HDL-c (1.1 ± 0.3 mmol/L) as well as mildly decreased low-density lipoprotein cholesterol (LDL-c) levels (2.8 ± 0.7 mmol/L), with an increased ApoB/ApoA1 ratio. In carriers, HDL-c levels were normal, but LDL-c levels were decreased (2.7 ± 0.8 mmol/L). Mean cIMT measurements were not different in the three study groups (patients: 0.63 ± 0.1 mm versus carriers: 0.64 ± 0.1 mm versus control subjects: 0.65 ± 0.1 mm). Conclusion In Gaucher disease low HDL-c levels do not lead to premature atherosclerosis as assessed by cIMT measurement. This indicates that the inverse relationship between levels of HDL-c and risk of cardiovascular disease in the general population may not be present in all conditions characterised by low HDL-c levels.

Adiponectin prevents atherosclerosis by increasing cholesterol efflux from macrophages

Plasma high density lipoprotein (HDL)-cholesterol levels are inversely correlated to the risk of atherosclerotic cardiovascular diseases. Reverse cholesterol transport (RCT) is one of the major protective systems against atherosclerosis, in which HDL particles play a crucial role to carry cholesterol derived from peripheral tissues to the liver. Recently, ATP-binding cassette transporters (ABCA1, ABCG1) and scavenger receptor (SR-BI) have been identified as important membrane receptors to generate HDL by removing cholesterol from foam cells. Adiponectin (APN) secreted from adipocytes is one of the important molecules to inhibit the development of atherosclerosis. Epidemiological studies have revealed a positive correlation between plasma HDL-cholesterol and APN concentrations in humans, although its mechanism has not been clarified. Therefore, in the present study, we investigated the role of APN on RCT, in particular, cellular cholesterol efflux from human monocyte-derived and APN-knockout (APN-KO) mice macrophages. APN up-regulated the expression of ABCA1 in human macrophages, respectively. ApoA-1-mediated cholesterol efflux from macrophages was also increased by APN treatment. Furthermore, the mRNA expression of LXRα and PPARγ was increased by APN. In APN-KO mice, the expression of ABCA1, LXRα, PPARγ, and apoA-I-mediated cholesterol efflux was decreased compared with wild-type mice. In summary, APN might protect against atherosclerosis by increasing apoA-I-mediated cholesterol efflux from macrophages through ABCA1-dependent pathway by the activation of LXRα and PPARγ.

Nonalcoholic fatty liver disease is associated with hepatic and skeletal muscle insulin resistance in overweight adolescents

BackgroundNonalcoholic fatty liver disease (NAFLD) and insulin resistance are common in overweight adolescents. ObjectiveThe purpose of this study was to determine the relation between NAFLD and insulin sensitivity in liver and skeletal muscle by studying overweight adolescents with a normal or high intrahepatic triglyceride (IHTG) content, who were matched for age, sex, body mass index (BMI; in kg/m2), and Tanner stage. DesignStable-isotope-labeled tracer infusion and the hyperinsulinemic-euglycemic clamp procedure were used to assess skeletal muscle and hepatic insulin sensitivity, and magnetic resonance spectroscopy was used to assess the IHTG content in 10 overweight (BMI = 35.9 ± 1.3) adolescents with NAFLD (IHTG = 28.4 ± 3.4%) and 10 overweight (BMI = 36.6 ± 1.5) adolescents with a normal IHTG content (3.3 ± 0.5%). ResultsThe baseline plasma glucose concentration and the rate of appearance of glucose in plasma were the same in subjects with a normal (87.1 ± 1.2 mg/dL, 16.2 ± 1.1 μmol · kg fat-free mass−1 · min−1) or high (89.2 ± 2.5 mg/dL, 16.3 ± 1.2 μmol · kg fat-free mass−1 · min−1) IHTG content. However, compared with subjects who had a normal IHTG content, subjects with NAFLD had a lower hepatic insulin sensitivity index, based on baseline glucose kinetics and insulin concentrations (4.0 ± 0.5 compared with 2.4 ± 0.4; P < 0.05) and an impaired increase in glucose uptake during insulin infusion (169 ± 28.1% compared with 67 ± 9.6% above baseline; P < 0.01). In addition, the plasma triglyceride concentration was greater and the plasma HDL-cholesterol concentration was lower in subjects with NAFLD than in those with a normal IHTG content. ConclusionAn elevated IHTG content in overweight adolescents is associated with dyslipidemia and with insulin-resistant glucose metabolism in both liver and skeletal muscle.

