Sacks, Frank M; Rudel, Lawrence L; Conner, Adam; Akeefe, Hassibullah; Kostner, Gerhard; Baki, Talal; Rothblat, George; de la Llera-Moya, Margarita; Asztalos, Bela; Perlman, Timothy; Zheng, Chunyu; Alaupovic, Petar; Maltais, Jo-Ann B; Brewer, H Bryan
Uptake of cholesterol from peripheral cells by nascent small HDL circulating in plasma is necessary to prevent atherosclerosis. This process, termed reverse cholesterol transport, produces larger cholesterol-rich HDL that transfers its cholesterol to the liver facilitating excretion. Most HDL in plasma is cholesterol-rich. We demonstrate that treating plasma with a novel selective delipidation procedure converts large to small HDL [HDL-selectively delipidated (HDL-sdl)]. HDL-sdl contains several cholesterol-depleted species resembling small alpha, prebeta-1, and other prebeta forms. Selective delipidation markedly increases efficacy of plasma to stimulate ABCA1-mediated cholesterol transfer from monocytic cells to HDL. Plasma from African Green monkeys underwent selective HDL delipidation. The delipidated plasma was reinfused into five monkeys. Prebeta-1-like HDL had a plasma residence time of 8 +/- 6 h and was converted entirely to large alpha-HDL having residence times of 13-14 h. Small alpha-HDL was converted entirely to large alpha-HDL. These findings suggest that selective HDL delipidation activates reverse cholesterol transport, in vivo and in vitro. Treatment with delipidated plasma tended to reduce diet-induced aortic atherosclerosis in monkeys measured by intravascular ultrasound. These findings link the conversion of small to large HDL, in vivo, to improvement in atherosclerosis.
Toledo-Ibelles, Paola; García-Sánchez, Cynthia; Ávila-Vazzini, Nydia; Carreón-Torres, Elizabeth; Posadas-Romero, Carlos; Vargas-Alarcón, Gilberto; Pérez-Méndez, Oscar
The aim of this study was to develop an enzymatic cholesterol staining method to determine HDL subclasses in a polyacrylamide gradient gel electrophoresis, which further allows staining by protein in the same electrophoresis lane. HDLs from 120 healthy individuals were separated through nondenaturing PAGE. HDLs were stained for cholesterol using an enzymatic semisolid mixture. Once the gels were unstained, they were stained again for proteins with Coomassie blue. The proportions of HDL subclasses were determined by densitometry. HDL subclasses were transformed to concentrations using as reference HDL-cholesterol plasma levels. This method is comparable in linearity and reproducibility to Coomassie blue staining, although it provides quantitative data. As expected, HDL size distribution shifted toward larger particles when determined by cholesterol as compared with protein. With this method, we observed different proportions of HDL subclasses between men and women as compared with Coomassie blue staining. We described a method to determine HDL size distribution by enzymatic cholesterol staining on polyacrylamide gels. The method allows the quantification of the cholesterol plasma concentration of each HDL subclass with the possibility to further stain the protein in the same sample. The combination of HDL staining by cholesterol and protein on electrophoresis gels provides information that may have clinical relevance. PMID:20097938
... Lipoprotein Cholesterol Related tests: Cholesterol ; LDL Cholesterol ; Triglycerides ; Lipid Profile ; Cardiac Risk Assessment ; Lp-PLA2 All content on ... HDL-C) is used as part of a lipid profile to screen for unhealthy levels of lipids and ...
Keidar, Shlomo; Guttmann, Hadassa; Stam, Tamar; Fishman, Ilana; Shapira, Chen
A paradoxical plasma HDL-Cholesterol (HDL-C) reducing effect following combined fibrate and thiazolidinediones (TZDs) therapy was recently reported in occasional cases. As HDL-C level is inversely related to cardiovascular disease (CVD) risk, we have studied the incidence of reduced HDL-C level following mono- and combined therapy with these drugs in a large diabetic population. This study was designed as a retrospective 5-year study. Lipid profile records of 54 000 diabetic patients were searched for transient reduction of HDL-C to levels lower than 17 mg/dL, which was correlated with fibrates and/or TZD treatment. Transient reduction in plasma HDL-C to values lower than 17 mg/dL was observed in 0.02% (2/11 175) of the patients treated with fibrates alone, none of the rosiglitazone-treated patients (0/3213) and in 1.39% (9/649) of patients treated with combination of fibrate and TZD. HDL-C lowering effect was reversible upon stopping either fibrate or rosiglitazone and in some patients it occurred within 2 weeks. In two of the patients, the effect was dose-dependent. Severe reduction in plasma HDL-C is not rare when TZD and fibrates are co-administrated to diabetic hyperlipidemic patients. As low plasma HDL cholesterol is a risk factor for CVD, the physician should be alert to this phenomenon.
Increased cholesterol efflux from cultured fibroblasts to plasma from hypertriglyceridemic type 2 diabetic patients: roles of pre beta-HDL, phospholipid transfer protein and cholesterol esterification.
de Vries, R; Groen, A K; Perton, F G; Dallinga-Thie, G M; van Wijland, M J A; Dikkeschei, L D; Wolffenbuttel, B H R; van Tol, A; Dullaart, R P F
We tested whether hypertriglyceridemia associated with type 2 diabetes mellitus is accompanied by alterations in pre beta-HDL, which are considered to be initial acceptors of cell-derived cholesterol, and by changes in the ability of plasma to promote cellular cholesterol efflux. In 28 hypertriglyceridemic and 56 normotriglyceridemic type 2 diabetic patients, and in 56 control subjects, we determined plasma lipids, HDL cholesterol and phospholipids, plasma pre beta-HDL and pre beta-HDL formation, phospholipid transfer protein (PLTP) activity, plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) and the ability of plasma to stimulate cholesterol efflux out of cultured human fibroblasts. HDL cholesterol and HDL phospholipids were lower, whereas plasma PLTP activity, EST and CET were higher in hypertriglyceridemic diabetic patients than in the other groups. Pre beta-HDL levels and pre beta-HDL formation were unaltered, although the relative amount of pre beta-HDL (expressed as % of total plasma apo A-I) was increased in hypertriglyeridemic diabetic patients. Cellular cholesterol efflux to plasma from hypertriglyceridemic diabetic patients was increased compared to efflux to normotriglyceridemic diabetic and control plasma, but efflux to normotriglyceridemic diabetic and control plasma did not differ. Multiple linear regression analysis demonstrated that cellular cholesterol efflux to plasma was positively and independently related to pre beta-HDL formation, PLTP activity and EST (multiple r=0.48), but not to the diabetic state. In conclusion, cholesterol efflux from fibroblasts to normotriglyceridemic diabetic plasma is unchanged. Efflux to hypertriglyceridemic diabetic plasma is enhanced, in association with increased plasma PLTP activity and cholesterol esterification. Unaltered pre beta-HDL formation in diabetic hypertriglyceridemia, despite low apo A-I, could contribute to maintenance of cholesterol efflux.
Murguía-Romero, Miguel; Jiménez-Flores, J. Rafael; Sigrist-Flores, Santiago C.; Espinoza-Camacho, Miguel A.; Jiménez-Morales, Mayra; Piña, Enrique; Méndez-Cruz, A. René; Villalobos-Molina, Rafael; Reaven, Gerald M.
Studies in mature adults suggest that the plasma concentration ratio of triglyceride (TG)/HDL-cholesterol (HDL-C) provides a simple way to identify apparently healthy individuals who are insulin resistant (IR) and at increased cardiometabolic risk. This study extends these observations by examining the clinical utility of the TG/HDL-C ratio and the metabolic syndrome (MetS) in 2,244 healthy college students (17–24 years old) of Mexican Mestizo ancestry. The TG/HDL-C ratio separating the 25% with the highest value was used to identify IR and increased cardiometabolic risk. Cardiometabolic risk factors were more adverse in men and women whose TG/HDL-C ratios exceeded 3.5 and 2.5, respectively, and approximately one third were identified as being IR. The MetS identified fewer individuals as being IR, but their risk profile was accentuated. In conclusion, both a higher TG/HDL-C ratio and a diagnosis of the MetS identify young IR individuals with an increased cardiometabolic risk profile. The TG/HDL-C ratio identified a somewhat greater number of “high risk” subjects, whereas the MetS found a group whose risk profile was somewhat magnified. These findings suggest that the TG/HDL-C ratio may serve as a simple and clinically useful approach to identify apparently healthy, young individuals who are IR and at increased cardiometabolic risk. PMID:23863983
Churchill, Gary A.
