Buoyant LDL Particles Research Articles

Dairy foods and cardiometabolic diseases: an update and a reassessment of the impact of SFA.

Type 2 diabetes (T2D) and CVD are major causes of mortality and chronic morbidity. Whilst mortality from CVD has decreased they remain the largest cause of death in Europe and the prevalence of T2D is increasing rapidly. A consistent component of public health advice is to reduce intake of SFA to reduce CVD in particular, which implies limiting dairy food consumption. The prospective studies and randomised controlled trials included in this review show that for dairy foods at least, SFA are not consistently associated with CVD or T2D risk. For CVD the association with dairy foods is generally neutral despite dairy foods being the major source of SFA in many diets. This creates considerable doubt, at least for dairy foods, concerning the validity of the traditional diet-heart hypothesis which positively relates SFA intake to increased serum LDL-cholesterol and subsequent increased CVD. There is now emerging evidence to explain this which is highly relevant to dairy foods. These include the potentially counterbalancing effect of SFA-stimulated HDL-cholesterol and specific food matrix factors. In addition, SFA are associated with the less atherogenic large buoyant LDL particles and possible counterbalancing hypotensive effects of dairy proteins. Overall, dairy foods have either a neutral or beneficial association with CVD and T2D. Beneficial associations are seen for blood pressure and the reduced T2D risk linked to yoghurt consumption, a subject that needs urgent attention given the sharp rise in T2D prevalence in many countries.

Fish Lipids Functionality in Health and Disease

Aim: This literature review discusses the roles of fish lipids in health and disease.
 Duration and Location: It was done between July 2021 and September 2022 by the author at the Department of Food Science and Nutrition, Karatina University, Kenya.
 Results: Adipocyte overabundance can result in cholesterol plaque deposition in arterial walls, which is a risk factor for diabetes, hypertension and cardiovascular diseases (CVD). Cholesterol is required for many cellular processes and its availability in oligodendrocytes may be the limiting factor in brain maturation, myelination and neurotransmission. The ω-3 and 6 fatty acids regulate cholesterol metabolism, blood clotting and control inflammation. They are important for brain activity, structure and function, form nerve cell membranes, and insulate neurons. Eicosapentaenoic acid (EPA), decosahexaenoic acid (DHA) and decosapentaenoic acid (DPA) are associated with reduced risk of CVD, cardiac arrhythmias and sudden cardiac death by reducing small, dense, low-density lipoprotein (sdLDL) particles, which are more atherogenic and hence can shift some sdLDL to larger more buoyant LDL particles that are likely to reduce the risk of CVD. EPA is anti-atherosclerotic, anti-inflammatory, reduces platelet aggregation, increases vasodilation and lowers plasma triglycerides. DHA is necessary for cognitive development and visual function, while DPA reduces platelet aggregation, improves lipid metabolism, reduces endothelial cell migration and improves resolution of chronic inflammation.
 Conclusion: Regular intake of EPA and DHA is important for nursing or pregnant women, as a child needs DHA to form the brain and other parts of the nervous system up to about 2 years of age. While regular intake of the ω-3 FA seems beneficial for brain health and alleviation of major mental-depression, further research is needed to better understand their roles in brain health and in related dystrophies. Also, the roles of DPA vis-a-vis those of EPA and DHA require further investigation.

A Moderate-Fat Diet with One Avocado per Day Increases Plasma Antioxidants and Decreases the Oxidation of Small, Dense LDL in Adults with Overweight and Obesity: A Randomized Controlled Trial

Background:Avocados are a nutrient-dense source of MUFAs and are rich in antioxidants. Avocados have an additional LDL cholesterol (LDL-C) lowering effect beyond that observed when their MUFAs are substituted for SFAs, especially on small, dense LDL (sdLDL) particles, which are susceptible to in vivo oxidation and associated with increased risk of cardiovascular disease (CVD). Objectives:We investigated whether a healthy diet with 1 avocado daily decreased the following secondary outcomes: circulating oxidized LDL (oxLDL) and related oxidative stress markers. Methods:A randomized, crossover, controlled feeding trial was conducted with 45 men and women, aged 21–70 y, with overweight or obesity and elevated LDL-C (25th–90th percentile). Three cholesterol-lowering diets were provided (5 wk each) in random sequences: a lower-fat (LF) diet (24% calories from fat—7% SFAs, 11% MUFAs, 6% PUFAs) and 2 moderate-fat (MF) diets (34% calories from fat—6% SFAs, 17% MUFAs, 9% PUFAs): the avocado (AV) diet included 1 Hass avocado (~136 g) per day, and the MF diet used high oleic acid oils to match the fatty acid profile of 1 avocado. A general linear mixed model was used to analyze the treatment effects. Results:Compared with baseline, the AV diet significantly decreased circulating oxLDL (—7.0 U/L, –8.8%, P = 0.0004)and increased plasma lutein concentration (19.6 nmol/L, 68.7%, P < 0.0001), and both changes differed significantlyfrom that after the MF and LF diets (P ≤ 0.05). The change in oxLDL caused by the AV diet was significantly correlatedwith the changes in the number of sdLDL particles (r = 0.32, P = 0.0002) but not large, buoyant LDL particles. Conclusions:One avocado a day in a heart-healthy diet decreased oxLDL in adults with overweight and obesity, and the effect was associated with the reduction in sdLDL. This trial was registered at http://www.clinicaltrials.gov as NCT01235832.

