Hypertriglyceridemic States Research Articles

Increased serum amiodarone concentration in hypertriglyceridemic patients: Effects of drug distribution to serum lipoproteins.

Amiodarone and its main metabolite, desethylamiodarone (DEA), are highly distributed to serum lipoproteins such as very‐low‐density lipoprotein (VLDL) and low‐density lipoprotein (LDL), which are the carriers of triglyceride and cholesterol. This study aimed to investigate the association of serum concentrations of amiodarone and DEA with the levels of serum lipids in terms of drug distribution to lipoprotein fractions in patients with hyperlipidemia. Total serum concentrations of amiodarone and DEA were examined in 116 patients receiving amiodarone for tachyarrhythmias. The concentration‐to‐dose (C/D) ratio of amiodarone positively correlated with the level of serum triglyceride (rs = 0.541, p < 0.001) and was higher in the hypertriglyceridemic state than in normotriglyceridemic state (479 ± 211 vs. 320 ± 161, p < 0.001). No correlation was found between the C/D ratio of DEA and serum triglyceride levels (rs = 0.272), although higher values were observed in the hypertriglyceridemic state (322 ± 125 vs. 285 ± 143, p < 0.001). In the hypertriglyceridemic state, the distribution of amiodarone increased in LDL/VLDL fraction and decreased in high‐density lipoprotein and albumin fractions. The ratio of serum amiodarone to serum DEA, a metabolic ratio of amiodarone, positively correlated with serum triglyceride levels (rs = 0.572, p < 0.001) and was higher in the hypertriglyceridemic state, suggesting that amiodarone metabolism decreased in hyperlipidemia. The results of this study reveal that serum concentrations of amiodarone increase in the hypertriglyceridemic state through the increased lipoprotein‐binding and decreased metabolism of amiodarone.

Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society.

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.

Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition

Plasma apoC-III levels correlate with triglyceride (TG) levels and are a strong predictor of CVD outcomes. ApoC-III elevates TG in part by inhibiting LPL. ApoC-III likely inhibits LPL by competing for lipid binding. To probe this, we used oil-drop tensiometry to characterize binding of six apoC-III variants to lipid/water interfaces. This technique monitors the dependence of lipid binding on surface pressure, which increases during TG hydrolysis by LPL. ApoC-III adsorption increased surface pressure by upward of 18 mN/m at phospholipid/TG/water interfaces. ApoC-III was retained to high pressures at these interfaces, desorbing at 21–25 mN/m. Point mutants, which substituted alanine for aromatic residues, impaired the lipid binding of apoC-III. Adsorption and retention pressures decreased by 1–6 mN/m in point mutants, with the magnitude determined by the location of alanine substitutions. Trp42 was most critical to mediating lipid binding. These results strongly correlate with our previous results, linking apoC-III point mutants to increased LPL binding and activity at lipid surfaces. We propose that aromatic residues in the C-terminal half of apoC-III mediate binding to TG-rich lipoproteins. Increased apoC-III expression in the hypertriglyceridemic state allows apoC-III to accumulate on lipoproteins and inhibit LPL by preventing binding and/or access to substrate.

Hypertriglyceridemia in the genomic era: a new paradigm.

Hypertriglyceridemia (HTG) is a highly prevalent condition that is associated with increased cardiovascular disease risk. HTG may arise as a result of defective metabolism of triglyceride-rich lipoproteins and their remnants, ie, impaired clearance, or increased production, or both. Current categorization of HTG segregates primary and secondary cases, implying genetic and nongenetic causes for each category. Many common and rare variants of the genes encoding factors involved in these pathways have been identified. Although monogenic forms of HTG do occur, most cases are polygenic and often coexist with nongenetic conditions. Cumulative, multiple genetic variants can increase the risks for HTG, whereas environmental and lifestyle factors can force expression of a dyslipidemic phenotype in a genetically susceptible person. HTG states are therefore best viewed as a complex phenotype resulting from the interaction of cumulated multiple susceptibility genes and environmental stressors. In view of the heterogeneity of the HTG states, the absence of a unifying metabolic or genetic abnormality, overlap with the metabolic syndrome and other features of insulin resistance, and evidence in some patients that accumulation of numerous small-effect genetic variants determines whether an individual is susceptible to HTG only or to HTG plus elevated low-density lipoprotein cholesterol, we propose that the diagnosis of primary HTG and further delineation of familial combined hyperlipidemia from familial HTG is neither feasible nor clinically relevant at the present time. The hope is that with greater understanding of genetic and environmental causes and their interaction, therapy can be intelligently targeted in the future.