Stressful environmental factors, such as a high-fat diet, can induce responses in the expression of genes that act to maintain physiological homeostasis. We observed variation in plasma concentrations of high-density lipoprotein (HDL) cholesterol across inbred mouse strains in response to high dietary fat intake. Several strains, including C57BL/6J, have stable levels of plasma HDL independent of diet, whereas other strains, including DBA2/J, show marked changes in plasma HDL. To explore this phenomenon further, we used publicly available data from a C57BL/6J × DBA/2J intercross to identify genetic factors that associate with HDL under high-fat diet conditions. Our analysis identified an epistatic interaction that plays a role in the buffering of HDL levels in C57BL/6J mice, and we have identified Arl4d as a candidate gene that mediates this effect. Structural modeling further elucidates the interaction of genetic factors that contribute to the robustness of HDL in response to high-fat diet in the C57BL/6J strain. PMID:20858711
Ramírez, Cristina M.; Rotllan, Noemi; Vlassov, Alexander V.; Dávalos, Alberto; Li, Mu; Goedeke, Leigh; Aranda, Juan F.; Cirera-Salinas, Daniel; Araldi, Elisa; Salerno, Alessandro; Wanschel, Amarylis; Zavadil, Jiri; Castrillo, Antonio; Kim, Jungsu; Suárez, Yajaira; Fernández-Hernando, Carlos
Rationale Foam cell formation due to excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis, the major cause of morbidity and mortality in Western societies. Liver X nuclear receptors (LXRs) regulate the expression of the adenosine triphosphate-binding cassette (ABC) transporters, including ABCA1 and ABCG1. ABCA1 and ABCG1 facilitate the efflux of cholesterol from macrophages and regulate high-density lipoprotein (HDL) biogenesis. Increasing evidence supports the role of microRNA (miRNAs) in regulating cholesterol metabolism through ABC transporters. Objective We aimed to identify novel miRNAs that regulate cholesterol metabolism in macrophages stimulated with LXR agonists. Methods and Results To map the miRNA expression signature of macrophages stimulated with LXR agonists, we performed a miRNA profiling microarray analysis in primary mouse peritoneal macrophages stimulated with LXR ligands. We report that LXR ligands increase miR-144 expression in macrophages and mouse livers. Overexpression of miR-144 reduces ABCA1 expression and attenuates cholesterol efflux to ApoA1 in macrophages. Delivery of miR-144 oligonucleotides to mice attenuates ABCA1 expression in the liver, reducing HDL levels. Conversely, silencing of miR-144 in mice increases the expression of ABCA1 and plasma HDL levels. Thus, miR-144 appears to regulate both macrophage cholesterol efflux and HDL biogenesis in the liver. Conclusions 1) miR-144 regulates cholesterol metabolism via suppressing ABCA1 expression; and 2) modulation of miRNAs may represent a potential therapeutical intervention for treating dyslipidemia and atherosclerotic vascular disease. PMID:23519695
Voight, Benjamin F; Peloso, Gina M; Orho-Melander, Marju; Frikke-Schmidt, Ruth; Barbalic, Maja; Jensen, Majken K; Hindy, George; Hólm, Hilma; Ding, Eric L; Johnson, Toby; Schunkert, Heribert; Samani, Nilesh J; Clarke, Robert; Hopewell, Jemma C; Thompson, John F; Li, Mingyao; Thorleifsson, Gudmar; Newton-Cheh, Christopher; Musunuru, Kiran; Pirruccello, James P; Saleheen, Danish; Chen, Li; Stewart, Alexandre FR; Schillert, Arne; Thorsteinsdottir, Unnur; Thorgeirsson, Gudmundur; Anand, Sonia; Engert, James C; Morgan, Thomas; Spertus, John; Stoll, Monika; Berger, Klaus; Martinelli, Nicola; Girelli, Domenico; McKeown, Pascal P; Patterson, Christopher C; Epstein, Stephen E; Devaney, Joseph; Burnett, Mary-Susan; Mooser, Vincent; Ripatti, Samuli; Surakka, Ida; Nieminen, Markku S; Sinisalo, Juha; Lokki, Marja-Liisa; Perola, Markus; Havulinna, Aki; de Faire, Ulf; Gigante, Bruna; Ingelsson, Erik; Zeller, Tanja; Wild, Philipp; de Bakker, Paul I W; Klungel, Olaf H; Maitland-van der Zee, Anke-Hilse; Peters, Bas J M; de Boer, Anthonius; Grobbee, Diederick E; Kamphuisen, Pieter W; Deneer, Vera H M; Elbers, Clara C; Onland-Moret, N Charlotte; Hofker, Marten H; Wijmenga, Cisca; Verschuren, WM Monique; Boer, Jolanda MA; van der Schouw, Yvonne T; Rasheed, Asif; Frossard, Philippe; Demissie, Serkalem; Willer, Cristen; Do, Ron; Ordovas, Jose M; Abecasis, Gonçalo R; Boehnke, Michael; Mohlke, Karen L; Daly, Mark J; Guiducci, Candace; Burtt, Noël P; Surti, Aarti; Gonzalez, Elena; Purcell, Shaun; Gabriel, Stacey; Marrugat, Jaume; Peden, John; Erdmann, Jeanette; Diemert, Patrick; Willenborg, Christina; König, Inke R; Fischer, Marcus; Hengstenberg, Christian; Ziegler, Andreas; Buysschaert, Ian; Lambrechts, Diether; Van de Werf, Frans; Fox, Keith A; El Mokhtari, Nour Eddine; Rubin, Diana; Schrezenmeir, Jürgen; Schreiber, Stefan; Schäfer, Arne; Danesh, John; Blankenberg, Stefan; Roberts, Robert; McPherson, Ruth; Watkins, Hugh; Hall, Alistair S; Overvad, Kim; Rimm, Eric; Boerwinkle, Eric; Tybjaerg-Hansen, Anne; Cupples, L Adrienne; Reilly, Muredach P; Melander, Olle; Mannucci, Pier M; Ardissino, Diego; Siscovick, David; Elosua, Roberto; Stefansson, Kari; O'Donnell, Christopher J; Salomaa, Veikko; Rader, Daniel J; Peltonen, Leena; Schwartz, Stephen M; Altshuler, David; Kathiresan, Sekar
Summary Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Findings Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol
Padmanathan, S.; Green, M.H.; Kris-Etherton, P.M.
The present investigation was designed to study high density lipoprotein (HDL)-derived plasma cholesterol (C) turnover in hepatic and extrahepatic tissues of sedentary (S) and exercised (E) rats. 4-week-old Long Evans rats were exercised for 1 hr, 6 days weekly, for a period of 38 weeks, on a motor-driven treadmill at 0.8 mph at a 12% grade. Animals were injected with HDL that was labelled in vitro with /sup 3/H-cholesteryl ester. Serial blood samples and tissues were collected. HDL-C concentration was lower in E vs S rats (23.0 +/- 1.2 and 26.6 +/- 1.9 mg/dl, p < 0.01). While total plasma C was not different, liver C was higher in S vs E rats (8.2 +/- 0.8 and 7.2 +/- 0.5 mg/g). Adrenal C was higher in E vs S rats (29.5 +/- 2.3 and 20.7 +/- 2.3 mg/g, p < 0.01). Multicompartmental analysis of plasma and tissue tracer response led to development of an 8-component model (5 physiological; 3 nonphysiological) that depicted HDL-derived plasma C turnover. Plasma fraction of tracer declined more rapidly in E vs S rats. E rats cleared nonphysiological tracer more rapidly than S rats, but delayed release of tracer into the plasma longer. Fractional rate of tracer uptake into adrenals, liver, testes, and carcass was greater in E rats. There was a greater fractional turnover rate of tracer in adrenals and liver in S vs E rats. Hence HDL-derived plasma C turnover is altered with vigorous exercise.
Owecki, Maciej; Nikisch, Elżbieta; Miczke, Anna; Pupek-Musialik, Danuta; Sowiński, Jerzy
Plasma cholesterol, triglycerides and serum resisistin may all be influenced by diabetes and obesity, but their associations remain unclear. Therefore, we put forward a hypothesis that serum lipids might be parallel to resistin, as they all reflect the metabolic status of obese humans. We measured the concentrations of resistin, total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) and triglycerides (TG) in 134 obese non-diabetic (73 women and 61 men) and 65 obese diabetic (33 women, 32 men) humans, and examined their interrelations. Obesity was defined according to the WHO criterion (BMI, ≥ 30 kg/m²) The presence of diabetes was the only differentiating factor between two groups of frankly obese humans. Non-diabetic vs. diabetic, median and interquartile range, respectively: resistin (ng/mL) 26.08, 16.09 vs. 22.37, 14.54, p=0.736; TC (mmol/L) 5.02, 1.39 vs. 5.16, 1.56, p=0.374; HDL-C (mmol/L): 1.10, 0.41 vs. 1.02, 0.47 p<0.05; LDL-C (mmol/L): 3.00, 1.05 vs. 3.00, 1.30 p=0.978; TG (mmol/L) 1.70, 1.43 vs.1.95, 1.81 p<0.05. To investigate the interrelations between resistin and lipids, a simple regression analysis was used, and the results were for resistin & TC, HDL-C, LDL-C, and TG, respectively: in the whole cohort r=-0.1364, p=0.0670, r=0.1514, p=0.0437, r=-0.2573, p=0.0006, r=0.0434, p=0.5597; in non-diabetics: r=-0.2067, p=0.0213, r=0.1023, p=0.2621, r=-0.2399, p=0.0083 and r=0.0288, p=0.7497; in diabetics r=0.0280, p=0.8360, r=0.2267, p=0.0929, r=-0.2933, p=0.0298, r=0.1349, p=0.3127. In diabetic and non-diabetic subjects the atherogenic LDL cholesterol shows an inverse correlation with resistin, whereas the protective anti-atherosclerotic HDL cholesterol is positively correlated with resistin.
Zimetti, Francesca; De Vuono, Stefano; Gomaraschi, Monica; Adorni, Maria Pia; Favari, Elda; Ronda, Nicoletta; Ricci, Maria Anastasia; Veglia, Fabrizio; Calabresi, Laura; Lupattelli, Graziana
Acute phase reaction (APR) is a systemic inflammation triggered by several conditions associated with lipid profile alterations. We evaluated whether APR also associates with changes in cholesterol synthesis and absorption, HDL structure, composition, and cholesterol efflux capacity (CEC). We analyzed 59 subjects with APR related to infections, oncologic causes, or autoimmune diseases and 39 controls. We detected no difference in markers of cholesterol synthesis and absorption. Conversely, a significant reduction of LpA-I- and LpAI:AII-containing HDL (-28% and -44.8%, respectively) and of medium-sized HDL (-10.5%) occurred in APR. Total HDL CEC was impaired in APR subjects (-18%). Evaluating specific CEC pathways, we found significant reductions in CEC by aqueous diffusion and by the transporters scavenger receptor B-I and ABCG1 (-25.5, -41.1 and -30.4%, respectively). ABCA1-mediated CEC was not affected. Analyses adjusted for age and gender provided similar results. In addition, correcting for HDL-cholesterol (HDL-C) levels, the differences in aqueous diffusion total and ABCG1-CEC remained significant. APR subjects displayed higher levels of HDL serum amyloid A (+20-folds; P = 0.003). In conclusion, APR does not associate with cholesterol synthesis and absorption changes but with alterations of HDL composition and a marked impairment of HDL CEC, partly independent of HDL-C serum level reduction. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.
