Role Of High-density Lipoprotein Research Articles

Quantification of high-density lipoprotein particle number by proton nuclear magnetic resonance: don't believe the numbers.

Proton nuclear magnetic resonance (NMR) can rapidly assess lipoprotein concentrations and sizes in biological samples. It may be especially useful for quantifying high-density lipoprotein (HDL), which exhibits diverse particle sizes and concentrations. We provide a critical review of the strengths and limitations of NMR for quantifying HDL subclasses. Recent studies using NMR have shed light on HDL's role in various disorders, ranging from residual cardiovascular risk to host susceptibility to infection. However, accurately quantifying HDL particle number, size, and concentration (HDL-P) remains a challenge. Discrepancies exist between NMR and other methods such as gel electrophoresis, ion mobility analysis and size-exclusion chromatography in estimating the abundance of HDL species and the ratio of apolipoprotein A-I (APOA1) to HDL particles. NMR is a low-cost method for quantifying HDL-P that is readily applicable to clinical and translational studies. However, inconsistencies between the results of NMR quantification of HDL-P and other independent methods hinder the interpretation of NMR results. Because proton NMR apparently fails to accurately quantify the sizes and concentrations of HDL, the relevance of such studies to HDL biology poses challenges. This limits our understanding of pathophysiological implications of HDL-P as determined by NMR, particularly in determining cardiovascular disease (CVD) risk.

Relationships between HDL subpopulation proteome and HDL function in overweight/obese people with and without coronary heart disease

Background and aimsThe structure-function relationships of high-density lipoprotein (HDL) subpopulations are not well understood. Our aim was to examine the interrelationships between HDL particle proteome and HDL functionality in subjects with and without coronary heart disease (CHD). MethodsWe isolated 5 different HDL subpopulations based on charge, size, and apolipoprotein A1 (APOA1) content from the plasma of 33 overweight/obese CHD patients and 33 age-and body mass index (BMI)-matched CHD-free subjects. We measured the relative molar concentration of HDL-associated proteins by liquid chromatography tandem mass spectrometry (LC-MS/MS) and assessed particle functionality. ResultsWe quantified 110 proteins associated with the 5 APOA1-containing HDL subpopulations. The relative molar concentration of these proteins spanned five orders of magnitude. Only 10 proteins were present in >1% while 73 were present in <0.1% concentration. Only 6 of the 10 most abundant proteins were apolipoproteins. Interestingly, the largest (α-1) and the smallest (preβ-1) HDL particles contained the most diverse proteomes. The protein composition of each HDL subpopulation was altered in CHD cases as compared to controls with the most prominent differences in preβ-1 and α-1 particles. APOA2 concentration was positively correlated with preβ-1 particle functionality (ABCA1-CEC/mg APOA1 in preβ-1) (R2 = 0.42, p = 0.005), while APOE concentration was inversely correlated with large-HDL particle functionality (SRBI-CEC/mg APOA1 in α-1+α-2) (R2 = 0.18, p = 0.01). ConclusionsThe protein composition of the different HDL subpopulations was altered differentially in CHD patients. The functionality of the small and large HDL particles correlated with the protein content of APOA2 and APOE, respectively. Our data indicate that distinct particle subspecies and specific particle associated proteins provide new information about the role of HDL in CHD.

Inflammation and Oxidative Stress Induced by Obesity, Gestational Diabetes, and Preeclampsia in Pregnancy: Role of High-Density Lipoproteins as Vectors for Bioactive Compounds.

Inflammation and oxidative stress are essential components in a myriad of pathogenic entities that lead to metabolic and chronic diseases. Moreover, inflammation in its different phases is necessary for the initiation and maintenance of a healthy pregnancy. Therefore, an equilibrium between a necessary/pathologic level of inflammation and oxidative stress during pregnancy is needed to avoid disease development. High-density lipoproteins (HDL) are important for a healthy pregnancy and a good neonatal outcome. Their role in fetal development during challenging situations is vital for maintaining the equilibrium. However, in certain conditions, such as obesity, diabetes, and other cardiovascular diseases, it has been observed that HDL loses its protective properties, becoming dysfunctional. Bioactive compounds have been widely studied as mediators of inflammation and oxidative stress in different diseases, but their mechanisms of action are still unknown. Nonetheless, these agents, which are obtained from functional foods, increase the concentration of HDL, TRC, and antioxidant activity. Therefore, this review first summarizes several mechanisms of HDL participation in the equilibrium between inflammation and oxidative stress. Second, it gives an insight into how HDL may act as a vector for bioactive compounds. Third, it describes the relationships between the inflammation process in pregnancy and HDL activity. Consequently, different databases were used, including MEDLINE, PubMed, and Scopus, where scientific articles published in the English language up to 2023 were identified.