Hypertriglyceridemia

Hypertriglyceridemia (HTG) is commonly encountered in lipid and cardiology clinics. Severe HTG warrants treatment because of the associated increased risk of acute pancreatitis. However, the need to treat, and the correct treatment approach for patients with mild to moderate HTG are issues for ongoing evaluation. In the past, it was felt that triglyceride does not directly contribute to development of atherosclerotic plaques. However, this view is evolving, especially for triglyceride-related fractions and variables measured in the non-fasting state. Our understanding of the etiology, genetics and classification of HTG states is also evolving. Previously, HTG was considered to be a dominant disorder associated with variation within a single gene. The old nomenclature includes the term “familial” in the names of several hyperlipoproteinemia (HLP) phenotypes that included HTG as part of their profile, including combined hyperlipidemia (HLP type 2B), dysbetalipoproteinemia (HLP type 3), simple HTG (HLP type 4) and mixed hyperlipidemia (HLP type 5). This old thinking has given way to the idea that genetic susceptibility to HTG results from cumulative effects of multiple genetic variants acting in concert. HTG most is often a “polygenic” or “multigenic” trait. However, a few rare autosomal recessive forms of severe HTG have been defined. Treatment depends on the overall clinical context, including severity of HTG, concomitant presence of other lipid disturbances, and the patient's global risk of cardiovascular disease. Therapeutic strategies include dietary counselling, lifestyle management, control of secondary factors, use of omega-3 preparations and selective use of pharmaceutical agents.

Effect of weight loss, independent of change in diet composition, on apolipoprotein AI kinetic in men with metabolic syndrome

We investigated the effect of weight loss, independent of change in diet composition, on HDL and apoAI metabolism in men with metabolic syndrome (MetS). Subjects (19 men with MetS [NCEP-ATPIII]) were fed an isoenergetic Mediterranean-style diet for 5 weeks (all foods provided). Participants then underwent a 20-week free-living period during which they were counseled to restrict energy intake, after which they were again fed an isoenergetic Mediterranean-style diet for 5 weeks. At the end of the two controlled diets, participants received a single bolus of [5,5,5-(2)H(3)] (L)-leucine, and fasting blood samples were collected over a 96 h period. ApoAI kinetic was assessed using multicompartmental modeling of the tracer enrichment data. Participants achieved a 9.1 ± 2.8% reduction in body weight (P < 0.001). Weight loss resulted in an increase in plasma HDL-cholesterol (HDL-C) concentrations of 6.0% (P = 0.059) and HDL(3)-C of 7.9% (P = 0.045), attributable to a reduction in apoAI fractional catabolic rate (-7.8%; P = 0.046) with no change in apoAI production rate (2.2%; P = 0.58). These data indicate that weight loss, independent of variation in diet composition, increases plasma HDL primarily by delaying the catabolism of apoAI.

Atherogenic alterations in hypertriglyceridemic patients would not depend on insulin resistance

Background and aimsSeveral studies have been carried out to characterize the different alterations associated with hypertriglyceridemia (HTG) and to identify this dyslipemia as an independent risk factor for cardiovascular disease (CVD). HTG is frequently, but not always, associated with insulin resistance (IR). The present study was aimed to evaluate if the alterations observed in biomarkers of CVD were similar in HTG states independently of IR. MethodsHTG was defined as triglycerides ≥1.69mmol/l and IR as HOMA-IR ≥3.1. HTG-IR patients (n=15) were compared with HTG subjects without IR (WIR) (n=15) and with normotriglyceridemic (NTG)-WIR individuals (n=30). ResultsBoth HTG groups shared the increment in VLDL-C and non-HDL-C, HDL enrichment in triglycerides and depletion in phospholipids, the decrease in adiponectin concentration, and the increase in CETP activity. HDL-C and VCAM-1 levels were altered only in HTG-IR patients in comparison with the other groups, while oxidized LDL was only higher in HTG-IR than the control group. Multiple regression analysis identified triglycerides as the independent predictor of HDL-C, CETP activity and oxidized LDL levels. ConclusionThe increase in triglycerides is the major determinant factor of the atherogenic modifications observed, while IR would be an amplifier factor.