Berryman, Claire E; Fleming, Jennifer A; Kris-Etherton, Penny M
Background: Almonds may increase circulating HDL cholesterol when substituted for a high-carbohydrate snack in an isocaloric diet, yet little is known about the effects on HDL biology and function.Objective: The objective was to determine whether incorporating 43 g almonds/d in a cholesterol-lowering diet would improve HDL subspecies and function, which were secondary study outcomes.Methods: In a randomized, 2-period, crossover, controlled-feeding study, a diet with 43 g almonds/d (percentage of total energy: 51% carbohydrate, 16% protein, and 32% total and 8% saturated fat) was compared with a similar diet with an isocaloric muffin substitution (58% carbohydrate, 15% protein, and 26% total and 8% saturated fat) in men and women with elevated LDL cholesterol. Plasma HDL subspecies and cholesterol efflux from J774 macrophages to human serum were measured at baseline and after each diet period. Diet effects were examined in all participants (n = 48) and in normal-weight (body mass index: <25; n = 14) and overweight or obese (≥25; n = 34) participants by using linear mixed models.Results: The almond diet, compared with the control diet, increased α-1 HDL [mean ± SEM: 26.7 ± 1.5 compared with 24.3 ± 1.3 mg apolipoprotein A-I (apoA-I)/dL; P = 0.001]. In normal-weight participants, the almond diet, relative to the control diet, increased α-1 HDL (33.7 ± 3.2 compared with 28.4 ± 2.6 mg apoA-I/dL), the α-1 to pre-β-1 ratio [geometric mean (95% CI): 4.3 (3.3, 5.7) compared with 3.1 (2.4, 4.0)], and non-ATP-binding cassette transporter A1 cholesterol efflux (8.3% ± 0.4% compared with 7.8% ± 0.3%) and decreased pre-β-2 (3.8 ± 0.4 compared with 4.6 ± 0.4 mg apoA-I/dL) and α-3 (23.5 ± 0.9 compared with 26.9 ± 1.1 mg apoA-I/dL) HDL (P < 0.05). No diet effects were observed in the overweight or obese group.Conclusions: Substituting almonds for a carbohydrate-rich snack within a lower-saturated-fat diet may be a simple strategy to maintain a favorable
Girard, Romuald; Khanna, Omaditya; Shenkar, Robert; Zhang, Lingjiao; Wu, Meijing; Jesselson, Michael; Zeineddine, Hussein A; Gangal, Anupriya; Fam, Maged D; Gibson, Christopher C; Whitehead, Kevin J; Li, Dean Y; Liao, James K; Shi, Changbin; Awad, Issam A
Aim: To correlate cerebral cavernous malformations (CCMs) disease aggressiveness with peripheral blood biomarkers hypothesized mechanistically. Patients & methods: A prospective case–control study enrolled 43 CCM patients, where 25-(OH) vitamin D, HDL and non-HDL cholesterol, CRP plasma levels and leukocyte ROCK activity were correlated with parameters of disease aggressiveness reflecting chronic and acute domains. Results: Patients with one or more features of chronically aggressive disease (early age at symptom onset, two or more symptomatic bleeds, high lesion burden) had significantly lower 25-(OH) vitamin D and non-HDL cholesterol levels in comparison to patients without these features. Conclusion: Validation of these biomarkers and their potential treatment modulation may influence the clinical care of patients with CCM disease. PMID:26861901
Eapen, Danny J; Kalra, Girish L; Rifai, Luay; Eapen, Christina A; Merchant, Nadya; Khan, Bobby V
High-density lipoprotein cholesterol (HDL-C) concentration is essential in the determination of coronary heart disease (CHD) risk in women. This is especially true in the postmenopausal state, where lipid profiles and CHD risk mimic that of age-matched men. Thus, interventions designed to reduce CHD risk by raising HDL-C levels may have particular significance during the transition to menopause. This review discusses HDL-C-raising therapies and the role of HDL in the primary prevention of CHD in women. Lifestyle-based interventions such as dietary change, aerobic exercise regimens, and smoking cessation are initial steps that are effective in raising HDL-C, and available data suggest women respond similarly to men with these interventions. When combined with pharmacotherapy, the effects of these lifestyle alterations are further amplified. Though studies demonstrating gender-specific differences in therapy are limited, niacin continues to be the most effective agent in raising HDL-C levels, especially when used in combination with fibrate or statin therapy. Emerging treatments such as HDL mimetic therapy show much promise in further raising HDL-C levels and improving cardiovascular outcomes.
Natali, Andrea; Baldi, Simona; Bonnet, Fabrice; Petrie, John; Trifirò, Silvia; Tricò, Domenico; Mari, Andrea
Experimental data support the notion that lipoproteins might directly affect beta cell function, however clinical data are sparse and inconsistent. We aimed at verifying whether, independently of major confounders, serum lipids are associated with alterations in insulin secretion or clearance non-diabetic subjects. Cross sectional and observational prospective (3.5yrs), multicentre study in which 1016 non-diabetic volunteers aged 30-60yrs. and with a wide range of BMI (20.0-39.9kg/m(2)) were recruited in a setting of University hospital ambulatory care (RISC study). baseline fasting lipids, fasting and OGTT-induced insulin secretion and clearance (measured by glucose and C-peptide modeling), peripheral insulin sensitivity (by the euglycemic clamp). Lipids and OGTT were repeated in 980 subjects after 3.5years. LDL-cholesterol did not show independent associations with fasting or stimulated insulin secretion or clearance. After accounting for potential confounders, HDL-cholesterol displayed negative and triglycerides positive independent associations with fasting and OGTT insulin secretion; neither with insulin clearance. Low HDL-cholesterol and high triglycerides were associated with an increase in glucose-dependent and a decrease in non-glucose-dependent insulin secretion. Over 3.5years both an HDL-cholesterol decline and a triglycerides rise were associated with an increase in fasting insulin secretion independent of changes in body weight or plasma glucose. LDL-cholesterol does not seem to influence any major determinant of insulin bioavailability while low HDL-cholesterol and high triglycerides might contribute to sustain the abnormalities in insulin secretion that characterize the pre-diabetic state. Copyright © 2017 Elsevier Inc. All rights reserved.
Niedmann, P D; Luthe, H; Wieland, H; Schaper, G; Seidel, D
The widespread use of different methods for the determination of HDL-cholesterol (in Europe: sodium phosphotungstic acid/MgCl2) in connection with enzymatic procedures (in the USA: heparin/MnCl2 followed by the Liebermann-Burchard method) but common reference values makes it necessary to evaluate not only accuracy, specificity, and precision of the precipitation step but also of the subsequent cholesterol determination. A high ratio of serum vs. concentrated precipitation reagent (10:1 V/V) leads to the formation of variable amounts of delta-3.5-cholestadiene. This substance is not recognized by cholesterol oxidase but leads to an 1.6 times overestimation by the Liebermann-Burchard method. Therefore, errors in HDL-cholesterol determination should be considered and differences up to 30% may occur between HDL-cholesterol values determined by the different techniques (heparin/MnCl2 - Liebermann-Burchard and NaPW/MgCl2-CHOD-PAP).
DiMarco, Diana M; Missimer, Amanda; Murillo, Ana Gabriela; Lemos, Bruno S; Malysheva, Olga V; Caudill, Marie A; Blesso, Christopher N; Fernandez, Maria Luz
Eggs are a source of cholesterol and choline and may impact plasma lipids and trimethylamine-N-oxide (TMAO) concentrations, which are biomarkers for cardiovascular disease (CVD) risk. Therefore, the effects of increasing egg intake (0, 1, 2, and 3 eggs/day) on these and other CVD risk biomarkers were evaluated in a young, healthy population. Thirty-eight subjects [19 men/19 women, 24.1 ± 2.2 years, body mass index (BMI) 24.3 ± 2.5 kg/m(2)] participated in this 14-week crossover intervention. Participants underwent a 2-week washout with no egg consumption, followed by intake of 1, 2, and 3 eggs/day for 4 weeks each. Anthropometric data, blood pressure (BP), dietary records, and plasma biomarkers (lipids, glucose, choline, and TMAO) were measured during each intervention phase. BMI, waist circumference, systolic BP, plasma glucose, and plasma triacylglycerol did not change throughout the intervention. Diastolic BP decreased with egg intake (P < 0.05). Compared to 0 eggs/day, intake of 1 egg/day increased HDL cholesterol (HDL-c) (P < 0.05), and decreased LDL cholesterol (LDL-c) (P < 0.05) and the LDL-c/HDL-c ratio (P < 0.01). With intake of 2-3 eggs/day, these changes were maintained. Plasma choline increased dose-dependently with egg intake (P < 0.0001) while fasting plasma TMAO was unchanged. These results indicate that in a healthy population, consuming up to 3 eggs/day results in an overall beneficial effect on biomarkers associated with CVD risk, as documented by increased HDL-c, a reduced LDL-c/HDL-c ratio, and increased plasma choline in combination with no change in plasma LDL-c or TMAO concentrations.
Nishimura, Naomichi; Tanabe, Hiroki; Yamamoto, Tatsuro; Fukushima, Michihiro
We examined the effects of raw Chinese yam (Dioscorea opposita), containing resistant starch (RS), on lipid metabolism and cecal fermentation in rats. Raw yam (RY) and boiled yam (BY) contained 33.9% and 6.9% RS, respectively. Male Sprague-Dawley rats were fed a cholesterol-free, control (C) diet supplemented with or without 15 and 30 g of RY or BY/100 g for 3 wk. Plasma total cholesterol concentrations in the tail vein of rats fed the 30% RY diet were significantly lower than in the C group throughout the feeding period. Compared with the C group, non-HDL concentrations in arterial plasma in the 30% RY group was significantly reduced. Liver cholesterol concentration in rats fed the 30% RY diet was significantly higher compared with those fed the C diet. Hepatic cholesterol 7α-hydroxylase mRNA and fecal bile acid excretion were significantly higher in the BY, but not the RY group, compared with the C group. Fecal cholesterol excretion in the 30% RY group was greater compared with the C group. Hepatic microsomal triacylglycerol transfer protein mRNA was significantly lower in the 30% RY group compared with the C group. Cecal pools of acetate, propionate and butyrate were 113-257%, 181-476% and 410-789% greater in the RY group compared with the C group. These results suggest raw yam is effective as a source of RS and facilitates production of short chain fatty acid (SCFA), especially butyrate, in the rat cecum. In addition, RY has a plasma-cholesterol lowering effect, possibly due to the inhibited release of VLDL.
Niacin can boost 'good' cholesterol Niacin is a B vitamin that may raise your HDL ("good") cholesterol. But side effects might outweigh benefits for most ... been used to increase high-density lipoprotein (HDL) cholesterol — the "good" cholesterol that helps remove low-density ...
Reissner, J; Herrmann, W
The present paper describes the sensitivity to quantification of changes of HDL-cholesterol in serum by two different precipitation and analytical techniques during the treatment of patients. After the precipitation of VLDL and LDL by phosphotungstic acid/magnesium chloride the chemical determination of HDL-cholesterol in serum with the Liebermann-Burchard reaction yields different results in comparison to enzymatic HDL-cholesterol determined in serum supernatant after the precipitation by polyethylene glycol 20.000. Correlation analyses of apolipoprotein A-I with enzymatic HDL-, HDL2-, HDL3-cholesterol or electrophoretic alpha-cholesterol demonstrate that the therapeutically induced changes (by training and diet) of lipid composition are more correctly reflected by the enzymatic determination of HDL-cholesterol after serum precipitation by polyethylene glycol.
Herrmann, W; Schütz, C; Reuter, W
For the clinical practice methods of the determination of HDL-cholesterol made their way which are based on the precipitation of apolipoprotein-B-containing lipoproteins and a determination of cholesterol following. The expensive methods of the ultracentrifugation serve as reference methods. The most-spread precipitation techniques (heparin/MCl2, dextran sulphate/CaCl2 or MgCl2 photungstic acid/MgCl2) are comparatively observed with regard to their effectiveness, practicability and methodical and technical conditions (influence of the concentration of the precipitation reagents, pH-value, temperature, incubation and centrifugation conditions). Results of own investigations as well as data from literature are presented to the problem of the harmonization of the cholesterol determination with the precipitation technique. According to the opinion of the authors for the enzymatic determination of cholesterol by means of the CHOD-PAP-method the phosphotungstic acid precipitation well stood the test, whereas for the chemical determination of cholesterol after Liebermann-Burchard in manual or automatized works the precipitation by means of dextran sulphate/CaCl2 (40 g/l, 2.0 mol/l) is to be recommended. The superabundant precipitations with phosphotungstic acid and dextran sulphate/MgCl2 (20 g/l, 2.0 mol/l) achieve higher results in Liebermann-Burchard's reaction likely on account of interferences.