HDL Function across the Lifespan: From Childhood, to Pregnancy, to Old Age.

The function of high-density lipoprotein (HDL) particles has emerged as a promising therapeutic target and the measurement of HDL function is a promising diagnostic across several disease states. The vast majority of research on HDL functional biology has focused on adult participants with underlying chronic diseases, whereas limited research has investigated the role of HDL in childhood, pregnancy, and old age. Yet, it is apparent that functional HDL is essential at all life stages for maintaining health. In this review, we discuss current data regarding the role of HDL during childhood, pregnancy and in the elderly, how disturbances in HDL may lead to adverse health outcomes, and knowledge gaps in the role of HDL across these life stages.

#4015 RECOMBINANT HIGH-DENSITY LIPOPROTEIN MODULATES INFLAMMATORY RESPONSE AND RENAL DYSFUNCTION IN A SWINE MODEL OF SEPSIS-INDUCED ACUTE KIDNEY INJURY

Abstract Background and Aims Sepsis is a severe and dysregulated inflammatory disease that often precedes the development of acute kidney injury (AKI) with consequent worsening outcome. Although clinical data demonstrate that high-density lipoprotein (HDL) levels drop in septic patients with a poor prognosis, little is known about the molecular basis of HDL's role in systemic inflammation and renal function. Here we investigate the possible effects of a novel engineered HDL-mimetic (CER-001) in a swine model of lipopolysaccharide (LPS)-induced AKI. Method Sepsis was induced by intravenous infusion of a saline solution containing 300 μg/kg of LPS in a porcine model. The animals were randomized into three groups: LPS (endotoxemic pigs, n = 6), CER20 (endotoxemic pigs treated with a single dose of CER-001 20mg/kg; n = 6), and CER20 × 2 (endotoxemic pigs treated with two doses of CER001 20mg/kg; n = 6). Animals were sacrificed after 24h from the start of experimental procedure. Renal histologic and biochemical changes were analyzed. Endothelial dysfunction biomarkers, circulating pro-inflammatory mediators, LPS and Apolipoprotein A-I (Apo A-I) levels were quantified with ELISA assay. Systemic complement activation was evaluated by Wieslab kit. Results Untreated animals were highly susceptible to LPS challenge and usually succumbed before completing the study protocol (LPS group 16.7%). CER-001 treatment increased the survival rate of endotoxemic pigs, compared to the LPS group (CER20, 50%; CER20 × 2, 66.7%). Furthermore, as shown in Figure 1A, LPS injection led to a time-dependent increase of IL-6 in endotoxemic animals respect to basal condition (T0). CER-001 treatment was able to reverse LPS effects. In particular, the second infusion of CER-001 three hours after the first dose (T3) strongly reduced IL-6 serum levels back to basal level (LPS p &amp;lt;0.05). Similarly, we found high levels of TNF-α and MCP-1 in endotoxemic pigs that were significantly decreased in both CER-001 treatment arms (T24, CER20 × 2 vs LPS group, IL-6, p = 0.0086; TNF-α, p&amp;lt;0.0001; MCP-1, p = 0.0009). In addition, CER-001 treatment ameliorated systemic endothelial dysfunction by reducing VCAM and ICAM serum levels. A significant activation of classical and alternative complement pathway (vs T0 p &amp;lt;0.05) was observed at 1h, 3h and 24h after LPS infusion. CER001 treatment significantly prevented systemic complement activation in both treated groups (vs LPS p &amp;lt;0.05). We also investigated whether CER001 infusions significantly prevented renal tissue damage. Endotoxemic pigs presented oliguric AKI with increased tubulo-interstitial infiltrate, extensive collagen deposition, and glomerular thrombi; CER-001 treatment preserved renal parenchyma, recovered urine output, decreased creatine levels, and reduced the biomarkers of tubular damage, Cystatin C and KIM-1, both in serum and urine samples. Considering that HDL has a very high affinity for LPS, we evaluated the circulating LPS concentration in treated animals. We observed that LPS levels were greatly reduced in treated animals and the effects are more evident after the second infusion of CER-001(Figure 1B). Therefore, we also examined LPS levels in bile samples and we observed a dose-dependent increasing amount of endotoxin in the CER001 treated septic pigs. Conclusion This preclinical data indicates that CER001 treatment prevents systemic inflammation thereby limiting renal damage. The mechanism of action is two-fold consisting of both the scavenging of endotoxin and a direct anti-inflammatory effect of CER-001.