Effects of Regular Recreational Exercise Training on Serum ANGPTL3-Like Protein and Lipid Profile in Young Healthy Adults.

Evidence of the role of ANGPTL3, a liver-secreted glycoprotein, in serum lipid turnover, led us to hypothesize that this protein may be involved in modification of the lipid profile induced by exercise-training. Given the lack of data regarding this issue, the main goal of the present study was to investigate the effects of regular participation in a recreational physical activity program on serum ANGPTL3 and selected lipid profile measures in young, apparently healthy female and male adults. We compared serum ANGPTL3, lipid profile measures, common lipid ratios, the Atherogenic Index of Plasma (AIP) and glucose in fasting blood samples derived from 22 active physical education students including active females (AF, N=6) and males (AM, N=16) with samples from 28 relatively sedentary age-matched peers, including female (SF, N=9) and male (SM, N=19) individuals not involved in any regular physical conditioning program. Despite high inter-individual variability of serum ANGPTL3, there was a general tendency toward higher serum ANGPTL3 and HDL-C in women compared to men, but without significant differences related to their physical activity status. Based on both routine lipid profile measures and lipid ratios, all participants had normal lipid profiles, normal glycemia, as well as favorable anthropometric indices not suggesting increased cardiometabolic risk. However, lower levels of the TG/HDL-C ratio and AIP in physically active compared to relatively sedentary participants, reflecting the predominance of large, buoyant LDL particles, strongly support the view of beneficial health-promoting effects of regular participation in recreational sport activities.

Salsalate-induced changes in lipid, lipoprotein, and apoprotein concentrations in overweight or obese, insulin-resistant, nondiabetic individuals

Although salsalate administration consistently lowers plasma triglyceride concentrations in patients with type II diabetes, prediabetes, and/or insulin resistance, changes in low-density lipoprotein cholesterol (LDL-C) concentrations have been inconsistent; varying from no change to a significant increase. To evaluate the clinical relevance of this discordance in more detail, we directly measured LDL-C and obtained a comprehensive assessment of changes in lipid, lipoprotein, and apoprotein concentrations associated with salsalate use in insulin-resistant individuals, overweight or obese, but without diabetes, using vertical auto profile method. A single-blind, randomized, placebo-controlled study was performed in volunteers who were overweight or obese, without diabetes, and insulin resistant on the basis of their steady-state plasma glucose concentration during an insulin suppression test. Participants were randomized 2:1 to receive salsalate 3.5 g/d (n = 27) or placebo (n = 14) for 4 weeks. Comprehensive lipid, lipoprotein, and apoprotein analysis by vertical auto profile was obtained after an overnight fast, before and after study intervention. There was no change in directly measured LDL-C concentration in salsalate-treated individuals. However, salsalate administration was associated with various changes considered to decrease atherogenicity; including decreases in triglyceride and total very low-density lipoprotein cholesterol (VLDL-C) concentrations, a shift from small denser LDL lipoproteins toward larger, more buoyant LDL particles, decreases in VLDL(1+2)-C and LDL(4)-C, and nonsignificant decreases in non-high-density lipoprotein cholesterol and apolipoprotein B. No significant changes occurred in the placebo-treated group. Atherogenicity of the lipid, lipoprotein, and apoprotein profile of insulin-resistant individuals who were overweight or obese improved significantly in association with salsalate treatment. The clinical importance of this finding awaits further study.

The effect of rosuvastatin on low-density lipoprotein subfractions in patients with impaired fasting glucose.