Jansen, S; Lopez-Miranda, J; Ordovas, J M; Zambrana, J L; Marin, C; Ostos, M A; Castro, P; McPherson, R; Lopez Segura, F; Blanco, A; Jimenez Pereperez, J A; Perez-Jimenez, F
In order to determine whether genetic variability of apolipoprotein (apo) A-IV is responsible for the improvement in lipid profile when dietary saturated fats are replaced by carbohydrates or monounsaturated fats, 41 healthy male subjects were studied: 33 were homozygous for the 360Gln allele and 8 were heterozygote carriers of the 360His allele. These were administered three consecutive 4-week diets. The first was a diet rich in saturated fat (SAT diet, with 38% fat, 20% saturated. This was followed by a low fat diet (NCEP-I, with < 30% fat, < 10% saturated). The final diet was rich in monounsaturated fat (MUFA diet, with 38% fat, 22% monounsaturated). There was no difference in plasma lipid and apolipoprotein levels of both groups of individuals after consuming the SAT diet. Switching from this diet to the NCEP-I diet, carriers of the 360His allele presented a greater decrease in high density lipoprotein-cholesterol (HDL-C) (-10 vs. -1 mg/dL, P < 0.004) and apoA-I levels (-19 vs. -8 mg/dL, P < 0.037). Similarly, replacement of carbohydrates by monounsaturated fats produced a greater increase in HDL-C (9 vs. 1 mg/dL, P < 0.003) and apoA-I levels (9 vs. 2 mg/dL, P < 0.036) in carriers of the 360His mutation. Lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities and apoA-IV levels were also measured. However, no genotype-related differences were observed for these parameters. Our results suggest that variability in HDL-C and apoA-I response to diet is, at least partially, determined by the 360His mutation of apoA-IV.
Wilson, Thomas A; Nicolosi, Robert J; Delaney, Bryan; Chadwell, Kim; Moolchandani, Vikas; Kotyla, Timothy; Ponduru, Sridevi; Zheng, Guo-Hua; Hess, Richard; Knutson, Nathan; Curry, Leslie; Kolberg, Lore; Goulson, Melanie; Ostergren, Karen
Consumption of concentrated barley beta-glucan lowers plasma cholesterol because of its soluble dietary fiber nature. The role of molecular weight (MW) in lowering serum cholesterol is not well established. Prior studies showed that enzymatic degradation of beta-glucan eliminates the cholesterol-lowering activity; however, these studies did not evaluate the MW of the beta-glucan. The current study was conducted to evaluate whether barley beta-glucan concentrates, partially hydrolyzed to reduce MW, possess cholesterol-lowering and antiatherogenic activities. The reduced MW fraction was compared with a high MW beta-glucan concentrate from the same barley flour. Concentrated beta-glucan preparations were evaluated in Syrian Golden F(1)B hamsters fed a hypercholesterolemic diet (HCD) with cholesterol, hydrogenated coconut oil, and cellulose. After 2 wk, hamsters were fed HCD or diets that contained high or reduced MW beta-glucan at a concentration of 8 g/100 g at the expense of cellulose. Decreases in plasma total cholesterol (TC) and non-HDL-cholesterol (non-HDL-C) concentrations occurred in the hamsters fed reduced MW and high MW beta-glucan diets. Plasma HDL-C concentrations did not differ. HCD-fed hamsters had higher plasma triglyceride concentrations. Liver TC, free cholesterol, and cholesterol ester concentrations did not differ. Aortic cholesterol ester concentrations were lower in the reduced MW beta-glucan-fed hamsters. Consumption of either high or reduced MW beta-glucan increased concentrations of fecal total neutral sterols and coprostanol, a cholesterol derivative. Fecal excretion of cholesterol was greater than in HCD-fed hamsters only in those fed the reduced MW beta-glucan. Study results demonstrate that the cholesterol-lowering activity of barley beta-glucan may occur at both lower and higher MW.
Kareinen, Ilona; Cedó, Lídia; Silvennoinen, Reija; Laurila, Pirkka-Pekka; Jauhiainen, Matti; Julve, Josep; Blanco-Vaca, Francisco; Escola-Gil, Joan Carles; Kovanen, Petri T.; Lee-Rueckert, Miriam
Reverse cholesterol transport (RCT) pathway from macrophage foam cells initiates when HDL particles cross the endothelium, enter the interstitial fluid, and induce cholesterol efflux from these cells. We injected [3H]cholesterol-loaded J774 macrophages into the dorsal skin of mice and measured the transfer of macrophage-derived [3H]cholesterol to feces [macrophage-RCT (m-RCT)]. Injection of histamine to the macrophage injection site increased locally vascular permeability, enhanced influx of intravenously administered HDL, and stimulated m-RCT from the histamine-treated site. The stimulatory effect of histamine on m-RCT was abolished by prior administration of histamine H1 receptor (H1R) antagonist pyrilamine, indicating that the histamine effect was H1R-dependent. Subcutaneous administration of two other vasoactive mediators, serotonin or bradykinin, and activation of skin mast cells to secrete histamine and other vasoactive compounds also stimulated m-RCT. None of the studied vasoactive mediators affected serum HDL levels or the cholesterol-releasing ability of J774 macrophages in culture, indicating that acceleration of m-RCT was solely due to increased availability of cholesterol acceptors in skin. We conclude that disruption of the endothelial barrier by vasoactive compounds enhances the passage of HDL into interstitial fluid and increases the rate of RCT from peripheral macrophage foam cells, which reveals a novel tissue cholesterol-regulating function of these compounds. PMID:25473102
Kareinen, Ilona; Cedó, Lídia; Silvennoinen, Reija; Laurila, Pirkka-Pekka; Jauhiainen, Matti; Julve, Josep; Blanco-Vaca, Francisco; Escola-Gil, Joan Carles; Kovanen, Petri T; Lee-Rueckert, Miriam
Reverse cholesterol transport (RCT) pathway from macrophage foam cells initiates when HDL particles cross the endothelium, enter the interstitial fluid, and induce cholesterol efflux from these cells. We injected [(3)H]cholesterol-loaded J774 macrophages into the dorsal skin of mice and measured the transfer of macrophage-derived [(3)H]cholesterol to feces [macrophage-RCT (m-RCT)]. Injection of histamine to the macrophage injection site increased locally vascular permeability, enhanced influx of intravenously administered HDL, and stimulated m-RCT from the histamine-treated site. The stimulatory effect of histamine on m-RCT was abolished by prior administration of histamine H1 receptor (H1R) antagonist pyrilamine, indicating that the histamine effect was H1R-dependent. Subcutaneous administration of two other vasoactive mediators, serotonin or bradykinin, and activation of skin mast cells to secrete histamine and other vasoactive compounds also stimulated m-RCT. None of the studied vasoactive mediators affected serum HDL levels or the cholesterol-releasing ability of J774 macrophages in culture, indicating that acceleration of m-RCT was solely due to increased availability of cholesterol acceptors in skin. We conclude that disruption of the endothelial barrier by vasoactive compounds enhances the passage of HDL into interstitial fluid and increases the rate of RCT from peripheral macrophage foam cells, which reveals a novel tissue cholesterol-regulating function of these compounds.
Fisher, Edward A.; Feig, Jonathan E.; Hewing, Bernd; Hazen, Stanley L.; Smith, Jonathan D.
Although high HDL-cholesterol levels are associated with decreased cardiovascular risk in epidemiological studies, recent genetic and pharmacological findings have raised doubts about the beneficial effects of HDL. Raising HDL levels in animal models by infusion or over expression of apolipoprotein A-I has shown clear vascular improvements, such as delayed atherosclerotic lesion progression and accelerated lesion regression, along with increased reverse cholesterol transport. Inflammation and other factors, such as myeloperoxidase mediated oxidation, can impair HDL production and HDL function, in regard to its reverse cholesterol transport, antioxidant, and anti-inflammatory activities. Thus, tests of HDL function, which have not yet been developed as routine diagnostic assays, may prove useful and be a better predictor of cardiovascular risk than HDL-cholesterol levels. PMID:23152494
März, Winfried; Kleber, Marcus E; Scharnagl, Hubert; Speer, Timotheus; Zewinger, Stephen; Ritsch, Andreas; Parhofer, Klaus G; von Eckardstein, Arnold; Landmesser, Ulf; Laufs, Ulrich
While several lines of evidence prove that elevated concentrations of low-density lipoproteins (LDL) causally contribute to the development of atherosclerosis and its clinical consequences, high-density lipoproteins are still widely believed to exert atheroprotective effects. Hence, HDL cholesterol (HDL-C) is in general still considered as "good cholesterol". Recent research, however, suggests that this might not always be the case and that a fundamental reassessment of the clinical significance of HDL-C is warranted. This review article is based on a selective literature review. In individuals without a history of cardiovascular events, low concentrations of HDL-C are inversely associated with the risk of future cardiovascular events. This relationship may, however, not apply to patients with metabolic disorders or manifest cardiovascular disease. The classical function of HDL is to mobilise cholesterol from extrahepatic tissues for delivery to the liver for excretion. These roles in cholesterol metabolism as well as many other biological functions of HDL particles are dependent on the number as well as protein and lipid composition of HDL particles. They are poorly reflected by the HDL-C concentration. HDL can even exert negative vascular effects, if its composition is pathologically altered. High serum HDL-C is therefore no longer regarded protective. In line with this, recent pharmacological approaches to raise HDL-C concentration have not been able to show reductions of cardiovascular outcomes. In contrast to LDL cholesterol (LDL-C), HDL-C correlates with cardiovascular risk only in healthy individuals. The calculation of the ratio of LDL-C to HDL-C is not useful for all patients. Low HDL-C should prompt examination of additional metabolic and inflammatory pathologies. An increase in HDL-C through lifestyle change (smoking cessation, physical exercise) has positive effects and is recommended. However, HDL-C is currently not a valid target for drug therapy.