The Role of High-Density Lipoprotein in Cardiovascular Disease: Benefits, Functions, and Treatments

There is evidence that high-density lipoprotein (HDL) can prevent the development of cardiovascular disease, particularly atherosclerotic. The beneficial effects of HDL on the arterial wall are largely due to its rich function. For example, one of the essential components of HDL's atherosclerotic protective characteristics is reverse cholesterol transport (RCT). The low-density lipoprotein (LDL) oxidation risk may be decreased attributable to the anti-oxidation function of HDL, which would also decrease the possibility of atherosclerosis. In recent years, the anti-inflammatory function of HDL has been demonstrated to modulate and participate in several inflammatory phenomena of atherosclerotic plaque formation. Since various functional features of HDL have gradually shown to have positive effects on the treatment and prevention of atherosclerotic plaque development, a growing number of researchers are working to develop effective strategies to boost HDL. Fortunately, several treatment options have developed to increase HDL levels, including drugs and dietary patterns. This article will focus on the functional properties of HDL levels and several therapeutic approaches to raise HDL levels.

Apolipoprotein A1 Protects Against Necrotic Core Development in Atherosclerotic Plaques: PDZK1-Dependent High-Density Lipoprotein Suppression of Necroptosis in Macrophages.

Atherosclerosis is a chronic disease affecting artery wall and a major contributor to cardiovascular diseases. Large necrotic cores increase risk of plaque rupture leading to thrombus formation. Necrotic cores are rich in debris from dead macrophages. Programmed necrosis (necroptosis) contributes to necrotic core formation. HDL (high-density lipoprotein) exerts direct atheroprotective effects on different cells within atherosclerotic plaques. Some of these depend on the SR-B1 (scavenger receptor class B type I) and the adapter protein PDZK1 (postsynaptic density protein/Drosophila disc-large protein/Zonula occludens protein containing 1). However, a role for HDL in protecting against necroptosis and necrotic core formation in atherosclerosis is not completely understood. Low-density lipoprotein receptor-deficient mice engineered to express different amounts of ApoA1 (apolipoprotein A1), or to lack PDZK1 were fed a high fat diet for 10 weeks. Atherosclerotic plaque areas, necrotic cores, and key necroptosis mediators, RIPK3 (receptor interacting protein kinase 3), and MLKL (mixed lineage kinase domain-like protein) were characterized. Cultured macrophages were treated with HDL to determine its effects, as well as the roles of SR-B1, PDZK1, and the PI3K (phosphoinositide 3-kinase) signaling pathway on necroptotic cell death. Genetic overexpression reduced, and ApoA1 knockout increased necrotic core formation and RIPK3 and MLKL within atherosclerotic plaques. Macrophages were protected against necroptosis by HDL and this protection required SR-B1, PDZK1, and PI3K/Akt pathway. PDZK1 knockout increased atherosclerosis in LDLRKO mice, increasing necrotic cores and phospho-MLKL; both of which were reversed by restoring PDZK1 in BM-derived cells. Our findings demonstrate that HDL in vitro and ApoA1, in vivo, protect against necroptosis in macrophages and necrotic core formation in atherosclerosis, suggesting a pathway that could be a target for the treatment of atherosclerosis.

Cholesterol Transport to the Endoplasmic Reticulum.