Healthy Lifestyle Behaviors and Triglycerides

Healthy Lifestyle Behaviors and Triglycerides

A hypertriglyceridemic state increases high sensitivity C-reactive protein of Japanese men with normal glucose tolerance

Both fasting and postprandial hypertriglyceridemia have been identified as risk markers for cardiovascular disease. High-sensitivity C-reactive protein (hs-CRP), known to independently predict future cardiovascular disease, has also been reported to be a direct participant in the progression of atherosclerosis. We evaluated whether or not fasting and/or postprandial hypertriglyceridemia influence hs-CRP of men with normal glucose tolerance. According to the triglyceride (TG) level, measured before and 1 and 2 h after a meal tolerance test, subjects were classified into a normotriglyceridemic (NTG) group (n = 86), a postprandial hypertriglyceridemia (PHTG) group (n = 50), or a fasting hypertriglyceridemia (FHTG) group (n = 53). Hs-CRP and HOMA-R were significantly higher in the FHTG group than in the other groups (P < 0.01). The PHTG group had higher hs-CRP than the NTG group (P < 0.05). No significant differences in age, BMI, LDL cholesterol, or carotid intima-media thickness were found in comparison of the three groups. Multivariate linear regression analysis showed that the area under the TG curve (AUC-TG), HbA1c, and BMI were independently correlated with hs-CRP (P < 0.001, P = 0.016, P = 0.032, respectively). Our data suggests that a hypertriglyceridemic state is associated with hs-CRP irrespective of BMI, LDL-C, and HDL-C, indicating that hs-CRP might represent chronic inflammation induced by hypertriglyceridemia in Japanese men with normal glucose tolerance.

Remnant-like particle cholesterol and serum amyloid A–low-density lipoprotein levels in obese subjects with metabolic syndrome

Although the circulating levels of remnant-like particle cholesterol (RLP-C) or serum amyloid A-low-density lipoprotein (SAA-LDL) can individually be increased in subjects with metabolic syndrome (MetS), the correlation between the two markers has not yet been previously studied. In the present study, we aimed to investigate the correlation between RLP-C and SAA-LDL in obese subjects with MetS in comparison to those without MetS. A total of 436 obese subjects were divided into groups with MetS and without MetS (male/female 75/143, mean age 49 years, current smokers 16% in both groups) by applying the age-, gender-, and smoking habit-matching method based on the database in the multicenter Japan Obesity and Metabolic Syndrome Study (JOMS). The data, including RLP-C and SAA-LDL, were compared in each group. Significantly greater levels of RLP-C or SAA-LDL were observed in subjects with MetS in comparison with those without MetS. There was a significantly positive correlation between RLP-C and SAA-LDL, with a relatively greater correlation in subjects with MetS (coefficient= 0.290, P<.01) in comparison with those without MetS (coefficient= 0.181, P < .01). Multivariate-adjusted correlation analyses showed a greater correlation between RLP-C and SAA-LDL in subjects with MetS, relative to those without MetS, although the significant correlation decreased in both groups when the hypertriglyceridemic states were taken into account. A relatively greater and positive correlation between greater levels of RLP-C and SAA-LDL in obese subjects with MetS, in comparison with those without MetS, may be linked to the development of MetS-related cardiovascular disease.

54 EFFECT OF ONE YEAR TREATMENT WITH INSULIN AND ORAL GLUCOSE-LOWERING AGENTS ON LIPID LEVELS IN NON-OBESE PATIENTS WITH TYPE 2-DIABETES

The importance of different lipid and lipoprotein measurements, including LDL particle concentration and levels of apolipoproteins and triglycerides, in the prediction of future cardiac events continues to be debated. In summary, apo B is a strong, independent predictor of initial and recurrent coronary events, even during statin treatment, and recent studies show its predictive superiority over LDL and non-HDL cholesterol. Importantly, determination of apo B levels is unaffected in a non-fasted or hypertriglyceridemic state and is not derived from other measurements. Thus, clear advantages exist for using apo B as a predictor of CHD. Likewise, triglycerides and triglyceride-rich lipoproteins are also strong, independent predictors of coronary events (initial and recurrent) during statin treatment. Triglycerides or especially triglyceride-rich lipoproteins with apo C-III may provide additional information to apo B. Apo C-III not only impairs lipoprotein metabolism but also stimulates directly the vascular inflammatory process. In contrast, evidence from large epidemiological studies is coalescing toward the view that small LDL size is more of a marker of these atherogenic triglyceride-rich lipoproteins than an independent predictor of CHD. Clearly, there remains considerable interest, both in terms of research and clinical practice, in the role of apo B, triglycerides, and specific apo B-containing lipoprotein particles as independent predictors of CHD risk as well as their potential to improve risk prediction and response to lipid-modifying treatment.

