Capacity of HDL to Efflux Cellular Cholesterol from Lipid-Loaded Macrophages Is Reduced in Patients with Familial Hypercholesterolemia

: This study aimed to evaluate the high-density lipoprotein (HDL) capacity to efflux cellular cholesterol from lipid-loaded macrophages to find a reliable and low-cost biomarker with the purpose of better evaluating the risk of premature cardiovascular (CV) events in FH patients. This case-controlled study comprised 16 homozygous (HOFH) and 18 heterozygous (HEFH) FH patients, as well as 20 healthy subjects recruited as controls. Two main subfractions of HDL (HDL2 (d = 1.063-1.125 g/mL) and HDL3 (d = 1.125-1.210 g/mL)) were isolated from the patients' serum samples using sequential ultracentrifugation. After compositional characterization, the capacity of HDL to efflux cholesterol (CEC%) from lipid-laden macrophages was measured. The HDL2 and HDL3 subfractions showed some differences in lipid and protein composition between the studied groups. In addition, both HDL subfractions (p < 0.001) revealed significantly reduced CEC% in HOFH patients (HDL2: 2.5 ± 0.1 and HDL3: 3.2 ± 0.2) in comparison with the HEFH (HDL2: 3.2 ± 0.1% and HDL3: 4.1 ± 0.2%) and healthy (HDL2: 3.3 ± 0.2% and HDL3: 4.5 ± 0.3%) subjects. Additionally, multinomial logistic regression results indicated that the CEC% of both HDL2 (OR: 0.091; 95% CI: 0.018-0.452, p < 0.01) and HDL3 (OR: 0.118; 95% CI: 0.035-0.399, p < 0.01) subfractions are strongly and inversely associated with the homozygous form of FH. A decreased capacity of HDL particles to efflux cholesterol from macrophages might identify homozygous FH patients who are at elevated risk for premature CVDs. Prospective studies with a large sample size are warranted to evaluate this hypothesis

Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small, dense HDL3c

High-density lipoprotein (HDL) possesses multiple biological activities; small, dense HDL3c particles displaying distinct lipidomic composition exert potent antiatherogenic activities which can be compromised in dyslipidemic, hyperglycemic insulin-resistant states. However, it remains indeterminate (i) whether such functional HDL deficiency is related to altered HDL composition, and (ii) whether it originates from atherogenic dyslipidemia, dysglycemia, or both. In the present work we analyzed compositional characteristics of HDL subpopulations and functional activity of small, dense HDL3c particles in treatment-naïve patients with well-controlled (n=10) and poorly-controlled (n=8) type 2 diabetes (T2D) and in normolipidemic age- and sex-matched controls (n=11). Our data reveal that patients with both well- and poorly-controlled T2D displayed dyslipidemia and low-grade inflammation associated with altered HDL composition. Such compositional alterations in small, dense HDL subfractions were specifically correlated with plasma HbA1c levels. Further analysis using a lipidomic approach revealed that small, dense HDL3c particles from T2D patients with poor glycemic control displayed additional modifications of their chemical composition. In parallel, antioxidative activity of HDL3c towards oxidation of low-density lipoprotein was diminished. These findings indicate that defective functionality of small, dense HDL particles in patients with T2D is not only affected by the presence of atherogenic dyslipidemia, but also by the level of glycemic control, reflecting compositional alterations of HDL. Keywords: Antioxidative activity; Functionality; HDL; Lipidomics; Type 2 diabetes

Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload

Abstract Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high-density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex-and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment-estimated insulin resistance): +93 %, P < 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n = 7) presented a reduced β-cell function and insulin secretion compared with non-C282Y patients (n = 11) (−58 % and −73 %, respectively, P < 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43 + − 5; non-C282Y: 25 + − 8; controls: 32 + − 7 %; P < 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23 + − 5; non-C282Y: 39 + − 10; controls: 26 + − 4 %; P < 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined

HDL and Reverse Remnant-Cholesterol Transport (RRT): Relevance to Cardiovascular Disease

International audienceCardiovascular diseases predominantly result from atherosclerosis, a natural biological phenomenon reflecting food intake and energy production in humans. Lipolysis of plasma triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase (LPL) is an essential element of energy production that delivers free fatty acids to peripheral cells. High-density lipoprotein (HDL) plays a key role in this process by acquiring surface lipids, including free cholesterol, that are released upon TGRL lipolysis. According to the reverse remnant-cholesterol transport (RRT) hypothesis, such removal of cholesterol from remnant lipoproteins followed by transport to the liver and excretion into the bile represents a major biological function of HDL that is essential for energy production, and which can reduce cholesterol influx into the arterial wall by accelerating the removal of atherogenic TGRL remnants from the circulation

Lipid peroxidation and Alzheimer’s disease: Key role of Amyloid-β

Increased lipid peroxidation and elevated oxidative stress represent well-established characteristics of Alzheimer’s disease (AD). Amyloid-β (Aβ) peptide, a major component of amyloid plaques, can strongly influence oxidative processes. In aggregated form, Aβ has prooxidative properties, whereas in monomeric form it functions as an antioxidant. The antioxidative properties of monomeric Aβ are related to its ability to chelate transition metal ions, which are potent catalysts of oxidation. Aβ possesses an amphiphilic structure, associates with lipoproteins in vivo and may therefore function as a preventive antioxidant which protects lipoproteins from oxidation by transition metal ions. Increased production of Aβ in response to elevated oxidative stress has been documented in a number of in vitro studies, implying that production of monomeric Aβ as a lipoprotein antioxidant can be abnormally increased in response to elevated oxidative stress in aging. Subsequent accumulation of Aβ-metal aggregates, production of reactive oxygen species and toxic action to neuronal cells may represent a gain-of-function transformation and form temporal sequence of events in the development of AD