Most cholesterol in mammalian cells is stored in the plasma membrane (PM). Cholesterol transport from the PM to low-sterol regulatory regions of the endoplasmic reticulum (ER) controls cholesterol synthesis and uptake, and thereby influences the rates of cholesterol flux between tissues of complex organisms. Cholesterol transfer to the ER is also required for steroidogenesis, oxysterol and bile acid synthesis, and cholesterol esterification. The ER-resident Aster proteins (Aster-A, -B, and -C) form contacts with the PM to move cholesterol to the ER in mammals. Mice lacking Aster-B have low adrenal cholesteryl ester stores and impaired steroidogenesis because of a defect in cholesterol transport from high-density lipoprotein (HDL) to the ER. This work reviews the molecular characteristics of Asters, their role in HDL- and low-density lipoprotein (LDL)-cholesterol movement, and how cholesterol transferred to the ER is utilized by cells. The roles of other lipid transporters and of membrane lipid organization in maintaining aspects of cholesterol homeostasis are also highlighted.

Post-Stroke Administration of L-4F Promotes Neurovascular and White Matter Remodeling in Type-2 Diabetic Stroke Mice.

Patients with type 2 diabetes mellitus (T2DM) exhibit a distinct and high risk of ischemic stroke with worse post-stroke neurovascular and white matter (WM) prognosis than the non-diabetic population. In the central nervous system, the ATP-binding cassette transporter member A 1 (ABCA1), a reverse cholesterol transporter that efflux cellular cholesterol, plays an important role in high-density lipoprotein (HDL) biogenesis and in maintaining neurovascular stability and WM integrity. Our previous study shows that L-4F, an economical apolipoprotein A member I (ApoA-I) mimetic peptide, has neuroprotective effects via alleviating neurovascular and WM impairments in the brain of db/db-T2DM stroke mice. To further investigate whether L-4F has neurorestorative benefits in the ischemic brain after stroke in T2DM and elucidate the underlying molecular mechanisms, we subjected middle-aged, brain-ABCA1 deficient (ABCA1−B/−B), and ABCA1-floxed (ABCA1fl/fl) T2DM control mice to distal middle cerebral artery occlusion. L-4F (16 mg/kg, subcutaneous) treatment was initiated 24 h after stroke and administered once daily for 21 days. Treatment of T2DM-stroke with L-4F improved neurological functional outcome, and decreased hemorrhage, mortality, and BBB leakage identified by decreased albumin infiltration and increased tight-junction and astrocyte end-feet densities, increased cerebral arteriole diameter and smooth muscle cell number, and increased WM density and oligodendrogenesis in the ischemic brain in both ABCA1−B/−B and ABCA1fl/fl T2DM-stroke mice compared with vehicle-control mice, respectively (p < 0.05, n = 9 or 21/group). The L-4F treatment reduced macrophage infiltration and neuroinflammation identified by decreases in ED-1, monocyte chemoattractant protein-1 (MCP-1), and toll-like receptor 4 (TLR4) expression, and increases in anti-inflammatory factor Insulin-like growth factor 1 (IGF-1) and its receptor IGF-1 receptor β (IGF-1Rβ) in the ischemic brain (p < 0.05, n = 6/group). These results suggest that post-stroke administration of L-4F may provide a restorative strategy for T2DM-stroke by promoting neurovascular and WM remodeling. Reducing neuroinflammation in the injured brain may contribute at least partially to the restorative effects of L-4F independent of the ABCA1 signaling pathway.

HDL, heart disease, and the lung

HDL, heart disease, and the lung

The Role of High-Density Lipoprotein in Lowering Risk of Dementia in the Elderly: A Review.

