Atherogenic Triglyceride-rich Lipoproteins Research Articles

Does Adopting Western Low-density Lipoprotein Cholesterol Targets Expose Indians to a Higher Risk of Cardiovascular Events? Expert Opinion From the Lipid Association of India.

Adverse cardiovascular (CV) events have declined in Western countries due at least in part to aggressive risk factor control, including dyslipidemia management. The American and European (Western) dyslipidemia treatment guidelines have contributed significantly to the reduction in atherosclerotic cardiovascular disease (ASCVD) incidence in the respective populations. However, their direct extrapolation to Indian patients does not seem appropriate for the reasons described below. In the US, mean low-density lipoprotein cholesterol (LDL-C) levels have markedly declined over the last 2 decades, correlating with a proportional reduction in CV events. Conversely, poor risk factor control and dyslipidemia management have led to increased CV and coronary artery disease (CAD) mortality rates in India. The population-attributable risk of dyslipidemia is about 50% for myocardial infarction, signifying its major role in CV events. In addition, the pattern of dyslipidemia in Indians differs considerably from that in Western populations, requiring unique strategies for lipid management in Indians and modified treatment targets. The Lipid Association of India (LAI) recognized the need for tailored LDL-C targets for Indians and recommended lower targets compared to Western guidelines. For individuals with established ASCVD or diabetes with additional risk factors, an LDL-C target of <50 mg/dL was recommended, with an optional target of ≤30 mg/dL for individuals at extremely high risk. There are several reasons that necessitate these lower targets. In Indian subjects, CAD develops 10 years earlier than in Western populations and is more malignant. Additionally, Indians experience higher CAD mortality despite having lower basal LDL-C levels, requiring greater LDL-C reduction to achieve a comparable CV event reduction. The Indian Council for Medical Research-India Diabetes study described a high prevalence of dyslipidemia among Indians, characterized by relatively lower LDL-C levels, higher triglyceride levels, and lower high-density lipoprotein cholesterol (HDL-C) levels compared to Western populations. About 30% of Indians have hypertriglyceridemia, aggravating ASCVD risk and complicating dyslipidemia management. The levels of atherogenic triglyceride-rich lipoproteins, including remnant lipoproteins, are increased in hypertriglyceridemia and are predictive of CV events. Hypertriglyceridemia is also associated with higher levels of small, dense LDL particles, which are more atherogenic, and higher levels of apolipoprotein B (Apo B), reflecting a higher burden of circulating atherogenic lipoprotein particles. A high prevalence of low HDL-C, which is often dysfunctional, and elevated lipoprotein(a) [Lp(a)] levels further contribute to the heightened atherogenicity and premature CAD in Indians. Considering the unique characteristics of atherogenic dyslipidemia in Indians, lower LDL-C, non-HDL-C, and Apo B goals compared to Western guidelines are required for effective control of ASCVD risk in Indians. South Asian ancestry is identified as a risk enhancer in the American lipid management guidelines, highlighting the elevated ASCVD risk of Indian and other South Asian individuals, suggesting a need for more aggressive LDL-C lowering in such individuals. Hence, the LDL-C goals recommended by the Western guidelines may be excessively high for Indians and could result in significant residual ASCVD risk attributable to inadequate LDL-C lowering. Further, the results of Mendelian randomization studies have shown that lowering LDL-C by 5-10 mg/dL reduces CV risk by 8-18%. The lower LDL-C targets proposed by LAI can yield these incremental benefits. In conclusion, Western LDL-C targets may not be suitable for Indian subjects, given the earlier presentation of ASCVD at lower LDL-C levels. They may result in greater CV events that could otherwise be prevented with lower LDL-C targets. The atherogenic dyslipidemia in Indian individuals necessitates more aggressive LDL-C and non-HDL-C lowering, as recommended by the LAI, in order to stem the epidemic of ASCVD in India.