Identifying new Risk Markers and Potential Targets: The Value of the Proteome

International audienceSeveral protein biomarkers, including cardiac troponin T, cardiac troponin I, B-type natriuretic peptide, C-reactive protein and apolipoprotein A-I, are widely employed in the evaluation of cardiovascular disease. Several of such potential biomarkers, or their multiscores, have been assessed over the last years for the prediction of cardiovascular risk but only a few of them have been validated for clinical use. Substantial improvement in the cardiovascular risk prediction and reclassification relative to traditional models therefore remains a difficult task presently unresolved. Hence, a potential importance of alternative approaches which may rely on novel proteomic biomarkers among others. Plasma or serum concentrations of numerous proteins were measured using proteomic approaches to establish their relationships with cardiovascular disease; none of them was however evaluated for cardiovascular risk prediction and subject stratification in rigorous large-scale studies. Thus, further research is needed to identify novel candidates that can improve cardiovascular risk prediction, subject stratification and standard care. Proteomics will undoubtedly remain a key approach to address this major clinical and scientific challenge

Etude quantitative et qualitative des HDL chez des patients à risque cardiovasculaire (impact thérapeutique d'interventions nutritionnelles et pharmacologiques)

La concentration sérique du HDL-Cholestérol (HDL-C) est un facteur de risque indépendant de maladie cardio-vasculaire (CV). Augmenter le taux du HDL-C, reflet de la quantité des HDL, et améliorer la qualité des activités biologiques des HDL sont donc des approches thérapeutiques prometteuses pour réduire le risque CV. Bien que les principaux facteurs qui déterminent la concentration du HDL-C soient assez bien connus, il n'en est pas de même de la quantification de leur rôle relatif, ni du bénéfice CV de l'augmentation du HDL-C liée à chacun de ces facteurs en particulier. En second lieu, peu de travaux ont tenté d'améliorer la qualité des particules HDL par des thérapeutiques usuelles. Notre travail nous a permis de progresser dans deux aspects différents : 1) Nous avons mis en évidence, chez 14 000 sujets dyslipidémiques, huit paramètres associés de façon indépendante à la concentration de HDL-C. Par ordre d'importance, ce sont les triglycérides plasmatiques, le sexe, l'âge, le tour de taille, la consommation d'alcool, la CRPus, l'index HOMA et le tabagisme. Dans une seconde étude, centrée spécifiquement sur le " déterminant alcool ", effectuée chez près de 150 000 sujets, nous établissons des relations statistiques en J entre la consommation d'alcool et la plupart des facteurs de risque, traditionnels ou non, des maladies CV. Cependant il ressort de l'étude que ces relations ne sont pas nécessairement causales. L'effet cardioprotecteur supposé de l'alcool peut être lié à des facteurs de confusion non pris en compte dans les études épidémiologiquesPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Phosphatidylserine in atherosclerosis

International audiencePurpose of review: It is now widely acknowledged that phosphatidylserine is a multifunctional bioactive lipid. In this review, we focus on the function of phosphatidylserine in modulating cholesterol metabolism, influencing inflammatory response and regulating coagulation system, and discuss promising phosphatidylserine-based therapeutic approaches and detection techniques in atherosclerosis

High-density lipoproteins (HDL): Novel function and therapeutic applications

International audienceThe failure of high-density lipoprotein (HDL)-raising agents to reduce cardiovascular disease (CVD) together with recent findings of increased cardiovascular mortality in subjects with extremely high HDL-cholesterol levels provide new opportunities to revisit our view of HDL. The concept of HDL function developed to explain these contradictory findings has recently been expanded by a role played by HDL in the lipolysis of triglyceride-rich lipoproteins (TGRLs) by lipoprotein lipase. According to the reverse remnant-cholesterol transport (RRT) hypothesis, HDL critically contributes to TGRL lipolysis via acquirement of surface lipids, including free cholesterol, released from TGRL. Ensuing cholesterol transport to the liver with excretion into the bile may reduce cholesterol influx in the arterial wall by accelerating removal from circulation of atherogenic, cholesterol-rich TGRL remnants. Such novel function of HDL opens wide therapeutic applications to reduce CVD in statin-treated patients, which primarily involve activation of cholesterol flux upon lipolysis

Why is HDL functionally deficient in type 2 diabetes?

International audienceHigh-density lipoprotein (HDL) particles exert a spectrum of atheroprotective activities that can be deficient in type 2 diabetes. Key mechanisms leading to the formation of functionally deficient HDL involve 1) HDL enrichment in triglycerides and depletion in cholesteryl esters with conformational alterations of apolipoprotein A-I; 2) glycation of apolipoproteins and/or HDL-associated enzymes; and 3) oxidative modification of HDL lipids, apolipoproteins, and/or enzymes. Available data identify hypertriglyceridemia, with concomitant compositional modification of the HDL lipid core and conformational change of apolipoprotein A-I, as a driving force in functional alteration of HDL particles in type 2 diabetes. Therapeutic options for correcting HDL functional deficiency should target hypertriglyceridemia by normalizing circulating levels of triglyceride-rich lipoproteins