166 WHAT CAN TEACH US CORRELATIONS BETWEEN MRNAS CONTENTS IN MACROPHAGES FROM MEN AND WOMEN?

Apolipoprotein C-III, like the other C apoproteins, is distributed in both the triglyceride-rich lipoprotein and in high-density lipoprotein (HDL). High-density lipoprotein acts as a reservoir for the C apoproteins, and during very low-density lipoprotein (VLDL) production or chylomicron production (from exogenous fat intake) apoC's transfer from HDL to chylomicrons for subsequent metabolism. Thus, with increasing triglyceride levels and, hence, increased concentrations of triglyceride-rich particles, greater proportions of apoC-II and apoC-III are present in the triglyceride-rich lipoproteins, with reciprocal decline in the amount of C apoproteins in HDL. During triglyceride-rich lipoprotein catabolism, in which apoC-II activates lipoprotein lipase, the C apoproteins are transferred back to HDL and the catabolic products of triglyceride-rich lipoproteins are taken up by the liver. Thus, it appears that apoC-II activates lipoprotein lipase and exposes apoE for the clearance of such particles by the liver and apoC-III appears to modulate this process. Excessive production of apoCIII, therefore, can lead to hypertriglyceridemic states that are characterized by increased contents of apoC-III relative to other apoproteins in such particles.

Triglycerides and Cardiovascular Disease

A long-standing association exists between elevated triglyceride levels and cardiovascular disease* (CVD).1,2 However, the extent to which triglycerides directly promote CVD or represent a biomarker of risk has been debated for 3 decades.3 To this end, 2 National Institutes of Health consensus conferences evaluated the evidentiary role of triglycerides in cardiovascular risk assessment and provided therapeutic recommendations for hypertriglyceridemic states.4,5 Since 1993, additional insights have been made vis-a-vis the atherogenicity of triglyceride-rich lipoproteins (TRLs; ie, chylomicrons and very low-density lipoproteins), genetic and metabolic regulators of triglyceride metabolism, and classification and treatment of hypertriglyceridemia. It is especially disconcerting that in the United States, mean triglyceride levels have risen since 1976, in concert with the growing epidemic of obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM).6,7 In contrast, mean low-density lipoprotein cholesterol (LDL-C) levels have receded.7 Therefore, the purpose of this scientific statement is to update clinicians on the increasingly crucial role of triglycerides in the evaluation and management of CVD risk and highlight approaches aimed at minimizing the adverse public health–related consequences associated with hypertriglyceridemic states. This statement will complement recent American Heart Association scientific statements on childhood and adolescent obesity8 and dietary sugar intake9 by emphasizing effective lifestyle strategies designed to lower triglyceride levels and improve overall cardiometabolic health. It is not intended to serve as a specific guideline but will be of value to the Adult Treatment Panel IV (ATP IV) of the National Cholesterol Education Program, from which evidence-based guidelines will ensue. Topics to be addressed include epidemiology and CVD risk, ethnic and racial differences, metabolic determinants, genetic and family determinants, risk factor correlates, and effects related to nutrition, physical activity, and lipid medications. In the United States, the National Health and …

Serum glycated albumin, but not glycated hemoglobin, is low in relation to glycemia in men with hypertriglyceridemia.

Aims/Introduction: Serum glycated albumin (GA) and glycated hemoglobin (HbA1c) are influenced by plasma glucose levels, and are used for monitoring chronic glycemic control in diabetic patients. Both glycated proteins are known to be influenced by various factors other than plasma glucose levels. In the present study, we examined the effects of hypertriglyceridemia on them. The present study comprised 273 non-diabetic men. They were grouped into men with normotriglyceridemia (serum triglyceride [TG] <150 mg/dL) and those with hypertriglyceridemia (serum TG ≥150 mg/dL). Body mass index (BMI) and high sensitivity C-reactive protein (hs-CRP) were significantly higher in the 160 men with hypertriglyceridemia than the 113 men with normotriglyceridemia. In men with hypertriglyceridemia, as compared with those with normotriglyceridemia, fasting plasma glucose, 2-h plasma glucose after 75 g oral glucose tolerance test, and HbA1c were significantly higher. By contrast, serum GA was significantly lower in men with hypertriglyceridemia. BMI-adjusted serum GA was also significantly lower in these men. In a multivariate analysis, serum TG was an inverse explanatory variable for serum GA. Serum GA is low in relation to plasma glucose levels in men with hypertriglyceridemia. This might be caused by increased albumin metabolism associated with hypertriglyceridemic state. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00049.x, 2010).