Abstract 17120: ARO-ANG3, an Investigational RNAi Therapeutic, Silences the Expression of ANGPTL3 and Decreases Atherogenic Lipoproteins in Patients With Mixed Dyslipidemia: ARCHES-2 Study Results

Background: Angiopoietin-like protein 3 (ANGPTL3) regulates lipoprotein metabolism by inhibiting lipoprotein and endothelial lipases. ANGPTL3 loss-of-function carriers have decreased circulating triglycerides (TGs), LDL-C, and HDL-C, and a lower risk of atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an investigational RNAi therapeutic designed to inhibit hepatic ANGPTL3 expression and reduce atherogenic lipoproteins. Aim: We report end-of-study results (data cutoff 09 December 2022) from ARCHES-2, a Phase 2b double-blind, placebo (pbo)-controlled study (NCT04832971) to evaluate the safety and efficacy of ARO-ANG3 in adults with mixed dyslipidemia (MD). Methods: Patients with fasting TGs 150-499 mg/dL and LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL were randomized to receive 50 mg, 100 mg or 200 mg ARO-ANG3 or pbo by subcutaneous injections on Day 1 and Week 12. Patients were on a stable diet and optimal lipid-lowering therapies. The primary endpoint was the percent change in TGs from baseline at Week 24. Liver fat was assessed at baseline and Week 24 in a subset of patients with hepatic steatosis. Mixed models repeated measures was used for statistical analyses. Results: At Week 24, ARO-ANG3 decreased ANGPTL3 (up to 77%), TGs (up to 56%), remnant cholesterol (up to 56%), and apolipoprotein B (apoB) (up to 20%). Other lipoproteins including LDL-C, non-HDL-C, lipoprotein(a) and HDL-C were also decreased. Liver fat decreased similarly in ARO-ANG3 and pbo groups. TEAEs were consistent with those expected in this patient population and with associated underlying comorbidities. Conclusions: ARCHES-2 data demonstrate ARO-ANG3 efficacy by significantly lowering ANGPTL3 and atherogenic triglyceride-rich lipoproteins (TRLs), LDL and total apoB in patients with MD. The favorable changes in serum lipids and lipoproteins and safety profile support the potential of ARO-ANG3 to treat residual ASCVD risk in patients with elevated TRLs not at LDL-C goal.

Cardio protective effect of intermittent fasting on the lumen area ratio of the coronary artery in rats with a high-calorie diet

Atherosclerosis is a principal cause of coronary artery disease (CAD), one of the major causes of global premature mortality and morbidity. The glycolysis pathway will process excess carbohydrates in a high-calorie diet (HCD) into triglycerides, which, if accumulated, will cause an increase in the concentration of atherogenic triglyceride-rich lipoproteins. Therefore, intermittent fasting (IF) is a recommended lifestyle to prevent CAD through metabolic reprogramming pathways. This study was designed to evaluate the cardioprotective effect of eight weeks of IF 5:2 on the lumen area ratio of the coronary artery in rats with four weeks of HCD. A total of 24 Wistar male albino rats were divided into SD (standard diet), IF (IF 5:2), HCD (daily injection 0.013 g/gBW glucose), and IF-HCD (IF 5:2 and HCD). At the end of the experiment, all the rats were sacrificed. The coronary artery preparations were stained with H&amp;E stain, then evaluated with the OLYMPUS cellSens Standard to measure the arterial lumen area. The statistical analysis was done using Brown Forsythe test. In this study, no significant differences between all groups, and the effect of IF will only be seen if an HCD intervention has a significant effect. However, the IF group achieved the highest mean in the arterial lumen area ratio (SD=0.526±0.097; IF=0.631±0.021; HCD=0.611±0.064; IF-HCD=0.594±0.060). In conclusion, IF 5:2 may have a cardioprotective effect in healthy individuals, but the effect is unknown in individuals with HCD.

Calculated Non-HDL Cholesterol Includes Cholesterol in Larger Triglyceride-Rich Lipoproteins in Hypertriglyceridemia.