Dementia is one of the major causes of disability and hospitalization in the elderly. As far as non-invasive markers of dementia are concerned, we only have age and Apolipoprotein-E (Apo-E) gene, which can be considered as clinically relevant. Modifiable risk factors have been found to be the cause in one-third of the patients who develop dementia. The compatible data supporting the same, in particular for dyslipidemia, is limited, which in turn makes it difficult to devise prevention and interventional methods for both dementia and mild cognitive impairment. Hence, the objective of the review is to summarize the findings on the relation established between the high-density lipoprotein type C( HDL-C) levels and lower the chance of dementia in the elderly, and the possible role of HDL-C as a potential predictive biomarker for cases of dementia in elderly people.Dyslipidemia, a known risk factor for the occurrence of cardiovascular diseases, seems to be linked to Alzheimer’s disease. Elevated levels of serum cholesterol in mid-adult life increases the risk of dementia in older age. But elevated high-density lipoprotein (HDL) level and its principal apolipoprotein A-I (ApoA-I ) equates with a low risk of dementia in the elderly populationHDL cholesterol has been found to promote endothelial nitric oxide synthase activity which in turn reduces the neural and vascular inflammation and suppresses vascular adhesion thereby exhibiting its vasoprotective function. It has been believed that all these factors have a role to play in the pathogenesis of dementia.The relation between the higher levels of HDL cholesterol or its key protein component ApoA-I and the lower dementia prevalence in the elderly had been documented in numerous observational studies. Some studies have reported conflicting results. Yet, observational studies measuring the baseline HDL level in middle age found a significant association between HDL level and dementia risk in the elderly, whereas those studies measuring HDL cholesterol level only in old age found no association. Likewise, a significant association between HDL cholesterol and dementia risk has been reported with studies that carry through to 10 years or longer. However, the studies with follow-up of fewer than 10 years had failed to document any such association between HDL cholesterol and dementia. HDL assays may also be used as a predictive biomarker for dementia patients to target the interventions. Although statins do not target HDL directly but can be an area of interest for dementia.

The Problem of Abnormal Body Weight and Dyslipidemia as Risk Factors for Cardiovascular Diseases in Children and Adolescents with Type 1 Diabetes.

Diabetes is a disease that affects many people around the world. Its complications are the cause of cardiovascular diseases (CVD) and increased mortality. That is why the search for predictive biomarkers is so important. The aim of the study was to show the prevalence of the problem and risk factors in children and adolescents with type 1 diabetes. These patients are often overweight and obese, and the percentage of lipid disorders is particularly high. The discussed markers of CVD risk in type 1 diabetes include apolipoproteins (apo-B and apo-C3), modified forms of LDL, and the role of high-density lipoprotein (HDL). Recently, a new look at the vasoprotective effect of HDL has appeared, which due to its dysfunctional form in type 1 diabetes may not protect against cardiovascular risk. The HDL proteome in type 1 diabetes has an altered protein composition compared to the healthy population. Another direction of research is determining the importance of trace elements (mainly Mg) in the development of diabetes complications.

The Role of High-Density Lipoprotein in COVID-19

The current Coronavirus disease 2019 (COVID-19) pandemic has become a global challenge. Managing a large number of acutely ill patients in a short time, whilst reducing the fatality rate and dealing with complications, brings unique difficulties. The most striking pathophysiological features of patients with severe COVID-19 are dysregulated immune responses and abnormal coagulation function, which can result in multiple-organ failure and death. Normally metabolized high-density lipoprotein (HDL) performs several functions, including reverse cholesterol transport, direct binding to lipopolysaccharide (LPS) to neutralize LPS activity, regulation of inflammatory response, anti-thrombotic effects, antioxidant, and anti-apoptotic properties. Clinical data shows that significantly decreased HDL levels in patients with COVID-19 are correlated with both disease severity and mortality. However, the role of HDL in COVID-19 and its specific mechanism remain unclear. In this analysis, we review current evidence mainly in the following areas: firstly, the pathophysiological characteristics of COVID-19, secondly, the pleiotropic properties of HDL, thirdly, the changes and clinical significance of HDL in COVID-19, and fourthly the prospect of HDL-targeting therapy in COVID-19 to clarify the role of HDL in the pathogenesis of COVID-19 and discuss the potential of HDL therapy in COVID-19.

Structure and Dynamics of Oxidized Lipoproteins In Vivo: Roles of High-Density Lipoprotein.