Cholesterol Ester Transfer Protein (CETP), Postprandial Lipemia and Hypolipidemic Drugs

Cholesterol ester transfer protein (CETP) plays a significant role in high density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT). A reduction in CETP activity leads to an increase in HDL-cholesterol levels. However, the relationship between reduced CETP function and atherosclerosis is complex and confusing. In the hypertriglyceridemic state, CETP is highly expressed and RCT leads to the formation of small dense low density lipoprotein (LDL) and small dense HDL, both of which are involved in the progression of atherosclerosis. Significant associations of the B1B1 genotype with higher plasma CETP concentration and/or CETP activity and lower HDL cholesterol were reported in several, but not all, studies. The magnitude of postprandial lipemia is also associated with plasma CETP concentration and lipoprotein content and size. Several conditions such as metabolic syndrome, hypertension, insulin resistance, obesity and familial hypercholesterolaemia are characterized by a more pronounced postprandial hypertriglyceridemia and delayed TG clearance than normal states. Thus, CETP is considered as a candidate target for drug therapy. A number of synthetic CETP inhibitors (CGS25159 and JTT-705) were evaluated in animals with satisfactory results. In humans, two CETP inhibitors were evaluated, JTT-705 and torcetrapib, leading to HDL increase. However, torcetrapib administration was associated with an increase in blood pressure and other "off-target" effects. It is also not clear whether the HDL produced during treatment with torcetrapib is bioactive (i.e. an "on target" undesirable action). In the current review, CETP function regarding lipid metabolism (in fasting and fed states) from human and animal studies as well as the current knowledge on CETP inhibitors are discussed. We also discuss gender influence on the action of hypolipidemic drugs and their effect on CETP mass and activity, as well as on the lipid profile.

D 008 Association of the Atherosclerosis with tLR2, TLR4 and IL-6 Polymorphisms in Type 2 Diabetics Patients

The importance of different lipid and lipoprotein measurements, including LDL particle concentration and levels of apolipoproteins and triglycerides, in the prediction of future cardiac events continues to be debated. In summary, apo B is a strong, independent predictor of initial and recurrent coronary events, even during statin treatment, and recent studies show its predictive superiority over LDL and non-HDL cholesterol. Importantly, determination of apo B levels is unaffected in a non-fasted or hypertriglyceridemic state and is not derived from other measurements. Thus, clear advantages exist for using apo B as a predictor of CHD. Likewise, triglycerides and triglyceride-rich lipoproteins are also strong, independent predictors of coronary events (initial and recurrent) during statin treatment. Triglycerides or especially triglyceride-rich lipoproteins with apo C-III may provide additional information to apo B. Apo C-III not only impairs lipoprotein metabolism but also stimulates directly the vascular inflammatory process. In contrast, evidence from large epidemiological studies is coalescing toward the view that small LDL size is more of a marker of these atherogenic triglyceride-rich lipoproteins than an independent predictor of CHD. Clearly, there remains considerable interest, both in terms of research and clinical practice, in the role of apo B, triglycerides, and specific apo B-containing lipoprotein particles as independent predictors of CHD risk as well as their potential to improve risk prediction and response to lipid-modifying treatment.

Role of Endothelial Lipase in Plasma HDL levels in a Murine Model of Hypertriglyceridemia