Prediabetes substantially increases cardiovascular risk. We examined the effect of rosuvastatin on the quantity and quality of low-density lipoprotein cholesterol (LDL-C) in patients with dyslipidemia having impaired fasting glucose (IFG) compared to normoglycemic patients with dyslipidemia. This was a prospective observational study including patients with dyslipidemia and IFG (IFG group, n = 49) matched with normoglycemic patients with dyslipidemia (control group, n = 64). Study participants, following dietary intervention, were prescribed rosuvastatin 10 or 20 mg/d to achieve LDL-C goals. Baseline as well as 24 weeks posttreatment changes in the serum lipid profile were evaluated. Moreover, analysis of the LDL subfraction profile was conducted using a polyacrylamide tube gel electrophoresis method. Similar effects were observed in lipid profile in both treatment groups. Patients with IFG experienced a greater decrease in the cholesterol concentration of small dense LDL particles (-65.7%, P < .001 vs baseline) compared to controls (-38.5%, P < .001 vs baseline; P = .018 vs patients with IFG). There was no significant difference in the changes of cholesterol concentration of large and buoyant LDL particles in the IFG group when compared to the control group. A greater increase in the mean LDL particle size (+1.5%, P < .001 vs baseline) was noted in the IFG group compared to the control group at 24 weeks (+0.4%, P = .028 vs baseline; P = .008 vs IFG group). Targeting dyslipidemia with rosuvastatin was associated with more favorable changes in the LDL subfraction profile in patients with IFG compared to normoglycemic ones.

Avocado consumption decreases LDL particle number and small, dense LDL cholesterol in overweight and obese subjects (249.8)

We evaluated the effects of a moderate fat diet high in MUFA provided by one avocado per day on lipoprotein particle number and lipoprotein subfractions compared to a moderate fat diet (with equivalent fatty acid content) and a lower fat diet. A randomized 3‐period cross‐over, controlled feeding study was conducted in healthy, overweight and obese men and women (n=45, 21‐70 years, BMI 25‐35 kg/m2) with LDL‐C in the 25‐90th percentile. Following a 2 wk run‐in average American diet (AAD), 3 isocaloric diets (5 wk each) were fed: 1) a lower‐fat diet (LF: 24% fat, 59% CHO, 16% PRO); 2) a moderate fat diet providing one HASS avocado/day (136g) (AV: 34% fat, 49% CHO, 16% PRO); and 3) a moderate fat diet using high oleic acid oil as the main source of MUFA (MF: 34% fat, 49% CHO, 16% PRO). Fasting blood samples were collected after each diet. Lipoprotein subfractions were measured by the vertical auto profile (VAP), lipoprotein particle number was measured directly by proton nuclear magnetic resonance spectroscopy (NMR LipoProfile). Compared to the AAD, only the AV diet significantly decreased LDL particle number (LDL‐P) (‐5.8%, p=0.006). The MF diet did not change LDL‐P significantly (‐2.9%, p=0.2), and there was a trend for an increased LDL‐P on the LF diet (3.8%, p=0.08). We observed similar reductions of cholesterol in large, buoyant LDL particles (LDL1+2). However, only the AV diet significantly reduced cholesterol in small, dense LDL (sdLDL) (LDL3: ‐8.7%, P&lt;0.01; LDL3+4: ‐5.6%, P=0.05) and the sdLDL level after consumption of AV diet was significantly lower than MF diet (p&lt;0.05). The change in LDL‐P by diets was significantly correlated with the change in sdLDL (r=0.58, p&lt;0.001) and apoB (r=0.69, p&lt;0.001) but was not correlated with large, buoyant LDL (r=0.06, p=0.5). In conclusion, incorporation of one avocado/day as part of a healthy, moderate fat diet has beneficial effects beyond its MUFA content on decreasing both LDL‐P and sdLDL in overweight and obese subjects. ClincalTrials.gov Identifier: NCT01235832.

Beyond LDL Cholesterol in Assessing Cardiovascular Risk: apo B or LDL-P?