ContextCalculated non–high-density lipoprotein (HDL) cholesterol (non-HDLC) should selectively include cholesterol from atherogenic lipoproteins to be a reliable risk marker of cardiovascular disease. In hypertriglyceridemia (HTG), there is increased abundance of larger and less atherogenic triglyceride-rich lipoproteins (TRL), namely, larger very-low-density lipoproteins (VLDL), and chylomicrons.ObjectiveWe aim to demonstrate that serum triglyceride (TG) level has a substantial impact on non-HDLC’s ability to represent cholesterol from atherogenic lipoproteins, even though TG is not part of the calculation for non-HDLC.DesignAnalysis of lipid profile dataSettingsLipid Clinic patient cohort, and Biochemistry Laboratory patient cohortPatients or Other Participants7,492 patients in the Lipid Clinic cohort with baseline lipid profiles documented prior to starting lipid-lowering medications and 156,311 lipid profiles from The Ottawa Hospital Biochemistry Laboratory cohort.InterventionNoneMain Outcome MeasureOur modeling process includes derivation of TG-interval–specific lipoprotein composition factor (LCF) for TRL, which represents the mass ratio of cholesterol to TG in TRL. A high LCF indicates that the TRLs are mainly the cholesterol-rich atherogenic remnant lipoproteins. A low LCF indicates that the TRLs are mainly the TG-rich larger VLDL and chylomicrons.ResultsAs serum TG increases, there is progressive decline in the LCF for TRL, which indicates that the calculated non-HDLC level reflects progressive inclusion of cholesterol from larger TRL. This is shown in both cohorts.ConclusionsCalculated non-HDLC is influenced by TG level. As TG increases, non-HDLC gradually includes more cholesterol from larger TRL, which are less atherogenic than LDL and remnant lipoproteins.

Is APOC3 the driver of cardiovascular disease in people with type I diabetes mellitus?

In this issue of the JCI, Kanter et al. make a strong case for implicating apolipoprotein C3 (APOC3) as a central player in atherosclerotic cardiovascular disease that is commonly seen in individuals with type 1 diabetes mellitus (T1DM). Kanter and colleagues suggest that insulin deficiency elevates plasma APOC3 as well as atherogenic triglyceride-rich (TG-rich) lipoproteins (TRLs). Using two mouse models of T1DM, the authors investigated APOC3-mediated inhibition of both TG hydrolysis by lipoprotein lipase and hepatic uptake of remnant lipoproteins. They suggest that poorly catabolized lipoproteins, enriched in both APOC3 and APOE content, are particularly atherogenic. Notably, treating both mouse models with an APOC3 antisense oligonucleotide lowered both plasma APOC3 and TRLs, and prevented atherosclerosis. These impactful mouse studies were supported by the initial finding that APOC3 predicted coronary artery disease events in participants of the prospective Coronary Artery Calcification in Type 1 Diabetes study with normal TG levels.

Abstract 192: Intra-Individual Temporal Variation of Lipid and Apolipoprotein Levels in Patients With Type II Diabetes Mellitus and Normolipidemic Individuals

Hypertriglyceridemia is frequently observed with diabetes mellitus (DM) and is associated with increased cardiovascular disease (CVD) risk. In conditions of insulin deficiency or resistance, increased levels of free fatty acids are seen by the liver, which trigger increased lipogenesis and secretion of triglyceride (TG) rich lipoprotein (TRL) particles. However, a high number of specific ApoC-III on TRL particles suppress their return to the liver leading to a continuous circulation of highly atherogenic TRL remnants. To better understand the effect of intra-individual temporal variations on the differentiation of lipid and apolipoprotein profiles in DM vs. normal individuals, a small time course study over a 4 week period was performed on 3 normolipidemic, and 3 type II DM patients. Our laboratory has developed a method to separate lipoproteins based on hydrodynamic size coupled with mass spectrometry based analysis. Whole serum and lipoprotein size fractions were analyzed for 8 apolipoproteins (ApoA-I, ApoA-II, ApoA-IV, B-100, ApoC-I, ApoC-II, ApoC-III and E) and non-polar lipids (FC, CE, TG) while monitoring other proteins (ApoD, ApoM, CETP, LCAT, PLTP, PON1 and SAA4). In whole serum over the course of 4 weeks, ApoA-IV levels of DM vs. normal subjects differed the most, 3.2 (0.7) vs. 1.8 (0.4) μM, respectively, more significantly than intra-group or intra-individual variations. On the contrary, significantly lower whole serum levels were found for FC, CE, ApoM and PON1 (Prob&lt;0.01). HDL-ApoC-III/LDL-ApoC-III was also lower in DM vs. normal subjects, 3.0 (1.9) vs. 7.2 (4.1). By metrics of molar ratio measured in 20-35 nm LDL fractions, the most significant difference was found between DM vs. normal subjects in ApoC-III/ApoB-100 (1.8 (0.6) vs. 0.9 (0.3)), C-II/ApoB-100 (0.8 (0.4) vs. 0.4 (0.2)) and ApoE/ApoC-III (0.11 (0.09) vs. 0.24 (0.15)). These LDL composition differences indicate lower lipase activity and inhibition of LDL uptake. However, no significant differences were observed in these molar ratios as function of LDL particle size. In conclusion, due to less significant temporal deviations, apolipoprotein molar ratios are a more useful and informative measure of CVD risk in DM subjects than LDL size distribution characteristics.