Hypertriglyceridemia is the most common cause of low plasma high-density lipoprotein cholesterol (HDL-C) levels; however, the correlation between high triglyceride (TG) and low HDL-C remains unclear. Endothelial lipase (EL) is a determinant of plasma HDL levels. We investigated the role of EL in HDL metabolism in a murine model of acute hypertriglyceridemia. To establish TG-dominant hyperlipidemia, EL-/- and wild-type (WT) mice were injected with Poloxamer-407 (P-407, 0.5 g/kg, i.p.). A single injection of P-407 resulted in a marked increase in plasma TG and cholesterol levels together with a decrease in HDL-C levels. Although plasma TG levels were similar in EL-/- and WT mice after P-407 injection, HDL-C levels were 80% higher and the HDL particle size was significantly larger in EL-/- mice than in WT mice. P-407 treatment inhibited plasma lipoprotein lipase activity and EL phospholipase activity, without decreasing their expressions. Adenovirus-mediated overexpression of EL in the liver reduced plasma HDL-C levels in both normo- and hyperlipidemic mice, while overexpression of catalytically inactive EL reduced HDL-C levels in hyperlipidemic mice. Cell culture experiments revealed that both catalytically active and inactive EL promoted cellular HDL uptake to the same extent. EL regulates plasma HDL levels in mice in the normolipidemic as well as the acute hypertriglyceridemic state. EL can modulate plasma HDL-CHOL levels through both its lipolytic and ligand-binding functions in hypertriglyceridemic mice, while lipolytic activity appears to be the main determinant for its effects on HDL metabolism in normolipidemic mice.

Plasma triglycerides and LDL cholesterol are related in a parabolic fashion in the general population and patients with Type 2 diabetes mellitus: long‐term follow‐up results from the Hoorn study

Low-density lipoprotein cholesterol (LDL-C) levels are often fairly normal in Type 2 diabetes mellitus (DM). We anticipated that a parabolic relation between plasma triglycerides and LDL-C, as previously demonstrated in familial combined hyperlipidaemia (FCHL), might account for this phenomenon. Our hypothesis was tested in 1343 subjects derived from the general population who were studied on two occasions 6 years apart (the Hoorn study). Three groups were constructed depending on plasma triglycerides: group A (individuals with both measurements below 1.5 mmol/l), group B (one measurement below and one above 1.5 mmol/l) and group C (both measurements above 1.5 mmol/l). Diabetes status was ascertained by an oral glucose tolerance test. In a mixed linear model, a significant, positive relation between triglycerides and LDL-C was observed for males in group A (beta(a) = 0.5, P < 0.001) and group B (beta(b) = 0.2, P < 0.001), whereas a significant negative relation was found for males in group C (beta(c) = -0.2, P = 0.003). The regression slopes did not differ between diabetic and non-diabetic subjects. Similar results were obtained for women, with the exception that the relation was not significantly negative in group C (beta(c) = -0.1, P = 0.4). Plasma triglycerides and LDL-C are related in a parabolic fashion, not only in FCHL, but also in the general population and Type 2 DM. These findings aid our interpretation of typical dyslipidaemia and the effects of treatment that are frequently observed in hypertriglyceridaemic states.

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 …

Distinct patterns of heparin affinity chromatography VLDL1 and VLDL2 subfractions in the different dyslipidaemias

Very low density lipoprotein (VLDL) 1 and 2 were fractionated by heparin affinity chromatography into a bound and an unbound fraction and the different subfractions were quantified in 17 normolipidaemic (NL), 13 hypercholesterolaemic (HC), 10 hypertriglyceridaemic (HTG) and 11 combined hyperlipidaemic subjects (CHL). Unbound VLDL1 and VLDL2 were, respectively, 1.9- and 2.2-fold richer in triglycerides than bound VLDL1 and VLDL2. In HTG and CHL the concentration of all the VLDL subfractions was increased and plasma triglyceride level was correlated to unbound VLDL1 and to bound VLDL1 (respectively, r = 0.86 ( p < 0.001) and r = 0.77 ( p < 0.01) in HTG and r = 0.73 ( p < 0.001) and r = 0.62 ( p < 0.05) in CHL). In HC unbound VLDL2 and bound VLDL2 concentration were increased compared to NL and in CHL, the concentration of bound VLDL2 was particularly increased (3.2-fold compared to NL ( p < 0.001)). In both HC and CHL bound VLDL2 concentration was correlated to low density lipoprotein cholesterol (LDL-C) concentration (respectively, r = 0.67 ( p < 0.01) and r = 0.62 ( p < 0.05)). In hypertriglyceridaemic states the intravascular accumulation of both unbound and bound VLDL1 appears as the determinant of plasma triglyceride concentration, whereas in moderately hypercholesterolaemic states the concentration of bound VLDL2 is strikingly correlated to LDL-C concentration, suggesting that these two species are linked metabolically, e.g. bound VLDL2 contain the precursor pool of LDL.