HDL: Close to Our Memories?

The last decade has witnessed an explosion in studies of the role of lipoproteins in brain function. Neurons require a continuous supply of lipids for membrane synthesis and acetylcholine production. Indeed, the brain is a site of intense lipid turnover—even though the central nervous system (CNS) accounts for only 2.1% of body weight, it contains 23% of total body cholesterol.1 Lipid metabolism in the brain is tightly controlled locally, as plasma lipoproteins are shielded from the brain by the blood-brain barrier. Although neuronal cells are capable of de novo synthesis of a wide spectrum of molecular species of lipids, they rely heavily on exogenous sources and readily bind and internalize lipoproteins of the extracellular fluid.2 Equally, neurons need to dispose of excess lipids; lipoprotein-mediated lipid transport is therefore bidirectional and includes cellular efflux of cholesterol.3 See accompanying article on page 1556 Human cerebrospinal fluid (CSF) primarily contains spherical lipoproteins of approximately 10 to 12 nm in diameter with hydrated density in the range 1.063 to 1.25 g/mL, thereby resembling HDL in human plasma.3,4⇓ Lipid concentrations in CSF are however much lower (eg, 300- to 400-fold for total cholesterol and phospholipids) as compared to the plasma compartment.4 Apolipoproteins (apo) E and A-I are the major apolipoproteins in human CSF (typical concentration range: 0.1 to 0.4 mg/dL3,4⇓), with apoA-II, A-IV, J, D, C-II, C-III, C-IV, and H equally present.3,4⇓ Importantly, CSF lipoproteins carry amyloid-β (Aβ), a 39- to 43-aa peptide produced in neuronal cells, which is the major component of senile amyloid plaques.5 The metabolism of CSF lipoproteins remains poorly characterized but seems to be distinct from that of plasma lipoproteins. ApoE-rich HDL are synthesized locally in CNS and secreted by astrocytes as discoidal complexes enriched in free cholesterol.6 High …

Cholesteryl Ester Enrichment of Plasma Low-Density Lipoproteins in Hamsters Fed Cereal-Based Diets Containing Cholesterol

Abstract. Male Syrian hamsters were fed 0.02, 0.03, or 0.05% cholesterol to test the hypothesis that moderate cholesterol intake increases the cholesteryl ester content of the plasma low-density lipoproteins (LDL). Dietary cholesterol levels of 0.02%–0.05% were chosen to reflect typical human intakes of cholesterol. Hamsters were fed ad libitum a cereal-based diet (modified NIH-07 open formula) for 15 weeks. Increasing dietary cholesterol from 0.02% to 0.05% resulted in significantly increased plasma LDL and high-density lipoprotein cholesterol concentration, increased liver cholesterol concentration, and increased total aorta cholesterol content. The cholesteryl ester content of plasma LDL was determined as the molar ratio of cholesteryl ester to apolipoprotein B and to surface lipid (i.e., phospholipid + free cholesterol). Increasing dietary cholesterol from 0.02% to 0.05% resulted in significantly increased cholesteryl ester content of LDL particles. Furthermore, cholesteryl ester content of LDL was directly associated with increased total aorta cholesterol, whereas a linear relationship between plasma LDL cholesterol concentration and aorta cholesterol was not observed. Thus, the data suggest that LDL cholesteryl ester content may be an important atherogenic feature of plasma LDL.