Fasting Triglycerides Predict Recurrent Ischemic Events in Patients With Acute Coronary Syndrome Treated With Statins

BackgroundMost patients with acute coronary syndrome (ACS) are treated with statins, which reduce atherogenic triglyceride-rich lipoproteins. It is uncertain whether triglycerides predict risk after ACS on a background of statin treatment. ObjectivesThis study examined the relationship of fasting triglyceride levels to outcomes after ACS in patients treated with statins. MethodsLong-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively. Analysis of dal-OUTCOMES included 15,817 patients (97% statin-treated) randomly assigned 4 to 12 weeks after ACS to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months. Analysis of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS and followed for 16 weeks. Fasting triglycerides at initial random assignment were related to risk of coronary heart disease death, nonfatal myocardial infarction, stroke, and unstable angina in models adjusted for age, sex, hypertension, smoking, diabetes, high-density lipoprotein cholesterol, and body mass index. ResultsFasting triglyceride levels were associated with both long-term and short-term risk after ACS. In dal-OUTCOMES, long-term risk increased across quintiles of baseline triglycerides (p < 0.001). The hazard ratio in the highest/lowest quintile (>175/≤80 mg/dl) was 1.61 (95% confidence interval: 1.34-1.94). There was no interaction of triglycerides and treatment assignment on the primary outcome. In the atorvastatin group of MIRACL, short-term risk increased across tertiles of baseline triglycerides (p = 0.03), with a hazard ratio of 1.50 (95% confidence interval: 1.05 to 2.15) in highest/lowest tertiles (>195/≤135 mg/dl). The relationship of triglycerides to risk was independent of low-density lipoprotein cholesterol in both studies. ConclusionsAmong patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride-rich lipoproteins may be an important additional target for therapy. (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome; NCT00658515)

Impact of extended-release niacin on atherogenic triglyceride-rich lipoproteins during the postprandial phase in subjects at high cardiovascular risk

Objectives: Niacin showed no benefit on cardiovascular events in 2 outcome trials in high-risk subjects. However, this broad spectrum lipid-modulating agent remains clinically relevant in patients who do not reach goals despite statin therapy; indeed, such patients typically display altered postprandial lipoprotein metabolism. While the effect of niacin on fasting lipids is well established, its impact on postprandial lipoprotein metabolism remains indeterminate.

PS3 - 15. Genetic Variation at the SULF2 Locus Affects Hepatic Postprandial Remnant Clearance in Patients with Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is characterized by elevated plasma levels of atherogenic triglyceride-rich lipoproteins (TRL). Recent animal data revealed that heparansulfate proteoglycans (HSPGs) contribute to hepatic clearance of TRL. Hepatic glucosamine-6-O-endosulfatase-2 (SULF2), an enzyme involved in HSPG remodeling, is strongly associated with triglyceride (TG) levels in db/db mice.

The effect of Omega-3 fatty acids on the atherogenic lipoprotein phenotype in patients with nephrotic range proteinuria

Patients with nephrotic range proteinuria are known to have an increased risk of cardiovascular disease partly due to possessing the atherogenic lipoprotein phenotype. The aim of this study was to examine the effect of high dose omega-3 fatty acids on atherogenic triglyceride rich lipoproteins in patients with nephrotic range proteinuria, comparing their effect on lipoprotein profiles in age and sex matched controls. 17 patients with nephrotic range proteinuria and 17 age and sex matched controls were studied. Fasting lipids and lipoproteins were measured before and after 8 weeks treatment with 4 g daily of omega-3 fatty acids (Omacor®). In patients with proteinuria treatment reduced plasma triglyceride by a mean of 0.45 mmol/l (95%CI 0.16 - 0.74, p = 0.005) and plasma very low density lipoprotein cholesterol by a mean of 0.38 (95%CI 0.01 - 0.75, p = 0.04). LDL III concentration fell from 178.8 mg/dl (61.6 - 231.0) to 96.1 mg/dl (49.3 - 204.5), p = 0.05. In patients treatment altered the LDL profile so that LDLIII which was the major subfraction present at baseline was reduced from 49.9% to 29.8% (p = 0.01). Remnant lipoproteins (RLP) also fell with a mean reduction of 3.5 mg/dl in RLP-Cholesterol (95%CI 0.1 - 6.9, p = 0.05) and 12.4 mg/dl in RLP-triglyceride (95%CI 2.6 - 22.2, p = 0.03). There was however a 0.6 mmol/l rise in LDL-C (p = 0.06) in the patients. Treatment did not alter HDL-C. In patients with nephrotic range proteinuria, omega-3 fatty acids reduced triglyceride rich lipoproteins, LDL III and remnant lipoproteins. A tendency to an increase in LDL-C was observed but this was offset by an alteration in the distribution of the LDL profile towards lighter, larger LDL particles. We propose that treatment with omega-3 fatty acids in conjunction with a statin may be the ideal therapy in these patients.