Tretjakovs, P; Kalnins, U; Dabina, I; Dinne, I; Erglis, A; Kumsars, I; Jurka, A
To evaluate nitric oxide (NO) production and [3H]arachidonic acid (AA) incorporation into platelet membranes of coronary artery disease (CAD) patients with/without HDL-hypocholesterolemia. 16 healthy controls (C), 14 CAD patients with plasma HDL-hypocholesterolemia (nCAD) and 14--without HDL-hypocholesterolemia (nCAD). All subjects were without peripheral vascular disease and hypertension. The groups were matched for age, sex, BMI. The diagnosis of CAD was substantiated by coronary angiography. Nitric oxide end products xNO (NO2- plus NO3-) levels in the platelet membranes were measured using anion-exchange chromatography. [3H]AA release from labelled platelets was studied by the method of Neufeld and Majerus; radioactivity was measured by liquid scintillation counting. Levels of plasma HDL-cholesterol (HDL-Ch) and triglycerides were enzymatically determined. Significant increase (mean +/- SD; Mann-Whitney U test) of [3H]AA incorporation into platelet membrane phospholipids was noted in CAD patients in comparison with healthy subjects (p < 0.001). A correlation (multiple regression analysis) was established between HDL-C level and [3H]AA (r = -0.58, p < 0.05, n = 28); and between HDL-Ch and NOx levels (r = 0.76, p < 0.05, n = 28) in CAD patients. CAD patients had lower NOx than healthy subjects (p < 0.0001), NOx was lower in the group with decreased HDL-Ch concentration (wCAD 36 +/- 5 vs. nCAD 42.3 +/- 6 mumol/mg, p < 0.002). CAD patients show decreased ability to produce platelet-derived NO that leads to higher platelet sensitivity to aggregating stimuli. Decreased plasma HDL-Ch may affect AA metabolism and NO production in the platelet membranes of CAD patients without LDL-hypercholesterolemia.
Paavola, Timo; Kuusisto, Sanna; Jauhiainen, Matti; Kakko, Sakari; Kangas-Kontio, Tiia; Metso, Jari; Soininen, Pasi; Ala-Korpela, Mika; Bloigu, Risto; Hannuksela, Minna L; Savolainen, Markku J; Salonurmi, Tuire
The potential of high-density lipoproteins (HDL) to facilitate cholesterol removal from arterial foam cells is a key function of HDL. We studied whether cholesterol efflux to serum and HDL subfractions is impaired in subjects with early coronary heart disease (CHD) or metabolic syndrome (MetS) in families where a low HDL-cholesterol level (HDL-C) predisposes to early CHD. HDL subfractions were isolated from plasma by sequential ultracentrifugation. THP-1 macrophages loaded with acetyl-LDL were used in the assay of cholesterol efflux to total HDL, HDL2, HDL3 or serum. While cholesterol efflux to serum, total HDL and HDL3 was unchanged, the efflux to HDL2 was 14% lower in subjects with MetS than in subjects without MetS (p<0.001). The efflux to HDL2 was associated with components of MetS such as plasma HDL-C (r = 0.76 in men and r = 0.56 in women, p<0.001 for both). The efflux to HDL2 was reduced in men with early CHD (p<0.01) only in conjunction with their low HDL-C. The phospholipid content of HDL2 particles was a major correlate with the efflux to HDL2 (r = 0.70, p<0.001). A low ratio of HDL2 to total HDL was associated with MetS (p<0.001). Our results indicate that impaired efflux to HDL2 is a functional feature of the low HDL-C state and MetS in families where these risk factors predispose to early CHD. The efflux to HDL2 related to the phospholipid content of HDL2 particles but the phospholipid content did not account for the impaired efflux in cardiometabolic disease, where a combination of low level and poor quality of HDL2 was observed.
Paavola, Timo; Kuusisto, Sanna; Jauhiainen, Matti; Kakko, Sakari; Kangas-Kontio, Tiia; Metso, Jari; Soininen, Pasi; Ala-Korpela, Mika; Bloigu, Risto; Hannuksela, Minna L.; Savolainen, Markku J.
Objective The potential of high-density lipoproteins (HDL) to facilitate cholesterol removal from arterial foam cells is a key function of HDL. We studied whether cholesterol efflux to serum and HDL subfractions is impaired in subjects with early coronary heart disease (CHD) or metabolic syndrome (MetS) in families where a low HDL-cholesterol level (HDL-C) predisposes to early CHD. Methods HDL subfractions were isolated from plasma by sequential ultracentrifugation. THP-1 macrophages loaded with acetyl-LDL were used in the assay of cholesterol efflux to total HDL, HDL2, HDL3 or serum. Results While cholesterol efflux to serum, total HDL and HDL3 was unchanged, the efflux to HDL2 was 14% lower in subjects with MetS than in subjects without MetS (p<0.001). The efflux to HDL2 was associated with components of MetS such as plasma HDL-C (r = 0.76 in men and r = 0.56 in women, p<0.001 for both). The efflux to HDL2 was reduced in men with early CHD (p<0.01) only in conjunction with their low HDL-C. The phospholipid content of HDL2 particles was a major correlate with the efflux to HDL2 (r = 0.70, p<0.001). A low ratio of HDL2 to total HDL was associated with MetS (p<0.001). Conclusion Our results indicate that impaired efflux to HDL2 is a functional feature of the low HDL-C state and MetS in families where these risk factors predispose to early CHD. The efflux to HDL2 related to the phospholipid content of HDL2 particles but the phospholipid content did not account for the impaired efflux in cardiometabolic disease, where a combination of low level and poor quality of HDL2 was observed. PMID:28207870
... are better. By Mayo Clinic Staff High-density lipoprotein (HDL) is known as the "good" cholesterol because ... bloodstream attached to proteins. These proteins are called lipoproteins. Low-density lipoprotein. High levels of low-density ...
Denimal, Damien; Pais de Barros, Jean-Paul; Petit, Jean-Michel; Bouillet, Benjamin; Vergès, Bruno; Duvillard, Laurence
Phospholipids and sphingolipids are major components of HDL. They play a critical role in HDL functionality and protective effects against atherosclerosis. As HDL are dysfunctional in type 1 diabetic patients, we ascertained whether they presented abnormalities in their phospholipid and sphingolipid profile, despite normal HDL cholesterol concentration. Using liquid chromatography-tandem mass spectrometry, we quantified the main species of phosphatidylcholines, sphingomyelins, lysophophatidylcholines, phosphatidylethanolamines, phosphatidylinositols, ceramides, plasmalogens and sphingosines 1-phosphate in the HDL2 and HDL3 from 54 type 1 diabetic patients and 50 controls. Serum HDL cholesterol was similar in the 2 groups of subjects. When data were expressed relative to the total amount of phospholipids and sphingolipids, sphingosines-1-phosphate (S1P) were 11.7% (NS) and 14.4% (p = 0.0062) lower in HDL2 and HDL3, respectively, from type 1 diabetic patients than from controls. Ceramides were 23% (p = 0.005) and 24% (borderline significance) lower in HDL2 and HDL3, respectively. The concentration of apolipoprotein M, the carrier of S1P, was similar in patients and controls. In type 1 diabetic patients compared to controls, the concentration of d18:1-S1P, the main S1P species, was decreased in total plasma (-17.0%, p < 0.0001), HDL fraction (-21.9%, p < 0.0001) and non-HDL fraction (-13.7%, p = 0.012). The concentration of ceramides was decreased in total plasma (-24.4%, p < 0.0001), HDL fraction (-27.9%, p = 0.0006) and non-HDL fraction (-22.0%, p = 0.0087). Despite normal HDL cholesterol level, the phospholipid + sphingolipid profile is impaired in HDL from type 1 diabetic patients. These abnormalities, especially the decrease in S1P, could contribute to the impaired HDL functionality observed in these patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Luo, Mengdie; Liu, Aiying; Wang, Shuai; Wang, Tianle; Hu, Die; Wu, Sha; Peng, Daoquan
Apolipoprotein CIII (apoCIII) has been reported to be tightly associated with triglyceride metabolism and the susceptibility to coronary artery disease (CAD). Besides, apoCIII has also been found to affect the anti-apoptotic effects of HDL. However, the effect of apoCIII on HDL-mediated cholesterol efflux, the crucial function of HDL, has not been reported. A hospital-based case-control study was conducted to compare the apoCIII distribution in lipoproteins between CAD patients and nonCAD controls and to explore the relationship between HDL-associated apoCIII (apoCIIIHDL) and HDL-mediated cholesterol efflux. One hundred forty CAD patients and nighty nine nonCAD controls were included. Plasma apoCIII, apoCIIIHDL and cholesterol efflux capacity was measured. The apoCIIIHDL ratio (apoCIIIHDL over plasma apoCIII) was significantly higher in CAD patients than that in control group (0.52 ± 0.24 vs. 0.43 ± 0.22, P = 0.004). Both apoCIIIHDL and apoCIIIHDL ratio were inversely correlated with cholesterol efflux capacity (r = -0.241, P = 0.0002; r = -0.318, P < 0.0001, respectively). Stepwise multiple regression analysis revealed that the apoCIIIHDL ratio was an independent contributor to HDL-mediated cholesterol efflux capacity (standardized β = -0.325, P < 0.001). This study indicates that the presence of apoCIII in HDL may affect HDL-mediated cholesterol efflux capacity, implying the alternative role of apoCIII in the atherogenesis.
Weissglas-Volkov, Daphna; Pajukanta, Päivi
Plasma levels of HDL cholesterol (HDL-C) have a strong inherited basis with heritability estimates of 40-60%. The well-established inverse relationship between plasma HDL-C levels and the risk of coronary artery disease (CAD) has led to an extensive search for genetic factors influencing HDL-C concentrations. Over the past 30 years, candidate gene, genome-wide linkage, and most recently genome-wide association (GWA) studies have identified several genetic variations for plasma HDL-C levels. However, the functional role of several of these variants remains unknown, and they do not always correlate with CAD. In this review, we will first summarize what is known about HDL metabolism, monogenic disorders associated with both low and high HDL-C levels, and candidate gene studies. Then we will focus this review on recent genetic findings from the GWA studies and future strategies to elucidate the remaining substantial proportion of HDL-C heritability. Comprehensive investigation of the genetic factors conferring to low and high HDL-C levels using integrative approaches is important to unravel novel pathways and their relations to CAD, so that more effective means of diagnosis, treatment, and prevention will be identified. PMID:20421590
Millán, Jesús; Hernández-Mijares, Antonio; Ascaso, Juan F; Blasco, Mariano; Brea, Angel; Díaz, Ángel; González-Santos, Pedro; Mantilla, Teresa; Pedro-Botet, Juan; Pintó, Xavier
Lowe density lipoproteins (LDL) are the causal agent of cardiovascular diseases. In practice, we identify LDL with cholesterol transported in LDL (cLDL). So, cLDL has become the major target for cardiovascular prevention. Howewer, we have progressive evidences about the role of triglycerides rich lipoproteins, particularly those very low density lipoprotein (VLDL) in promotion and progression of atherosclerosis, that leads cholesterol in VLDL and its remanents as a potential therapeutic target. This feature is particularly important and of a great magnitude, in patients with hypertiglyceridemia. We can to considere, that the non-HDL cholesterol -cLDL+cVLDL+c-remmants+Lp(a)- is the real measurement of atherogenic cholesterol. In addition, non-HDL-cholesterol do not show any variations between postprandial states. In fact, non-HDL-cholesterol should be an excellent marker of atherogenic cholesterol, and an major therapeutic target in patients with atherogenic dyslipidaemia. According with different clinical trials and with the epidemiological and mendelian studies, in patients with high cardiovascular risk, optimal level of cLDL will be under 70mg/dl, and under 100 ng/dl for non-HDL-cholesterol; and in high risk patients, 100mg/dl and 130mg/dl, respectively. Copyright Â© 2016. Publicado por Elsevier España, S.L.U.
Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C l...
Bosevski, M; Borozanov, V; Peovska, I; Georgievska-Ismail, L
Assessment of endothelial dysfunction (ED) in type 2 diabetic patients with coronary artery disease (CAD) and estimation of correlation of ED with metabolic parameters: low HDL, hypertriglyceridemia, obesity, systolic blood pressure and with inflammatory-hemostatic parameters: CRP and fibrinogen. 42 patients (age 60.0 +/- 8.5 years) with diagnosed type 2 diabetes and CAD were randomly included in a cross sectional study. B-mode ultrasound system with a linear transducer 7.5 MHz was used for evaluation of flow mediated vasodilation in brachial artery (FMV). FMV was presented as the percentage increase in brachial artery diameter, within 30 s after limb ischemia, previously provoked by cuff inflation. Percentage value up to 10% was defined as ED. Bivariate linear correlation model presented significant correlation between plasma fibrinogen and FMV percentage, with r -0.47, p < 0.01. Presence of ED correlates linearly with plasma level of HDL < 1.03 mmol/L (r -0.35, p < 0.03). Multivariate analysis using Backward Wald model presented fibrinogen (OR 3.14, 95% CI 0.87-11.28) and low HDL (OR 5.16, 95% CI 0.53-60.39) as factors correlated with the presence of endothelial dysfunction. These results presented plasma fibrinogen level and low HDL < 1.03 mmol/L as factors, independently correlated to the presence of endothelial dysfunction in type 2 diabetic patients with coronary artery disease (Tab. 8, Fig. 1, Ref. 25). Full Text (Free, PDF) www.bmj.sk.
Tosheska Trajkovska, Katerina; Topuzovska, Sonja
A key to effective treatment of cardiovascular disease is to understand the body's complex lipoprotein transport system. Reverse cholesterol transport (RCT) is the process of cholesterol movement from the extrahepatic tissues back to the liver. Lipoproteins containing apoA-I [highdensity lipoprotein (HDL)] are key mediators in RCT, whereas non-high-density lipoproteins (non-HDL, lipoproteins containing apoB) are involved in the lipid delivery pathway. HDL particles are heterogeneous; they differ in proportion of proteins and lipids, size, shape, and charge. HDL heterogeneity is the result of the activity of several factors that assemble and remodel HDL particles in plasma: ATP-binding cassette transporter A1 (ABCA1), lecithin cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), hepatic lipase (HL), phospholipid transfer protein (PLTP), endothelial lipase (EL), and scavenger receptor class B type I (SR-BI). The RCT pathway consists of the following steps: 1. Cholesterol efflux from peripheral tissues to plasma, 2. LCAT-mediated esterification of cholesterol and remodeling of HDL particles, 3. direct pathway of HDL cholesterol delivery to the liver, and 4. indirect pathway of HDL cholesterol delivery to the liver via CETP-mediated transfer There are several established strategies for raising HDL cholesterol in humans, such as lifestyle changes; use of drugs including fibrates, statins, and niacin; and new therapeutic approaches. The therapeutic approaches include CETP inhibition, peroxisome proliferator-activated receptor (PPAR) agonists, synthetic farnesoid X receptor agonists, and gene therapy. Results of clinical trials should be awaited before further clinical management of atherosclerotic cardiovascular disease.
Ferns, G A; Robinson, D; Stocks, J; Bevan, E; Williams, P; Galton, D J
The relationship between plasma HDL-cholesterol subfractions (HDL2 and HDL3), measured using a differential precipitation method, and serum triglycerides, was studied in 402 healthy Caucasian males attending a health screening centre in London. Mean values for HDL2 and HDL3 were 0.42 +/- 0.24 mmol/L and 0.81 +/- 0.15 mmol/L respectively. HDL2 was found to show a stronger negative correlation with serum triglyceride and a stronger positive correlation with total HDL than HDL3. HDL2 also showed a stronger correlation with age than either total HDL or HDL3. Mean levels of HDL2 were 20% higher in subjects over 55 years of age compared with those who were less than 55 years of age. Reference values of HDL2 and HDL3 are presented for different age ranges.
Stefanutti, Claudia; Labbadia, Giancarlo; Athyros, Vasilios G
Maintaining total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels within healthy limits decreases the risk of atherosclerotic vascular disease (AVD) and cardiovascular (CV) events. The predictive value of elevated TG levels for coronary artery disease (CAD) seen in univariate analysis tends to disappear on multivariate analyses, especially when correction is made for HDL-C. The relationship between TG and HDL-C is complex and not fully understood. Hydrolysis of TG by lipoprotein lipase converts HDL subclass 3 to a larger lipoprotein enriched in both phospholipid and TG. This process occurs in postprandial lipaemia (PPL). An additional factor for the complex relationship between TGs and CV risk is that the lipoproteins which transport plasma TG (chylomicrons, very low density lipoproteins and their remnants) are heterogeneous particles. Therefore, they may differ in their level of atherogenicity. PPL is a physiological process during which plasma lipoproteins and their subclasses undergo variations in concentration and composition following consumption of food, particularly fatty food. "Postprandial hyperlipidaemia" is the quantitative/qualitative alteration of this normal process. These lipoprotein alterations could play a role in the development of CV disease (CVD). However, lipid levels used to evaluate CV risk are usually measured in the fasting state. This review focuses on TG, PPL, postprandial hyperlipidaemia and non-HDL-C, their relationships and potential predictive role in atherogenesis and CVD.
Annema, Wijtske; Dikkers, Arne; Freark de Boer, Jan; Dullaart, Robin P. F.; Sanders, Jan-Stephan F.; Bakker, Stephan J. L.
High-density lipoprotein (HDL) particles are involved in the protection against cardiovascular disease by promoting cholesterol efflux, in which accumulated cholesterol is removed from macrophage foam cells. We investigated whether HDL cholesterol efflux capacity is associated with cardiovascular mortality, all-cause mortality, and graft failure in a cohort of renal transplant recipients (n=495, median follow-up 7.0 years). Cholesterol efflux capacity at baseline was quantified using incubation of human macrophage foam cells with apolipoprotein B–depleted plasma. Baseline efflux capacity was not different in deceased patients and survivors (P=0.60 or P=0.50 for cardiovascular or all-cause mortality, respectively), whereas recipients developing graft failure had lower efflux capacity than those with functioning grafts (P<0.001). Kaplan–Meier analysis demonstrated a lower risk for graft failure (P=0.004) but not cardiovascular (P=0.30) or all-cause mortality (P=0.31) with increasing gender-stratified tertiles of efflux capacity. Cox regression analyses adjusted for age and gender showed that efflux capacity was not associated with cardiovascular mortality (hazard ratio [HR], 0.89; 95% confidence interval [95% CI], 0.67 to 1.19; P=0.43). Furthermore, the association between efflux capacity and all-cause mortality (HR, .79; 95% CI, 0.63 to 0.98; P=0.031) disappeared after further adjustment for potential confounders. However, efflux capacity at baseline significantly predicted graft failure (HR, 0.43; 95% CI, 0.29 to 0.64; P<0.001) independent of apolipoprotein A-I, HDL cholesterol, or creatinine clearance. In conclusion, this prospective study shows that cholesterol efflux capacity from macrophage foam cells is not associated with cardiovascular or all-cause mortality but is a strong predictor of graft failure independent of plasma HDL cholesterol levels in renal transplant recipients. PMID:26319244
Brea Hernando, Ángel Julián
Atherogenic dyslipidemia (AD) consists of the combination of an increase in very low density lipoproteins (VLDL), which results in increased plasma triglyceride (TG) levels, with a reduction of levels of high-density lipoprotein bound cholesterol (HDL-C), also accompanied by a high proportion of small and dense LDL particles. AD is considered the main cause of the residual risk of experiencing cardiovascular disease (CVD), which is still presented by any patient on treatment with statins despite maintaining low-density lipoprotein bound cholesterol (LDL-C) levels below the values considered to be the objective. Non-HDL cholesterol (non-HDL-c) reflects the number of atherogenic particles present in the plasma. This includes VLDL, intermediate density lipoproteins (IDL) and LDL. Non-HDL-c provides a better estimate of cardiovascular risk than LDL-c, especially in the presence of hypertriglyceridemia or AD. The European guidelines for managing dyslipidemia recommend that non-HDL-c values be less than 100 and 130 mg/dL for individuals with very high and high cardiovascular risk, respectively. However, these guidelines state that there is insufficient evidence to suggest that raising HDL-c levels incontrovertibly results in a reduction in CVD. Therefore, the guidelines do not set recommended HDL-c levels as a therapeutic objective. The guidelines, however, state that individuals with AD on treatment with statins could benefit from an additional reduction in their risk by using fibrates. Copyright © 2014 Sociedad Española de Arteriosclerosis y Elsevier España, S.L. All rights reserved.
Taghizadeh, Mohsen; Hashemi, Teibeh; Shakeri, Hossein; Abedi, Fatemeh; Sabihi, Sima-Sadat; Alizadeh, Sabihe-Alsadat; Asemi, Zatolla
To our knowledge, no reports are available indicating the effects of synbiotic food consumption on blood lipid profiles and biomarkers of oxidative stress among pregnant women. This study was conducted to evaluate the effects of daily consumption of a synbiotic food on blood lipid profiles and biomarkers of oxidative stress in pregnant women. This randomized, double-blind, controlled clinical trial was performed among 52 primigravida pregnant women, aged 18 to 35-year-old at their third trimester. After a 2-week run-in period, subjects were randomly assigned to consume either a synbiotic (n = 26) or control food (n = 26) for 9 weeks. The synbiotic food consisted of a probiotic viable and heat-resistant Lactobacillus sporogenes (1 × 10⁷ CFU) and 0.04 g inulin (HPX)/g as the prebiotic. Patients were asked to consume the synbiotic and control foods two times a day. Biochemical measurements including blood lipid profiles, plasma total antioxidant capacity (TAC) and total glutathione (GSH) were conducted before and after 9 weeks of intervention. Consumption of a synbiotic food for 9 weeks resulted in a significant reduction in serum TAG (P = 0.04), VLDL (P = 0.04) and a significant rise in plasma GSH levels (P = 0.004) compared to the control food. No significant effects of the synbiotic food consumption on serum TC, LDL, HDL and plasma TAC levels (P > 0.05) were observed. Trial registry code: http://www.irct.ir . IRCT201212105623N3.