Cathepsin S genotypes are associated with Apo‐A1 and HDL‐cholesterol in lean and obese French populations

Cathepsin S (CTSS) is a cysteine protease that has a central role in remodeling the extracellular matrix and, as such, has been implicated in the etiology of cardiovascular disease. This study used five tag single nucleotide polymorphisms (tSNPs) to screen the CTSS gene in healthy lean (n = 1891) and obese French populations (n = 477) for their association with various phenotypes: body mass index, waist-to-hip ratio, glycemia, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo-A1) and apolipoprotein B. Significant associations were identified between rs11576175 tSNP (A/G) and Apo-A1 and HDL-C plasma levels in a sex-specific manner. Lean female subjects homozygous for the minor A-allele had higher levels of circulating Apo-A1 (p = 0.0003), while lean male A/A carriers had higher levels of HDL-C (p = 0.007) compared with the other genotypes. In the obese cohort, associations were found between three tSNPs and Apo-A1 levels in adult female subjects: rs10888390 (G/A), p = 0.01; rs10888394 (T/C), p = 0.03; and rs1136774 (C/T), p = 0.02; however, only rs10888390 remained significant in a combined model (p = 0.03). These results provide the first evidence that CTSS sequence variations are associated with two human metabolic risk factors for cardiovascular diseases: plasma Apo-A1 and HDL-C concentrations.

Blood concentrations of individual long-chain n–3 fatty acids and risk of nonfatal myocardial infarction

BackgroundWhereas dietary intake of long-chain n−3 fatty acids has been associated with risk of nonfatal myocardial infarction (MI), few studies have examined the relation for blood concentrations. ObjectiveWe aimed to investigate the effect of long-chain n−3 fatty acids in blood on the risk of nonfatal MI. DesignBaseline blood samples were collected from 32 826 participants of the Nurses' Health Study in 1989–1990, among whom 146 incident cases of nonfatal MI were ascertained during 6 y of follow-up and matched with 288 controls. ResultsAfter multivariate adjustment, the relative risks (95% CI) comparing the highest with the lowest quartiles in plasma were 0.23 (0.09, 0.55; P for trend = 0.001) for eicosapentaenoic acid (EPA), 0.40 (0.20, 0.82; P for trend = 0.004) for docosapentaenoic acid (DPA), and 0.46 (0.18, 1.16; P for trend = 0.07) for docosahexaenoic acid (DHA). The associations for these fatty acids in erythrocytes were generally weaker and nonsignificant. In contrast to EPA and DHA, blood concentrations of DPA were not correlated with dietary consumption of n−3 fatty acids. Higher plasma concentrations of EPA, DPA, and DHA were associated with higher plasma concentrations of HDL cholesterol and lower concentrations of triacylglycerol and inflammatory markers. ConclusionsHigher plasma concentrations of EPA and DPA are associated with a lower risk of nonfatal MI among women. These findings may partly reflect dietary consumption but, particularly for DPA, may indicate important risk differences based on metabolism of long-chain n−3 fatty acids.

Polymorphisms in the CD36 gene modulate the ability of fish oil supplements to lower fasting plasma triacyl glycerol and raise HDL cholesterol concentrations in healthy middle-aged men

Five SNPs in the CD36 gene, 25444G>A, 27645del>ins, 30294G>C, −31118G>A and −33137A>G in haplotypic combinations, link to fasting plasma NEFA concentrations. Fish oil lowers TAG concentrations. The influence of CD36 SNPs on hypotriglyceridemic effects is unknown. The study examines how four of the SNPs modify the effects of fish oil on fasting plasma TAG, NEFA, glucose LDL and HDL cholesterol concentrations in 111 healthy, middle-aged, Caucasian men. Subjects consumed habitual diets while taking 6 g MaxEPA daily for 12 weeks. TAG decreased from 1.48 mol/l to 0.11 mmol/l, and glucose and HDL rose from 5.92 to 0.15 mmol/l and from 1.27 to 0.04 mmol/l, respectively, irrespective of genotype. NEFA was unaffected. Significant falls in TAG only occurred in individuals with the GG variant of the 25444, 30294, −31118 or −33137 SNPs. The TAG-lowering effects may be via stimulation of CD36 activity in extrahepatic tissue in individuals with the GG variants of these SNPs.