Plasma concentrations of LDL cholesterol (LDL-C)4 are positively associated with increased risk of atherosclerotic cardiovascular disease. There is a variety of robust evidence indicating that this association is causal in nature. First, rare and common genetic variants that specifically influence LDL-C concentrations are also strongly associated with cardiovascular risk (1). Second, interventions that reduce LDL-C, especially but not exclusively statin therapy, reproducibly reduce cardiovascular events (2). In fact, the data with statins are so strong that they are often used in patients whose LDL-C concentrations are not particularly increased, a setting in which statins have still been shown to reduce cardiovascular risk. Thus there is substantial interest in lipoprotein-related biomarkers that provide information about future cardiovascular risk above and beyond LDL-C itself. LDL contains a core of hydrophobic lipid, mostly cholesteryl ester, a shell of phospholipids, and single molecule of the large protein apolipoprotein B-100 (apo B). It has long been appreciated that LDL particles vary in size and density, which is largely due to variation in the amount of cholesteryl ester in the particle (3). Because the LDL-C measurement is a measure of the amount of cholesterol being carried in LDL, it is not a reliable measure of LDL particle concentration: small, dense LDL particles have much less cholesterol than large, buoyant LDL particles. Interestingly, however, there is evidence that small, dense LDL may be more atherogenic, which has led to the concept that the overall number of LDL particles may be more predictive of cardiovascular risk than the LDL-C concentration itself (3). Several methods have emerged that allow a more direct quantification of the number of LDL particles. Because an LDL particle contains a single molecule of apo B, it is possible to directly estimate the number of particles through a simple measurement of apo B …

Small dense LDL and its Association with Hypertension: a Case-Control Study

Hypertension is one of the most common diseases affecting humans throughout the world. The commonest variety of hypertension is benign essential hypertension. Cardiovascular risk is more in hypertensive patients as their lipid profile is more atherogenic than normotensive subjects. Traditionally, estimation of total serum cholesterol and LDL-C are used as an indicator of atherogenicity. But subjects may develop hypertension and CHD with normal levels of LDL cholesterol. So assessment of LDL cholesterol concentration may not entirely reflect its atherogenic potential. Because LDL-C is not a single entity rather it consists of seven distinct subclasses of different particle size. The size of the LDL particle is inversely correlated to their atherogenicity. Smaller LDL particles are more atherogenic despite their less cholesterol content than the larger more buoyant LDL particles containing more cholesterol. Therefore individuals having smaller LDL particles are more atherogenic and more at risk to develop hypertension inspite of even normal LDL cholesterol concentration. So measurement of small dense LDL particle is more important than any other lipid measure. With this aim 122 subjects were included in this study, among them 82 were diagnosed cases of essential hypertension with the mean age of 42.56±9.98 years and 40 were healthy controls. Serum apo-B was measured in all study subjects. The amount of apoB is almost similar in every LDL subtypes but the amount of cholesterol increases with the increasing particle size. So the ratio of cholesterol to apo-B decreases as the particle size decreases, thus LDL cholesterol / apo-B £ 1 indicates the presence of atherogenic small dense LDL. So the prevalence of small dense LDL was evaluated by calculating the ratio of LDL-C/apo B. The ratio was significantly lower in hypertensive cases (0.093±0.18) compared to controls, indicating presence of sd LDL in hypertensive patients. When the risk ratio was calculated, the patients having small dense LDL in their plasma were found to have 2.87 times more risk for developing CVD then the persons who doesn't have small dense LDL in their plasma. DOI: http://dx.doi.org/10.3329/bjmb.v5i1.13427 Bangladesh J Med Biochem 2012; 5(1): 20-23

Association of Lipoprotein Subfractions and Coronary Artery Calcium In Patient at Intermediate Cardiovascular Risk

More precise estimation of the atherogenic lipid parameters could improve identification of residual risk beyond what is possible using traditional lipid risk factors. The aim of the present study was to explore the association between advanced analysis of lipoprotein subfractions and the prevalence of coronary artery calcium. Consecutive participants at intermediate cardiovascular risk who were undergoing computed tomographic assessment of coronary calcium (calcium score) were included. Using a validated ultracentrifugation method (the vertical autoprofile II test), cholesterol in eluting lipoprotein subfractions [i.e., low- (LDL), very-low-, intermediate-, and high-density lipoprotein subclasses, lipoprotein (a), and predominant LDL distribution] was directly quantified. A total of 410 patients were included (29% women, mean age 57 years), of whom 297 (72.4%) had coronary artery calcium. LDL pattern B (predominance of small dense particles) emerged as an independent predictor of coronary calcium after adjustment for traditional risk factors (odds ratio 4.46, 95% confidence interval 1.19 to 16.7). However, after additional stratification for dyslipidemia, as defined by conventional lipid profiling, a statistically significant prediction was only retained for high-density lipoprotein subfraction 2 (odds ratio 3.45, 95% confidence interval 2.03 to 50.1) and "real" LDL (odds ratio 6.10, 95% confidence interval 1.26 to 23.41) in the normolipidemia group and for lipoprotein (a) (odds ratio 7.81, 95% confidence interval 1.41 to 43.5) in the dyslipidemic group. In conclusion, advanced assessment of the lipoprotein subfractions [i.e., LDL pattern B, high-density lipoprotein subfraction 2, "real" LDL, and lipoprotein (a)] using the vertical autoprofile II test provided additional information to that of conventional risk factors on the prevalence of coronary artery calcium in patients at intermediate cardiovascular risk.