Oda, Eiji; Kawai, Ryu
The aims are to examine whether changes in body weight (dBW) are associated with changes in cardiovascular risk factors in Japanese men without abdominal obesity (waist circumference (WC) < 85 cm) and which anthropometric index, dBW or changes in WC (dWC), is more strongly associated with changes in cardiovascular risk factors in men without abdominal obesity. It is a retrospective study in 692 Japanese men without abdominal obesity who took annual health screening tests consecutively over one year. Standardized linear regression coefficients (SRCs) of dBW and dWC were calculated for changes in systolic blood pressure (dSBP), diastolic blood pressure (dDBP), fasting plasma glucose (dFPG), triglycerides (dTG), HDL cholesterol (dHDL), and high-sensitivity C-reactive protein (dCRP). The SRCs of dBW for dFPG and dHDL were significant in all men and in men with each risk factor corresponding to the component of metabolic syndrome (MetS). The SRCs of dWC for dTG and dCRP were significant in all men but not in men with each risk factor corresponding to the MetS component. In conclusions, dBW were significantly associated with dFPG and dHDL in Japanese men without abdominal obesity. Therefore, abdominal obesity should not be considered as a necessary component of MetS in Japanese men. dBW may be more useful than dWC as a marker of changes in cardiovascular risk factors in lifestyle intervention programs.
Sadananda, Singh N.; Foo, Jia Nee; Toh, Meng Tiak; Cermakova, Lubomira; Trigueros-Motos, Laia; Chan, Teddy; Liany, Herty; Collins, Jennifer A.; Gerami, Sima; Singaraja, Roshni R.; Hayden, Michael R.; Francis, Gordon A.; Frohlich, Jiri; Khor, Chiea Chuen; Brunham, Liam R.
A low level of HDL cholesterol (HDL-C) is a common clinical scenario and an important marker for increased cardiovascular risk. Many patients with very low or very high HDL-C have a rare mutation in one of several genes, but identification of the molecular abnormality in patients with extreme HDL-C is rarely performed in clinical practice. We investigated the accuracy and diagnostic yield of a targeted next-generation sequencing (NGS) assay for extreme levels of HDL-C. We developed a targeted NGS panel to capture the exons, intron/exon boundaries, and untranslated regions of 26 genes with highly penetrant effects on plasma lipid levels. We sequenced 141 patients with extreme HDL-C levels and prioritized variants in accordance with medical genetics guidelines. We identified 35 pathogenic and probably pathogenic variants in HDL genes, including 21 novel variants, and performed functional validation on a subset of these. Overall, a molecular diagnosis was established in 35.9% of patients with low HDL-C and 5.2% with high HDL-C, and all prioritized variants identified by NGS were confirmed by Sanger sequencing. Our results suggest that a molecular diagnosis can be identified in a substantial proportion of patients with low HDL-C using targeted NGS. PMID:26255038
Krauss, Ronald M.; Gross, Coleman; Ishida, Brian; Heinecke, Jay W.; Tang, Chongren; Amory, John K.; Schaefer, Peter M.; Cox, Cheryl J.; Kane, John; Purnell, Jonathan Q.; Weinstein, Richard L.; Vaisar, Tomáš
Context: Mifepristone is a glucocorticoid and progestin antagonist under investigation for the treatment of Cushing's syndrome. Mifepristone decreases high-density lipoprotein (HDL) cholesterol (HDL-C) levels in treated patients, but the clinical significance of this is unclear because recent studies suggest that functional properties of HDL predict cardiovascular disease status better than does HDL-C concentration. Objective: The aim of the study was to characterize the impact of mifepristone administration on HDL particle concentration and function. Design and Setting: We conducted a double-blind, randomized, placebo-controlled trial at a single-site, clinical research center. Participants: Thirty healthy postmenopausal female volunteers participated in the study. Intervention: Individuals were randomized to receive daily oral mifepristone (600 mg) or placebo for 6 wk. Main Outcome Measures: We measured HDL-C, serum HDL particle concentration, and HDL-mediated cholesterol efflux by treatment group. Results: As expected, ACTH, cortisol, estradiol, and testosterone levels increased in the mifepristone group. Mifepristone treatment decreased HDL-C and HDL particle concentration by 26 and 25%, respectively, but did not alter pre-β HDL concentration. In contrast, the serum HDL-mediated cholesterol efflux decreased with mifepristone treatment by only 12%, resulting in an effective increase of the efflux capacity per HDL particle. No changes were observed in cholesterol ester transfer protein or lecithin:cholesterol acyltransferase activity. Conclusions: Treatment with mifepristone reduced HDL-C, HDL particle concentration, and serum HDL cholesterol efflux in postmenopausal women. However, on a per particle basis, the efflux capacity of serum HDL increased. These observations support the concept that a decrease in HDL-C may not represent proportional impairment of HDL function. PMID:22399518
Lake, Nicole J; Taylor, Rachael L; Trahair, Hugh; Harikrishnan, K N; Curran, Joanne E; Almeida, Marcio; Kulkarni, Hemant; Mukhamedova, Nigora; Hoang, Anh; Low, Hann; Murphy, Andrew J; Johnson, Matthew P; Dyer, Thomas D; Mahaney, Michael C; Göring, Harald H H; Moses, Eric K; Sviridov, Dmitri; Blangero, John; Jowett, Jeremy B M; Bozaoglu, Kiymet
The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies.
Toledo-Ibelles, Paola; Franco, Martha; Carreón-Torres, Elizabeth; Luc, Gérald; Tailleux, Anne; Vargas-Alarcón, Gilberto; Fragoso, José Manuel; Aguilar-Salinas, Carlos; Luna-Luna, María; Pérez-Méndez, Oscar
The kidney has been proposed to play a central role in apo AI catabolism, suggesting that HDL structure is determined, at least in part, by this organ. Here, we aimed at determining the effects of a renal mass reduction on HDL size distribution, lipid content, and apo AI turnover. We characterized HDL subclasses in rabbits with a 75% reduction of functional renal mass (Nptx group), using enzymatic staining of samples separated on polyacrylamide electrophoresis gels, and also performed kinetic studies using radiolabeled HDL-apo AI in this animal model. Creatinine clearance was reduced to 35% after nephrectomy as compared to the basal values, but without increased proteinuria. A slight, but significant modification of the relative HDL size distribution was observed after nephrectomy, whereas cholesterol plasma concentrations gradually augmented from large HDL2b (+54%) to small HDL3b particles (+150%, P<0.05). Cholesteryl esters were the increased fraction; in contrast, free cholesterol phospholipids and triglycerides of HDL subclasses were not affected by nephrectomy. HDL-apo AI fractional catabolic rates were similar to controls. Reduction of functional renal mass is associated to enrichment of HDL subclasses with cholesteryl esters. Structural abnormalities were not related to a low apo AI turnover, suggesting renal contribution to HDL remodeling beyond being just a catabolic site for these lipoproteins. Copyright © 2013 Elsevier Inc. All rights reserved.
Moriyama, Kengo; Negami, Masako; Takahashi, Eiko
Recent data have suggested a relationship between the high-density lipoprotein (HDL) subclass ratio and metabolic syndrome (MetS). However, limited information is available regarding the relationships between the HDL subclass ratio and insulin resistance, associated adipocytokine levels, and MetS components. The associations of the high-density lipoprotein 2 cholesterol (HDL2-C) to high-density lipoprotein 3 cholesterol (HDL3-C) ratio with the homeostasis model assessment of insulin resistance (HOMA-IR) index, high-molecular-weight adiponectin (HMW-Ad) levels, and MetS components were examined. The study included 1155 Japanese subjects who met our inclusion criteria and underwent an annual health examination that included an HDL subclass analysis. The HDL2-C/HDL3-C ratio and the HMW-Ad level gradually decreased as the number of MetS components increased. In contrast, HOMA-IR gradually increased as the number of MetS components increased. The HDL2-C/HDL3-C ratio correlated inversely with HOMA-IR and positively with the HMW-Ad level. A strong positive correlation was observed between the HDL2-C/HDL3-C ratio and the HDL-C level. The HDL2-C/HDL3-C ratio exhibited moderate negative correlations with the body mass index, waist circumference, and triglyceride level. Weak negative correlations were observed for the HDL2-C/HDL3-C ratio with the systolic and diastolic blood pressure and fasting plasma glucose levels. Our data indicated that the HDL2-C/HDL3-C ratio was associated with insulin resistance, the HMW-Ad level, and MetS components, and it was useful for evaluating MetS in Japanese individuals. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Millar, Courtney L; Duclos, Quinn; Blesso, Christopher N
Strong experimental evidence confirms that HDL directly alleviates atherosclerosis. HDL particles display diverse atheroprotective functions in reverse cholesterol transport (RCT), antioxidant, anti-inflammatory, and antiapoptotic processes. In certain inflammatory disease states, however, HDL particles may become dysfunctional and proatherogenic. Flavonoids show the potential to improve HDL function through their well-documented effects on cellular antioxidant status and inflammation. The aim of this review is to summarize the basic science and clinical research examining the effects of dietary flavonoids on RCT and HDL function. Based on preclinical studies that used cell culture and rodent models, it appears that many flavonoids (e.g., anthocyanidins, flavonols, and flavone subclasses) influence RCT and HDL function beyond simple HDL cholesterol concentration by regulating cellular cholesterol efflux from macrophages and hepatic paraoxonase 1 expression and activity. In clinical studies, dietary anthocyanin intake is associated with beneficial changes in serum biomarkers related to HDL function in a variety of human populations (e.g., in those who are hyperlipidemic, hypertensive, or diabetic), including increased HDL cholesterol concentration, as well as HDL antioxidant and cholesterol efflux capacities. However, clinical research on HDL functionality is lacking for some flavonoid subclasses (e.g., flavanols, flavones, flavanones, and isoflavones). Although there has been a tremendous effort to develop HDL-targeted drug therapies, more research is warranted on how the intake of foods or specific nutrients affects HDL function.
Ikhlef, Souade; Berrougui, Hicham; Kamtchueng Simo, Olivier; Zerif, Echarki
This study was aimed to investigate the effect of human PON1 overexpression in mice on cholesterol efflux and reverse cholesterol transport. PON1 overexpression in PON1-Tg mice induced a significant 3-fold (p<0.0001) increase in plasma paraoxonase activity and a significant ~30% (p<0.0001) increase in the capacity of HDL to mediate cholesterol efflux from J774 macrophages compared to wild-type mice. It also caused a significant 4-fold increase (p<0.0001) in the capacity of macrophages to transfer cholesterol to apoA-1, a significant 2-fold (p<0.0003) increase in ABCA1 mRNA and protein expression, and a significant increase in the expression of PPARγ (p<0.0003 and p<0.04, respectively) and LXRα (p<0.0001 and p<0.01, respectively) mRNA and protein compared to macrophages from wild-type mice. Moreover, transfection of J774 macrophages with human PON1 also increased ABCA1, PPARγ and LXRα protein expression and stimulates macrophages cholesterol efflux to apo A1. In vivo measurements showed that the overexpression of PON1 significantly increases the fecal elimination of macrophage-derived cholesterol in PON1-Tg mice. Overall, our results suggested that the overexpression of PON1 in mice may contribute to the regulation of the cholesterol homeostasis by improving the capacity of HDL to mediate cholesterol efflux and by stimulating reverse cholesterol transport. PMID:28278274
Background-Low high-density lipoprotein cholesterol (HDL-C) is associated with an increased risk for atherosclerosis and concentrations are modulated by genetic and environmental factors such as smoking. Objective- To assess whether the association of common single nucleotide polymorphisms (SNPs...