Laboratory Assessment of HDL Heterogeneity and Function

Plasma concentrations of HDL cholesterol (HDL-C) and its major protein component apolipoprotein (apo) A-I are strongly inversely associated with cardiovascular risk, leading to the concept that therapy to increase HDL-C and apoA-I concentrations would be antiatherosclerotic and protective against cardiovascular events. The recent failure of the drug torcetrapib, a cholesteryl ester transfer protein inhibitor that substantially increased HDL-C concentrations, has brought focus on the issues of HDL heterogeneity and function as distinct from HDL-C concentrations. This review addresses the current state of knowledge regarding assays of HDL heterogeneity and function and their relationship to cardiovascular disease. HDL is highly heterogeneous, with subfractions that can be identified on the basis of density, size, charge, and protein composition, and the concept that certain subfractions of HDL may be better predictors of cardiovascular risk is attractive. In addition, HDL has been shown to have a variety of functions that may contribute to its cardiovascular protective effects, including promotion of macrophage cholesterol efflux and reverse cholesterol transport and antiinflammatory and nitric oxide-promoting effects. Robust laboratory assays of HDL subfractions and functions and validation of the usefulness of these assays for predicting cardiovascular risk and assessing response to therapeutic interventions are critically important and of great interest to cardiovascular clinicians and investigators and clinical chemists.

HDL Atheroprotection by Aerobic Exercise Training in Type 2 Diabetes Mellitus

In this study we analyzed the role played by aerobic exercise training in the plasma lipoprotein profile, prebeta 1-HDL concentration, and in the in vitro HDL3 ability to remove cholesterol from macrophages and inhibit LDL oxidation in type 2 diabetes mellitus (DM) patients and control subjects, in the fasting and postprandial states. Healthy controls (HTC, N = 11; 1 M/10 F) and subjects with type 2 diabetes mellitus (DMT, N = 11; 3M/8F) were engaged in a 4-month aerobic training program, and compared with a group of sedentary subjects with type 2 diabetes mellitus (DMS, N = 10; 4 M/6 F). All groups were submitted to an oral fat load test to analyze all parameters, both at the beginning of the investigation protocol (basal) and at the end of the study period (final). Exercising did not modify body weight, BMI, plasma concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides (TG), glucose, insulin, or HOMA-IR, but it reduced the waist circumference. The HDL3 composition did not change, and its ability to remove cell cholesterol was unaltered by aerobic training. In DMT but not in HTC, aerobic training improved 15% the HDL3 protective effect against LDL maximal oxidation rate in the fasting state, and reduced 24% the plasma prebeta 1-HDL concentration in the postprandial state, suggesting an enhanced prebeta 1-HDL conversion into larger, more mature HDL particles. In this regard, regular aerobic exercise enriched HDL2 with TG in the fasting and postprandial states in HTC and in the fasting phase in DMT. Our results show that aerobic exercise training in diabetes mellitus improves the HDL efficiency against LDL oxidation and favors HDL maturation. These findings were independent of changes in insulin resistance and of the rise of plasma HDL cholesterol concentration.

Study of the effect of trans fatty acids from ruminants on blood lipids and other risk factors for cardiovascular disease