Abstract 8706: Impact of Small Dense Low-Density Lipoproteins Cholesterol on Cardiovascular Disease in an Urban Japanese Cohort: The Suita Study

Aim: Increased plasma low-density lipoprotein cholesterol (LDL-C) concentrations have been shown to be one of the major risk factors for cardiovascular disease (CVD). Clinical evidence also indicates that small dense LDL (sd-LDL) particles are more atherogenic than large buoyant LDL particles. Because there was no easy assay to measure the amount of sd-LDL-C, few studies have addressed the association between sd-LDL-C and CVD. In this study, we hypothesized that higher sd-LDL-C is associated with increased risk for CVD. To this end, we examined the association between sd-LDL-C and CVD in Japanese by using a new kit to measure sd-LDL-C. Methods: We studied 2034 Japanese individuals (30 to 79 years old without stroke or coronary heart disease (CHD)) in the Suita Study, who completed measurement of direct LDL-C and sd-LDL-C by a kit based on the precipitation method with filtration, and then followed for 11.7 years on average. We calculated the Cox proportional adjusted hazard ratios (HRs) of LDL-C, sd-LDL-C, and sd-LDL-C/LDL-C ratio quartiles for incident CAD, stroke, and CVD (CHD + stroke) adjusting for age, sex, body mass index, diabetes, blood pressure category (defined on the basis of the ESH-ESC 2007 criteria), smoking and drinking at baseline. Results: The mean age of this cohort was 59.3 years old and 52.4% was women. The HR of the 4th quartile of sd-LDL-C for the development of CAD was 3.35 (95% confidence intervals: 1.38 to 8.13), which was higher than that in the analysis using LDL-C quartiles. In multivariable adjustment, the HR of the 4th quartile was almost similar. When we used the quartiles of sd-LDL/LDL ratio, increased sd-LDL/LDL ratio was associated with the incidence of CVD, CAD, and stroke. Sex-specific analysis showed that the association of sd-LDL-C with CAD and CVD was statistically significant in men, but not in women. Conclusions: We demonstrated that increased levels of sd-LDL-C are significantly associated with the development of CVD. Our data indicate that sd-LDL-C is a better risk factor for CVD than LDL-C for risk assessment.

Effect of Non-Statin Lipid Lowering and Anti-Obesity Drugs on LDL Subfractions in Patients with Mixed Dyslipidaemia

Small, dense low density lipoprotein (sdLDL) particles are considered an emerging cardiovascular risk factor. Obese patients with mixed dyslipidaemia frequently have elevated sdLDL cholesterol (sdLDL-C) levels. Therefore, agents that favourably modulate the LDL phenotype may be of clinical value in these patients. We review the efficacy of anti-obesity and lipid lowering drugs other than statins on LDL subfractions in patients with mixed dyslipidaemia primarily focusing on those who are overweight/obese. The literature search was based on PubMed listings up to 26 November 2009. In most studies ezetimibe decreases the large and medium LDL subclasses and, to a lesser extent, the sdLDL particles, while it does not substantially influence LDL size. Fibrates and niacin reduce sdLDL particles and shift LDL size towards large, buoyant LDL particles. More studies are needed to elucidate the effects of fish oils and resins on LDL phenotype. Orlistat and rimonabant have been associated with reductions in sdLDL-C levels along with an increase in LDL particle size. We did not find any literature describing the effect of sibutramine on sdLDL profile. Treatment with fibrates and niacin seems to be beneficial in patients with mixed dyslipidaemia. The addition of orlistat may further improve LDL phenotype in overweight/obese patients.