Oxidative modification of lipoproteins is implicated in the occurrence and development of atherosclerotic lesions. Earlier studies have elucidated on the mechanisms of foam cell formation and lipid accumulation in these lesions, which is mediated by scavenger receptor-mediated endocytosis of oxidized low-density lipoprotein (oxLDL). Mounting clinical evidence has supported the involvement of oxLDL in cardiovascular diseases. High-density lipoprotein (HDL) is known as anti-atherogenic; however, recent studies have shown circulating oxidized HDL (oxHDL) is related to cardiovascular diseases. A modified structure of oxLDL, which was increased in the plasma of patients with acute myocardial infarction, was characterized. It had two unique features: (1) a fraction of oxLDL accompanied oxHDL, and (2) apoA1 was heavily modified, while modification of apoB, and the accumulation of oxidized phosphatidylcholine (oxPC) and lysophosphatidylcholine (lysoPC) was less pronounced. When LDL and HDL were present at the same time, oxidized lipoproteins actively interacted with each other, and oxPC and lysoPC were transferred to another lipoprotein particle and enzymatically metabolized rapidly. This brief review provides a novel view on the dynamics of oxLDL and oxHDL in circulation.

The role of high-density lipoprotein in the regulation of the immune response: implications for atherosclerosis and autoimmunity.

Inflammation and immune dysfunction have been increasingly recognized as crucial mechanisms in atherogenesis. Modifications in cell lipid metabolism, plasma dyslipidaemia and particularly low high-density lipoprotein (HDL) levels occur both in atherosclerosis and in autoimmune rheumatic diseases (which are strongly associated with an increased risk of atherosclerosis), suggesting the presence of a crucial link. HDL, the plasma lipoprotein responsible for reverse cholesterol transport, is known for its several protective effects in the context of atherosclerosis. Among these, HDL immunomodulatory effects are possibly the less understood. Through the efflux of cholesterol from plasma cell membranes with the consequent disruption of lipid rafts and the interaction with the cholesterol transporters present in the plasma membrane, HDL affects both the innate and adaptive immune responses. Animal and human studies have demonstrated a predominance of HDL anti-inflammatory effects, despite some pro-inflammatory actions having also been reported. The HDL role on the modulation of the immune response is further suggested by the detection of low levels together with a dysfunctional HDL in patients with autoimmune diseases. Here, we review the current knowledge of the immune mechanisms of atherosclerosis and the modulatory effects HDL may have on them.

HDL-enriched miR-30a-5p is associated with HDL-cholesterol levels and glucose metabolism in healthy men and women.

Aim: To investigate the associations between high-density lipoprotein (HDL)-enriched miRNAs and the cardiometabolic profile of healthy men and women. Patients & methods: miRNAs were quantified using next-generation sequencing of miRNAs extracted from purified HDL and plasma from 17 healthy men and women couples. Results: Among the HDL-enriched miRNAs, miR-30a-5p correlated positively with HDL-cholesterol levels, whereas miR-144-5p and miR-30a-5p were negatively associated with fasting insulin levels and Homeostasis model assessment of insulin resistance index. Overall, miR-30a-5p, miR-150-5p and sex contributed to 45% of HDL-cholesterol variance. A model containing only miR-30a-5p, age and sex explained 41% of fasting glucose variance. Conclusion: HDL-enriched miRNAs, notably miR-30a-5p, are associated with cardiometabolic markers. These miRNAs could play a role in HDL's protective functions, particularly regarding glucose-insulin homeostasis.

HDL Cholesterol and Non-Cardiovascular Disease: A Narrative Review.

High density lipoprotein (HDL) cholesterol has traditionally been considered the “good cholesterol”, and most of the research regarding HDL cholesterol has for decades revolved around the possible role of HDL in atherosclerosis and its therapeutic potential within atherosclerotic cardiovascular disease. Randomized trials aiming at increasing HDL cholesterol have, however, failed and left questions to what role HDL cholesterol plays in human health and disease. Recent observational studies involving non-cardiovascular diseases have shown that high levels of HDL cholesterol are not necessarily associated with beneficial outcomes as observed for age-related macular degeneration, type II diabetes, dementia, infection, and mortality. In this narrative review, we discuss these interesting associations between HDL cholesterol and non-cardiovascular diseases, covering observational studies, human genetics, and plausible mechanisms.

ADAM17 Boosts Cholesterol Efflux and Downstream Effects of High-Density Lipoprotein on Inflammatory Pathways in Macrophages.