Background: The intake of trans fatty acids (TFA) from industrially hydrogenated vegetable oils (iTFA) is known to have a deleterious effect on cardiovascular health, the effects of TFA from ruminants (rTFA) are virtually unknown.Objective: The purpose of the present study was to compare the effects of rTFA and iTFA on plasma LDL concentrations and other cardiovascular disease risk factors in healthy subjects.Design: In a double-blind, randomized crossover controlled study, 38 healthy men were fed each of 4 experimental isoenergetic diets lasting 4 wk each. The 4 diets were high in rTFA (10.2 g/2500 kcal), moderate in rTFA (4.2 g/2500 kcal), high in iTFA (10.2 g/2500 kcal), and low in TFA from any source (2.2 g/2500 kcal) (control diet).Results: Plasma LDL-cholesterol concentrations were significantly higher after the high- rTFA diet than after the control (P = 0.03) or the moderate- rTFA (P = 0.002) diet. Plasma LDL-cholesterol concentrations also were significantly (P = 0.02) higher after the iTFA diet than after the moderate-rTFA diet. Plasma HDL-cholesterol concentrations were significantly (P = 0.02) lower after the high-rTFA diet than after the moderate-rTFA diet. Finally, all risk factors were comparable between the control and the moderate-rTFA diets.Conclusions: These results suggest that, whereas a high dietary intake of TFA from ruminants may adversely affect cholesterol homeostasis, moderate intakes of rTFA that are well above the upper limit of current human consumption have neutral effects on plasma lipids and other cardiovascular disease risk factors.

An apolipoprotein A-I mimetic dose-dependently increases the formation of preβ1 HDL in human plasma

Prebeta1 HDL is the initial plasma acceptor of cell-derived cholesterol in reverse cholesterol transport. Recently, small amphipathic peptides composed of D-amino acids have been shown to mimic apolipoprotein A-I (apoA-I) as a precursor for HDL formation. ApoA-I mimetic peptides have been proposed to stimulate the formation of prebeta1 HDL and increase reverse cholesterol transport in apoE-null mice. The existence of a monoclonal antibody (MAb 55201) and a corresponding ELISA method that is selective for the detection of the prebeta(1) subclass of HDL provides a means of establishing a correlation between apoA-I mimetic dose and prebeta1 HDL formation in human plasma. Using this prebeta1 HDL ELISA, we demonstrate marked apoA-I mimetic dose-dependent prebeta1 HDL formation in human plasma. These results correlated with increases in band density of the plasma prebeta1 HDL, when observed by Western blotting, as a function of increased apoA-I mimetic concentration. Increased prebeta1 HDL formation was observed after as little as 1 min and was maximal within 1 h. Together, these data suggest that a high-throughput prebeta1 HDL ELISA provides a way to quantitatively measure a key component of the reverse cholesterol transport pathway in human plasma, thus providing a possible method for the identification of apoA-I mimetic molecules.

Nicotinic acid: an old drug with a promising future

Nicotinic acid has been used for decades to treat dyslipidaemic states. In particular its ability to raise the plasma HDL cholesterol concentration has led to an increased interest in its pharmacological potential. The clinical use of nicotinic acid is somewhat limited due to several harmless but unpleasant side effects, most notably a cutaneous flushing phenomenon. With the recent discovery of a nicotinic acid receptor, it has become possible to better understand the mechanisms underlying the metabolic and vascular effects of nicotinic acid. Based on these new insights into the action of nicotinic acid, novel strategies are currently under development to maximize the pharmacological potential of this drug. The generation of both flush-reducing co-medications of nicotinic acid and novel drugs targeting the nicotinic acid receptor will provide future therapeutic options for the treatment of dyslipidaemic disorders.

Dietary Cholesterol from Eggs Increases Plasma HDL Cholesterol in Overweight Men Consuming a Carbohydrate-Restricted Diet ,2