Fenofibrate

Fenofibrate is a fibric acid derivative indicated for use in the treatment of primary hypercholesterolaemia, mixed dyslipidaemia and hypertriglyceridaemia in adults who have not responded to nonpharmacological measures. Its lipid-modifying effects are mediated by activation of peroxisome proliferator-activated receptor-alpha. Fenofibrate also has nonlipid (i.e. pleiotropic) effects (e.g. it reduces fibrinogen, C-reactive protein and uric acid levels and improves flow-mediated dilatation). Fenofibrate improves lipid levels (in particular triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with primary dyslipidaemia. Its lipid-lowering profile means that fenofibrate is particularly well suited for use in atherogenic dyslipidaemia (characterised by high TG levels, low HDL-C levels and small, dense low-density lipoprotein [LDL] particles), which is commonly seen in patients with the metabolic syndrome and type 2 diabetes mellitus. Indeed, fenofibrate improves the components of atherogenic dyslipidaemia in patients with these conditions, including a shift from small, dense LDL particles to larger, more buoyant LDL particles. Greater improvements in lipid levels are seen when fenofibrate is administered in combination with an HMG-CoA reductase inhibitor (statin) or in combination with ezetimibe, compared with monotherapy with these agents. In the DAIS study, fenofibrate significantly slowed the angiographic progression of focal coronary atherosclerosis in patients with type 2 diabetes. In terms of clinical outcomes, although no significant reduction in the risk of coronary events was seen with fenofibrate in the FIELD trial in patients with type 2 diabetes, treatment was associated with a significantly reduced risk of total cardiovascular disease (CVD) events, primarily through the prevention of non-fatal myocardial infarction and coronary revascularisation. Subgroup analyses revealed significant reductions in total CVD events and coronary heart disease events in patients with no previous CVD, suggesting a potential role for primary prevention with fenofibrate in patients with early type 2 diabetes. Improvements were also seen in microvascular outcomes with fenofibrate in the FIELD trial. Fenofibrate is generally well tolerated, both as monotherapy and when administered in combination with a statin. Combination therapy with fenofibrate plus a statin appears to be associated with a low risk of rhabdomyolysis; no cases of rhabdomyolysis were reported in patients receiving such therapy in the FIELD trial. Thus, fenofibrate is a valuable lipid-lowering agent, particularly in patients with atherogenic dyslipidaemia.

Plasma fatty acids and lipoproteins in type 2 diabetic patients

The dyslipidemia of type 2 diabetic patients is characterized by high VLDL, abnormal LDL composition and low HDL cholesterol concentrations. The aim of this study was to establish whether the type of dietary fats affects LDL size and density and HDL cholesterol concentrations in these patients. Plasma phospholipid fatty acid composition, which reflects the type of dietary fatty acids, was quantified by gas chromatography. LDL relative flotation (LDL-Rf), a measure of LDL particle size and density, was determined by single vertical spin density gradient ultracentrifugation in 97 type 2 diabetic patients. By linear regression analysis of the data, plasma fatty acids were associated neither with LDL-cholesterol levels nor with LDL-Rf. The HDL cholesterol concentrations were negatively related with saturated fatty acids (r = -0.23; p = 0.02) but positively related with monounsaturated fatty acids (r = +0.20; p = 0.00). Furthermore, higher HDL concentrations were associated with large and buoyant LDL particles (HDL cholesterol vs LDL-Rf: r = +0.47; p = 0.00). In the multiple regression analysis, the LDL-Rf was significantly related both to triglycerides (beta coefficient = -0.55, p = 0.000) and HDL cholesterol (beta coefficient = 0.19, p = 0.034) concentrations. In a stepwise regression analysis including both triglycerides and HDL cholesterol, triglycerides alone explained the 43.0% of the LDL-Rf variability. A reduction of the dietary saturated fats and an increment of monounsaturated fats might increase HDL cholesterol concentrations in type 2 diabetic patients. Modifications of LDL composition might be expected from interventions aimed to reduce plasma triglycerides.

Dose-dependent action of atorvastatin in type IIB hyperlipidemia: preferential and progressive reduction of atherogenic apoB-containing lipoprotein subclasses (VLDL-2, IDL, small dense LDL) and stimulation of cellular cholesterol efflux