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High-Density Lipoprotein Anti-Inflammatory Capacity and Incident Cardiovascular Events.

The role of high-density lipoprotein (HDL) function in cardiovascular disease represents an important emerging concept. The present study investigated whether HDL anti-inflammatory capacity is prospectively associated with first cardiovascular events in the general population. HDL anti-inflammatory capacity was determined as its ability to suppress TNFα (tumor necrosis factor α)-induced VCAM-1 (vascular cell adhesion molecule-1) mRNA expression in endothelial cells in vitro (results expressed as achieved percent reduction by individual HDL related to the maximum TNFα effect with no HDL present). In a nested case-control design of the PREVEND (Prevention of Renal and Vascular End Stage Disease) study, 369 cases experiencing a first cardiovascular event (combined end point of death from cardiovascular causes, ischemic heart disease, nonfatal myocardial infarction, and coronary revascularization) during a median of 10.5 years of follow-up were identified and individually matched to 369 controls with respect to age, sex, smoking status, and HDL cholesterol. Baseline samples were available in 340 cases and 340 matched controls. HDL anti-inflammatory capacity was not correlated with HDL cholesterol or hsCRP (high-sensitivity C-reactive protein). HDL anti-inflammatory capacity was significantly lower in cases compared with controls (31.6% [15.7-44.2] versus 27.0% [7.4-36.1]; P<0.001) and was inversely associated with incident CVD in a fully adjusted model (odds ratio [OR] per 1 SD, 0.74 [CI, 0.61-0.90]; P=0.002). Furthermore, this association was approximately similar with all individual components of the cardiovascular disease end point. The HDL anti-inflammatory was not correlated with cholesterol efflux capacity (r=-0.02; P>0.05). When combining these 2 HDL function metrics in 1 model, both were significantly and independently associated with incident cardiovascular disease in a fully adjusted model (efflux: OR per 1 SD, 0.74; P=0.002; anti-inflammatory capacity: OR per 1 SD, 0.66; P<0.001). Adding HDL anti-inflammatory capacity improved risk prediction by the Framingham risk score, with a model likelihood-ratio statistic increase from 10.50 to 20.40 (P=0.002). The HDL anti-inflammatory capacity, reflecting vascular protection against key steps in atherogenesis, was inversely associated with incident cardiovascular events in a general population cohort, independent of HDL cholesterol and HDL cholesterol efflux capacity. Adding HDL anti-inflammatory capacity to the Framingham risk score improves risk prediction.

Decreased Efficiency of Very-Low-Density Lipoprotein Lipolysis Is Linked to Both Hypertriglyceridemia and Hypercholesterolemia, but It Can Be Counteracted by High-Density Lipoprotein.

Impaired triglyceride-rich lipoprotein plasma catabolism is considered the most important factor for hypertriglyceridemia development. The aim of this study was to evaluate the impact of hypercholesterolemia and hypertriglyceridemia on the efficiency of lipoprotein lipase (LPL)-mediated very-low-density lipoprotein (VLDL)-triglyceride lipolysis and the role of high-density lipoprotein (HDL) in this process. Subjects with no history of cardiovascular disease (CVD) and untreated with lipid-lowering agents were recruited into the study and divided into normolipidemic, hypercholesterolemic, and hyperlipidemic groups. VLDL was isolated from serum and incubated with LPL in the absence or presence of HDL. For the hypercholesterolemic and hyperlipidemic groups, a significantly lower percentage of hydrolyzed VLDL-triglyceride was achieved compared to the normolipidemic group (p < 0.01). HDL enhanced the lipolysis efficiency in the hypercholesterolemic and hyperlipidemic groups on average by ~7% (p < 0.001). The lowest electrophoretic mobility of the VLDL remnants indicating the most effective lipolysis was obtained in the normolipidemic group (p < 0.05). HDL presence significantly reduced the electrophoretic mobility of the VLDL remnants for the hypercholesterolemic and hyperlipidemic groups (p < 0.05). The results of our study indicate that VLDL obtained from hypercholesterolemic and hyperlipidemic subjects are more resistant to lipolysis and are additional evidence of the need for early implementation of hypocholesterolemic treatment, already in asymptomatic CVD subjects.