Carbohydrate-restricted diets (CRD) significantly decrease body weight and independently improve plasma triglycerides (TG) and HDL cholesterol (HDL-C). Increasing intake of dietary cholesterol from eggs in the context of a low-fat diet maintains the LDL cholesterol (LDL-C)/HDL-C for both hyper- and hypo-responders to dietary cholesterol. In this study, 28 overweight/obese male subjects (BMI = 25–37 kg/m2) aged 40–70 y were recruited to evaluate the contribution of dietary cholesterol from eggs in a CRD. Subjects were counseled to consume a CRD (10–15% energy from carbohydrate) and they were randomly allocated to the EGG group [intake of 3 eggs per day (640 mg/d additional dietary cholesterol)] or SUB group [equivalent amount of egg substitute (0 dietary cholesterol) per day]. Energy intake decreased in both groups from 10,243 ± 4040 to 7968 ± 2401 kJ (P < 0.05) compared with baseline. All subjects irrespective of their assigned group had reduced body weight and waist circumference (P < 0.0001). Similarly, the plasma TG concentration was reduced from 1.34 ± 0.66 to 0.83 ± 0.30 mmol/L after 12 wk (P < 0.001) in all subjects. The plasma LDL-C concentration, as well as the LDL-C:HDL-C ratio, did not change during the intervention. In contrast, plasma HDL-C concentration increased in the EGG group from 1.23 ± 0.39 to 1.47 ± 0.38 mmol/L (P < 0.01), whereas HDL-C did not change in the SUB group. Plasma glucose concentrations in fasting subjects did not change. Eighteen subjects were classified as having the metabolic syndrome (MetS) at the beginning of the study, whereas 3 subjects had that classification at the end. These results suggest that including eggs in a CRD results in increased HDL-C while decreasing the risk factors associated with MetS.

Association between liver X receptor α gene polymorphisms and risk of metabolic syndrome in French populations

The metabolic syndrome is a complex and multifactorial disorder often associated with type 2 diabetes mellitus and cardiovascular diseases. The liver X receptor alpha (NR1H3) plays numerous roles in metabolic pathways involved in metabolic syndrome. In the search for susceptibility genes to metabolic syndrome, we hypothesized that common genetic variation in NR1H3 gene influences metabolic syndrome susceptibility. Two large French population-based studies (n=1130 and 1160) including overall 664 individuals with and 1626 individuals without metabolic syndrome were genotyped for three polymorphisms (rs12221497, rs11039155 and rs2279239) of NR1H3. We found that the -6A allele of rs11039155 was consistently associated with a 30% reduction in risk of metabolic syndrome in the two independent population samples (adjusted OR (95% CI)=0.68 (0.53-0.86), P=0.001 for the combined sample). Moreover, it was associated with an increase in plasma HDL-cholesterol concentrations (P=0.02 for the combined sample). Neither rs12221497 nor rs11039155, both polymorphisms located in the 5' region of NR1H3, had significant influence on NR1H3 and ATP-binding cassette transporter A1 (ABCA1) gene expression in primary human macrophages. These results suggest that NR1H3 plays an important role in the HDL-cholesterol metabolism and in the genetic susceptibility to metabolic syndrome.

Evaluation au laboratoire de l’hétérogénéité et des fonctions des HDL (version française)

Plasma concentrations of HDL cholesterol (HDL-C) and its major protein component apolipoprotein (Apo) A-I are strongly inversely associated with cardiovascular risk, leading to the concept that therapy to increase HDL-C and ApoA-I concentrations would be antiatherosclerotic and protective against cardiovascular events. The recent failure of the drug torcetrapib, a cholesteryl ester transfer protein inhibitor that substantially increased HDL-C concentrations, has brought focus on the issues of HDL heterogeneity and function as distinct from HDL-C concentrations. This review addresses the current state of knowledge regarding assays of HDL heterogeneity and function and their relationship to cardiovascular disease. HDL is highly heterogeneous, with subfractions that can be identified on the basis of density, size, charge, and protein composition, and the concept that certain subfractions of HDL may be better predictors of cardiovascular risk is attractive. In addition, HDL has been shown to have a variety of functions that may contribute to its cardiovascular protective effects, including promotion of macrophage cholesterol efflux and reverse cholesterol transport and antiinflammatory and nitric oxide-promoting effects. Robust laboratory assays of HDL subfractions and functions and validation of the usefulness of these assays for predicting cardiovascular risk and assessing response to therapeutic interventions are critically important and of great interest to cardiovascular clinicians and investigators and clinical chemists.