Altered metabolism of apolipoprotein C.III: a contributor in chronic kidney disease?

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD) [1]. While the precise mechanisms of the increased CVD risk are unknown, both traditional and novel CVD risk factors have been implicated [1,2]. Dyslipidemia, a well-established risk factor for CVD in the general population, is highly prevalent in CKD [3,4]. CKD patients develop complex qualitative and quantitative abnormalities in lipid and lipoprotein metabolism regardless of the etiology of renal disease. In brief, classic uremic dyslipidemia is characterized by elevated plasma concentrations of triglycerides and increased numbers of atherogenic triglyceride-rich lipoprotein (TRL) particles, particularly VLDL and IDL [3,5], coupled with low HDL-C. This dyslipidemia results from altered lipoprotein metabolism and may also be dependant on a small regulatory apoprotein, apolipoprotein (apo)C-III. Although this article briefly discusses lipoprotein metabolism in CKD, the primary focus is on the importance of apoC-III in CKD.

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.

Plasma apolipoprotein C-III metabolism in patients with chronic kidney disease

Moderate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, ²H₃]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III (P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was significantly and negatively correlated with apoC-III FCR (r = -0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR (P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR (P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modification of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate CKD.

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.

Nonfasting Lipemia and Inflammation as Cardiovascular Disease Risks After SCI

Fasting blood lipids are the bedrock of cardiovascular disease (CVD) assessment, although the human lifespan is primarily spent in the postprandial state. An exaggerated postprandial lipemia (PPL) facilitates accumulation of atherogenic triglyceride-rich lipoproteins in vascular endothelium. PPL worsens CVD risk associated with heart disease and diabetes and is now reported in persons with spinal cord injury (SCI). Studies also report elevated blood levels of pro-atherogenic inflammatory cytokines after SCI. As these cytokines are both markers and instigators of atherogenesis, and as nonfasting hypertriglyceridemia stimulates the inflammatory cascade, both PPL and inflammation merit serious consideration as newfound risks for CVD after SCI.

Lipolysis Stimulated Lipoprotein Receptor: A NOVEL MOLECULAR LINK BETWEEN HYPERLIPIDEMIA, WEIGHT GAIN, AND ATHEROSCLEROSIS IN MICE

The lipolysis-stimulated lipoprotein receptor, LSR, is a multimeric protein complex in the liver that undergoes conformational changes upon binding of free fatty acids, thereby revealing a binding site (s) that recognizes both apoB and apoE. Complete inactivation of the LSR gene is embryonic lethal in mice. Here we show that removal of a single LSR allele (LSR(-/+)) caused statistically significant increases in both plasma triglyceride and cholesterol levels, a 2-fold increase in plasma triglyceride changes during the post-prandial phase, and delayed clearance of lipid emulsions or a high fat meal. The longer postprandial lipoprotein clearance time observed in LSR(-/+) mice was further increased in LSR(-/+) mice lacking functional low density lipoprotein (LDL) receptors. LSR(-/+) mice placed on a Western-type diet displayed higher plasma triglycerides and cholesterol levels, increased triglyceride-rich lipoproteins and LDL, and increased aorta lipid content, as compared with control mice on the same diet. Furthermore, a direct correlation was observed between the hyperlipidemia and weight gain but only in the LSR(-/+) mice. Knockdown of LSR expression by small interfering RNA in mouse Hepa1-6 cells led to decreased internalization of both DiI-labeled cyclohexanedione-LDL and very low density lipoprotein in the presence of oleate. These data led us to conclude that LSR contributes to the physiological clearance of atherogenic triglyceride-rich lipoproteins and LDL. We propose that LSR cooperates with the LDL receptor in the final hepatic processing of apoB-containing lipoproteins and represents a novel therapeutic target for the treatment of hyperlipidemia associated with obesity and atherosclerosis.