Type IIB hyperlipidemia is associated with premature vascular disease, an atherogenic lipoprotein phenotype characterised by elevated levels of triglyceride-rich VLDL and small dense LDL, together with subnormal levels of HDL. The dose-dependent and independent effects of a potent HMGCoA reductase inhibitor, Atorvastatin, at daily doses of 10 and 40 mg, were evaluated on triglyceride-rich lipoprotein subclasses (VLDL-1, VLDL-2 and IDL), on the major LDL subclasses (light LDL, LDL-1+LDL-2, d: 1.019–1.029 g/ml; intermediate LDL, LDL-3, d: 1.029–1.039 g/ml and small dense LDL, LDL-4+LDL+5, d: 1.039–1.063 g/ml), on CETP-mediated cholesteryl ester transfer from HDL to apoB-containing lipoproteins, on phospholipid transfer protein activity and on plasma-mediated cellular cholesterol efflux in patients ( n=10) displaying type IIB hyperlipidemia. Plasma concentrations of triglyceride-rich lipoprotein subclasses (TRL: VLDL-1, Sf 60–400; VLDL-2, Sf 20–60 and IDL, Sf 12–20) and of LDL ( d: 1.019–1.063 g/ml) were markedly diminished after 6 weeks of statin treatment at 10 mg per day (−31 and −36%, respectively; P<0.002) and by 42 and 51%, respectively at the 40 mg per day dose. Increasing doses of atorvastatin progressively normalised both the quantitative and qualitative features of the LDL subclass profile, in which dense LDL predominated at baseline. Indeed, dense LDL levels were reduced by up to 57% at the 40-mg dose, leading to a shift in the peak of the density profile towards larger, buoyant LDL particles typical of normolipidemic subjects. In addition, marked reduction in numbers of apoB100-containing particle acceptors led to a 30% decrease ( P<0.02) in CETP-mediated CE transfer from HDL. Finally, a significant dose-dependent statin-mediated elevation (+15% at 10 mg; P=0.0003 and +35% at 40 mg; P<0.0001 compared to baseline) in the capacity of plasma from type IIB subjects to mediate free cholesterol efflux from Fu5AH hepatoma cells was observed. Moreover, atorvastatin (40 mg per day) significantly increased plasma apoAI levels (+24%; P<0.05), thereby suggesting that this statin enhances production of apoAI and with it, formation of nascent pre-β HDL particles. Plasma PLTP activity was not affected by either dose of atorvastatin. We conclude that increasing the dose of atorvastatin leads to dose-dependent, preferential and progressive reduction in particle numbers of atherogenic VLDL-2, IDL and dense LDL, and concomitantly, to enhanced cellular cholesterol efflux in type IIB dyslipidemia, thereby diminishing the atherosclerotic burden in subjects characterised by high cardiovascular risk.

In vivo evidence of a role for hepatic lipase in human apoB-containing lipoprotein metabolism, independent of its lipolytic activity

Hepatic lipase (HL) is a key player in lipoprotein metabolism by modulating, through its lipolytic activity, the triglyceride (TG) and phospholipid content of apolipoprotein B (apoB)-containing lipoproteins and of high density lipoproteins (HDL), thereby affecting their size and density. A new and separate role has been suggested for HL in cellular lipoprotein metabolism, in which it serves as a ligand promoting cellular uptake of apoB-containing remnant lipoproteins and HDL. We tested the hypothesis that HL has both a lipolytic and a nonlipolytic role in human lipoprotein metabolism, by measuring lipid plasma concentrations, lipoprotein density distribution by density gradient ultracentrifugation, and lipoprotein composition, in three subjects with HL deficiency: two of the patients (S-1 and S-3) were characterized as having neither plasma HL activity nor detectable HL protein; the third subject (S-2) had no plasma HL activity but a detectable amount (35.5 ng/ml) of HL protein. All HL-deficient subjects showed a severalfold increase in lipoprotein TG content across the lipoprotein density spectrum [very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), and HDL] as compared with control subjects. They also had remarkably more buoyant LDL particles (LDL-R(f) = 0.342;-0.394) as compared with the control subjects (LDL-R(f) = 0.303). Subjects S-1 and S-3 (no HL activity or protein) presented with a distinct increase in cholesterol and apoB levels in the IDL and VLDL density range as compared with patient S-2, with detectable HL protein, and the control subjects. This study provides evidence in humans that HL indeed plays an important role in lipoprotein metabolism independent of its enzymatic activity: in particular, inactive HL protein appears to affect VLDL and IDL particle concentration, whereas HL enzymatic activity seems to influence VLDL-, IDL-, LDL-, and HDL-TG content and their physical properties.

Phospholipase A2 and small, dense low-density lipoprotein.