Apolipoprotein AV: gene expression,physiological role in lipid metabolism and clinical relevance

The apolipoprotein APOA5 gene, a member of the gene cluster on chromosome 11q23 that includes APOA1, APOC3 and APOA4, has gained considerable interest as it encodes ApoAV, a key determinant of circulating levels of potentially atherogenic triglyceride-rich lipoproteins (TRL). Indeed, strong associations between genetic variants of the APOA5 gene sequence and elevated triglyceride (TG) levels have been established. This apolipoprotein may potentiate lipolysis of TRL through facilitation of lipoprotein interaction with lipoprotein lipase. In addition, ApoAV may enhance clearance of remnant lipoproteins by mediating their interaction with the LDL receptor-related protein (LRP)1. The implication of ApoAV in intravascular TRL metabolism is further supported by studies that have demonstrated upregulation of APOA5 gene expression by nuclear receptors (PPARα, FXR and HNF4α) and hormones (thyroxine) involved in hypotriglyceridemic pathways. APOA4 expression may equally be modulated by nutritional status and, more ...

High serum levels of remnant lipoproteins predict ischemic stroke in patients with metabolic syndrome and mild carotid atherosclerosis

Background and objective Metabolic syndrome is prevalently associated with stroke. Triglyceride-rich lipoproteins contribute to atherothrombotic complications in metabolic syndrome. This study examined whether high levels of remnant lipoprotein, atherogenic triglyceride-rich lipoprotein, may be associated with future ischemic stroke in metabolic syndrome. Methods and results We followed up 292 consecutive patients with metabolic syndrome meeting ATP III criteria and mild carotid plaques for a period of ≤24 months until occurrence of an ischemic stroke. Remnant lipoprotein (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method. Twenty-two ischemic stroke events occurred during follow-up. A multivariate Cox proportional hazards models showed that high RLP-C levels were a significant and independent predictor of ischemic stroke events ( p < 0.01). Echolucent carotid plaques were also a significant predictor of ischemic stroke that was independent of other carotid ultrasound parameters in Cox proportional hazards models ( p < 0.01). High RLP-C levels were intimately and independently associated with carotid plaque echolucency ( p < 0.01). Conclusions High RLP-C levels are an independent risk factor for future ischemic strokes in metabolic syndrome. High RLP-C levels may be related to echolucent carotid plaque, partly accounting for high risk for ischemic stroke in metabolic syndrome.

The apolipoprotein story

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.

Sphingomyelinase Induces Aggregation and Fusion of Small Very Low–Density Lipoprotein and Intermediate-Density Lipoprotein Particles and Increases Their Retention to Human Arterial Proteoglycans

Infiltration of low-density lipoprotein (LDL) into subendothelial space is an early step in atherosclerosis. In addition to LDL particles, small very low-density lipoprotein (sVLDL) and intermediate-density lipoprotein (IDL) particles are also able to enter the arterial intima and be retained within the subendothelial extracellular matrix. Here we compared how proteolysis with alpha-chymotrypsin and phospholipid hydrolysis with phospholipase A2 or sphingomyelinase (SMase) of sVLDL, IDL, and LDL particles can influence their aggregation, fusion, and binding to human arterial proteoglycans in vitro. In each of the 3 lipoprotein classes, the particles became only slightly aggregated with alpha-chymotrypsin or phospholipase A2. However, the particles strongly aggregated when treated with SMase. The aggregated/fused particles were found to bind to proteoglycans in proteoglycan affinity chromatography more tightly than the native-sized counterparts. In addition, in a microtiter well assay, the binding of SMase-treated lipoproteins was enhanced: the amounts of proteoglycan-bound SMase-treated LDL, IDL, and sVLDL were 4-, 5-, and 20-fold higher, respectively, than the amounts of proteoglycan-bound native lipoproteins. These results imply a specific role for SMase as an sVLDL- and IDL-modifying enzyme and also suggest a novel mechanism of lipid accumulation in atherogenesis, namely enhanced retention of atherogenic triglyceride-rich lipoprotein particles in intimal areas expressing extracellular SMase activity.