High levels of small, dense LDL in plasma are associated with increased risk for cardiovascular disease. There are some biochemical characteristics that may render small, dense LDL particles more atherogenic than larger, buoyant LDL particles. First, small, dense LDL particles contain less phospholipids and unesterified cholesterol in their surface monolayer than do large, buoyant LDL particles. This difference in lipid content appears to induce changes in the conformation of apolipoprotein B-100, leading to more exposure of proteoglycan-binding regions. This may be one reason for the high-affinity binding of small, dense LDL to arterial proteoglycans. Reduction of the phospholipid content in the surface monolayer LDL by treatment with secretory phospholipase A2 (sPLA2) forms small, dense LDL with an enhanced tendency to interact with proteoglycans. Circulating levels of sPLA2-IIA appears to be an independent risk factor for coronary artery disease and a predictor of cardiovascular events. In addition, in-vivo studies support the hypothesis that sPLA2 proteins contribute to atherogenesis and its clinical consequences. These data suggest that modification of LDL by sPLA2 in the arterial tissue or in plasma may be a mechanism for the generation of atherogenic lipoprotein particles in vivo, with a high tendency to be entrapped in the arterial extracellular matrix.

Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder with a frequency of 1–2% in the population. In addition to the hypercholesterolemia and/or hypertriglyceridemia that affected individuals exhibit, small, dense LDL particles and decreased HDL-cholesterol levels are traits frequently associated with FCH. Recently, we reported that families with FCH and families enriched for coronary artery disease (CAD) share genetic determinants for the atherogenic lipoprotein phenotype (ALP), a profile presenting with small, dense LDL particles, decreased HDL-cholesterol levels, and increased triglyceride levels. Other studies in normolipidemic populations have shown that the hepatic lipase (HL) gene is linked to HDL-cholesterol levels and that a polymorphism within the HL promoter (−514C→T) is associated with increased HDL-cholesterol levels as well as larger, more buoyant LDL particles. In the present study, we tested whether the HL gene locus also contributes to ALP in a series of Dutch FCH families using nonparametric sibpair linkage analysis and association analysis. Evidence for linkage of LDL particle size (P < 0.019), HDL-cholesterol (P < 0.003), and triglyceride levels (P < 0.026) to the HL gene locus was observed. A genome scan in a subset of these families exhibited evidence for linkage of PPD (LOD = 2.2) and HDL-cholesterol levels (LOD = 1.2) to the HL gene locus as well. The −514C→T promoter polymorphism was significantly associated (P < 0.0001) with higher HDL-cholesterol levels in the unrelated males of this population, but not in unrelated females. No association was observed between the polymorphism and LDL particle size or triglyceride levels. Our results provide support that ALP is a multigenic trait and suggest that the relationship between small, dense LDL particles, HDL-cholesterol, and triglyceride levels in FCH families is due, in part, to common genetic factors. —Allayee, H., K. M. Dominguez, B. E. Aouizerat, R. M. Krauss, J. I. Rotter, J. Lu, R. M. Cantor, T. W. A. de Bruin, and A. J. Lusis. Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial combined hyperlipidemia.

The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity

Four common polymorphisms in the promoter of the hepatic lipase gene (LIPC) that are in almost complete linkage disequilibrium have been described in different ethnic groups. The T and A alleles at positions −514 and −250, respectively, were observed to be associated with decreased hepatic lipase (HL) activity and increased triglyceride content of HDL and LDL particles. We investigated whether these polymorphisms have any effect on transcriptional activity of the proximal promoter (−639 to +29) in transient transfection assays. We found that the promoter with T at position −514 had approximately 30% lower activity than the one with C at the same position (P < 0.0005) regardless of the genotype at position −250. In conclusion, these data indicate that the −514T allele may contribute significantly to decreased HL activity and the resultant increase in plasma levels of triglyceride-rich HDL2 and large buoyant LDL particles. In addition, this promoter variant may explain the finding that its presence attenuates the increase in HL activity with increasing intra-abdominal fat in women. —Deeb, S. S., and R. Peng. The C-514T polymorphism in the human hepatic lipase gene promoter diminishes its activity.

LDL subfractions and coronary heart disease--an overview

Low density lipoproteins are heterogeneous in particle size, density, and physical as well as chemical properties. Regarding size and density, LDL can be divided into two main profiles, LDL pattern A with elevated concentration of large, buoyant LDL particles and LDL pattern B with increased concentration of small, dense LDL particles. The latter is particularly expressed in insulin resistance and is associated with elevated serum triglycerides and reduced concentrations of HDL and particularly HDL2 cholesterol. The LDL profile of increased concentration of small, dense LDL particles has shown to be associated with an increased risk of cardiovascular events. The LDL profile is partly genetically determined, but can be improved by non-pharmacological (exercise, diet) and pharmacological intervention. It remains to be confirmed whether the LDL subfraction profile is an independent lipid risk factor besides HDL2 cholesterol and triglycerides, but it is certainly a valuable indicator assessing metabolic cardiovascular risk.