Yamamoto, Suguru; Narita, Ichiei; Kotani, Kazuhiko
The macrophage and its related cholesterol efflux are considered to be a key player in atherosclerotic formation in relation to the function of high-density lipoprotein (HDL). The HDL function can be evaluated by the reaction between lipid-loaded macrophages and lipid-acceptors in the HDL fraction from the plasma, apolipoprotein B-depleted serum, and/or whole serum/plasma. Recent studies have reported that an impaired cholesterol efflux of HDL is observed in patients with cardiometabolic diseases, such as dyslipidemia, diabetes mellitus, and chronic kidney disease. A population-based cohort study has reported an inverse association between the cholesterol efflux capacity of HDL and the incidence of atherosclerotic disease, regardless of the serum HDL-cholesterol level. Moreover, in this paper, when we summarized several clinical interventional studies of statin treatment that examined cholesterol efflux, a potential increase in the efflux in patients treated with statins was implied. However, the effect was not fully defined in the current situation because of the small sample sizes, lack of a unified protocol for measuring the efflux, and short-term intervention periods without cardiovascular outcomes in available studies. Further investigation is necessary to determine the effect of drugs on cholesterol efflux. With additional advanced studies, cholesterol efflux is a promising laboratory index to understand the HDL function. Copyright © 2016 Elsevier B.V. All rights reserved.
Mani, Preethi; Rohatgi, Anand
High-density lipoprotein cholesterol (HDL-C) has been shown in epidemiologic studies to be associated with cardiovascular (CV) risk and thus significant efforts have been focused on HDL-C modulation. Multiple pharmaceutical agents have been developed with the goal of increasing HDL-C. Niacin, the most widely used medication to raise HDL-C, increases HDL-C by up to 25 % and was shown in multiple surrogate end point studies to reduce CV risk. However, two large randomized controlled trials of niacin, AIM-HIGH and HPS2-THRIVE, have shown that despite its effects on HDL-C, niacin does not decrease the incidence of CV events and may have significant adverse effects. Studies of other classes of agents such as cholesteryl ester transfer protein (CETP) inhibitors have also shown that even dramatic increases in HDL-C do not necessarily translate to reduction in clinical events. While these findings have cast doubt upon the importance of HDL-C modulation on CV risk, it is becoming increasingly clear that HDL function-related measures may be better targets for CV risk reduction. Increasing ApoA-I, the primary apolipoprotein associated with HDL, correlates with reduced risk of events, and HDL particle concentration (HDL-P) inversely associates with incident CV events adjusted for HDL-C and LDL particle measures. Cholesterol efflux, the mechanism by which macrophages in vessel walls secrete cholesterol outside cells, correlates with both surrogate end points and clinical events. The effects of niacin on these alternate measures of HDL have been conflicting. Further studies should determine if modulation of these HDL function markers translates to clinical benefits. Although the HDL cholesterol hypothesis may be defunct, the HDL function hypothesis is now poised to be rigorously tested.
Mani, Preethi; Rohatgi, Anand
High-density lipoprotein cholesterol (HDL-C) has been shown in epidemiologic studies to be associated with cardiovascular (CV) risk and thus significant efforts have been focused on HDL-C modulation. Multiple pharmaceutical agents have been developed with the goal of increasing HDL-C. Niacin, the most widely used medication to raise HDL-C, increases HDL-C by up to 25 % and was shown in multiple surrogate end point studies to reduce CV risk. However, two large randomized controlled trials of niacin, AIM-HIGH and HPS2-THRIVE, have shown that despite its effects on HDL-C, niacin does not decrease the incidence of CV events and may have significant adverse effects. Studies of other classes of agents such as cholesteryl ester transfer protein (CETP) inhibitors have also shown that even dramatic increases in HDL-C do not necessarily translate to reduction in clinical events. While these findings have cast doubt upon the importance of HDL-C modulation on CV risk, it is becoming increasingly clear that HDL function-related measures may be better targets for CV risk reduction. Increasing ApoA-I, the primary apolipoprotein associated with HDL, correlates with reduced risk of events, and HDL particle concentration (HDL-P) inversely associates with incident CV events adjusted for HDL-C and LDL particle measures. Cholesterol efflux, the mechanism by which macrophages in vessel walls secrete cholesterol outside cells, correlates with both surrogate end points and clinical events. The effects of niacin on these alternate measures of HDL have been conflicting. Further studies should determine if modulation of these HDL function markers translates to clinical benefits. Although the HDL cholesterol hypothesis may be defunct, the HDL function hypothesis is now poised to be rigorously tested. PMID:26048725
Vu, Catherine N; Ruiz-Esponda, Raul; Yang, Eric; Chang, Evelyn; Gillard, Baiba; Pownall, Henry J; Hoogeveen, Ron C; Coraza, Ivonne; Balasubramanyam, Ashok
Plasma triglycerides (TG) and HDL-C are inversely related in Metabolic Syndrome (MetS), due to exchange of VLDL-TG for HDL-cholesteryl esters catalyzed by cholesteryl ester transfer protein (CETP). We investigated the relationship of TG to HDL-C in highly-active antiretroviral drug (HAART)-treated HIV patients. Fasting plasma TG and HDL-C levels were compared in 179 hypertriglyceridemic HIV/HAART patients and 71 HIV-negative persons (31 normotriglyceridemic (NL) and 40 hypertriglyceridemic due to type IV hyperlipidemia (HTG)). CETP mass and activity were compared in 19 NL and 87 HIV/HAART subjects. Among the three groups, a plot of HDL-C vs. TG gave similar slopes but significantly different y-intercepts (9.24±0.45, 8.16±0.54, 6.70±0.65, sqrt(HDL-C) for NL, HIV and HTG respectively; P<0.001); this difference persisted after adjusting HDL-C for TG, age, BMI, gender, glucose, CD4 count, viral load and HAART strata (7.18±0.20, 6.20±0.05 and 4.55±0.15 sqrt(HDL-C) for NL, HIV and HTG, respectively, P<0.001). CETP activity was not different between NL and HIV, but CETP mass was significantly higher in HIV (1.47±0.53 compared to 0.93±0.27μg/mL, P<0.0001), hence CETP specific activity was lower in HIV (22.67±13.46 compared to 28.46±8.24nmol/μg/h, P=0.001). Dyslipidemic HIV/HAART patients have a distinctive HDL-C plasma concentration adjusted for TG. The weak inverse relationship between HDL-C and TG is not explained by altered total CETP activity; it could result from a non-CETP-dependent mechanism or a decrease in CETP function due to inhibitors of CETP activity in HIV patients' plasma. Copyright © 2013 Elsevier Inc. All rights reserved.
Vu, Catherine N.; Ruiz-Esponda, Raul; Yang, Eric; Chang, Evelyn; Gillard, Baiba; Pownall, Henry J.; Hoogeveen, Ron C.; Coraza, Ivonne; Balasubramanyam, Ashok
Introduction Plasma triglycerides (TG) and HDL-C are inversely related in Metabolic Syndrome (MetS), due to exchange of VLDL-TG for HDL-cholesteryl esters catalyzed by cholesteryl ester transfer protein (CETP). We investigated the relationship of TG to HDL-C in highly-active antiretroviral drug (HAART)-treated HIV patients. Methods Fasting plasma TG and HDL-C levels were compared in 179 hypertriglyceridemic HIV/HAART patients and 71 HIV-negative persons (31 normotriglyceridemic (NL) and 40 hypertriglyceridemic due to type IV hyperlipidemia (HTG)). CETP mass and activity were compared in 19 NL and 87 HIV/HAART subjects. Results Among the three groups, a plot of HDL-C vs. TG gave similar slopes but significantly different y-intercepts (9.24 ± 0.45, 8.16 ± 0.54, 6.70 ± 0.65, sqrt(HDL-C) for NL, HIV and HTG respectively; P<0.001); this difference persisted after adjusting HDL-C for TG, age, BMI, gender, glucose, CD4 count, viral load and HAART strata (7.18 ± 0.20, 6.20 ± 0.05 and 4.55 ± 0.15 sqrt(HDL-C) for NL, HIV and HTG, respectively, P <0.001). CETP activity was not different between NL and HIV, but CETP mass was significantly higher in HIV (1.47 ± 0.53 compared to 0.93 ± 0.27 μg/mL, P<0.0001), hence CETP specific activity was lower in HIV (22.67 ± 13.46 compared to 28.46 ± 8.24 nmol/μg/h, P=0.001). Conclusions Dyslipidemic HIV/HAART patients have a distinctive HDL-C plasma concentration adjusted for TG. The weak inverse relationship between HDL-C and TG is not explained by altered total CETP activity; it could result from a non-CETP-dependent mechanism or a decrease in CETP function due to inhibitors of CETP activity in HIV patients’ plasma. PMID:23522788
Zanoni, Paolo; Khetarpal, Sumeet A.; Larach, Daniel B.; Hancock-Cerutti, William F.; Millar, John S.; Cuchel, Marina; DerOhannessian, Stephanie; Kontush, Anatol; Surendran, Praveen; Saleheen, Danish; Trompet, Stella; Jukema, J. Wouter; De Craen, Anton; Deloukas, Panos; Sattar, Naveed; Ford, Ian; Packard, Chris; Majumder, Abdullah al Shafi; Alam, Dewan S.; Di Angelantonio, Emanuele; Abecasis, Goncalo; Chowdhury, Rajiv; Erdmann, Jeanette; Nordestgaard, Børge G.; Nielsen, Sune F.; Tybjærg-Hansen, Anne; Schmidt, Ruth Frikke; Kuulasmaa, Kari; Liu, Dajiang J.; Perola, Markus; Blankenberg, Stefan; Salomaa, Veikko; Männistö, Satu; Amouyel, Philippe; Arveiler, Dominique; Ferrieres, Jean; Müller-Nurasyid, Martina; Ferrario, Marco; Kee, Frank; Willer, Cristen J.; Samani, Nilesh; Schunkert, Heribert; Butterworth, Adam S.; Howson, Joanna M. M.; Peloso, Gina M.; Stitziel, Nathan O.; Danesh, John; Kathiresan, Sekar; Rader, Daniel J.
Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant). PMID:26965621
Zanoni, Paolo; Khetarpal, Sumeet A; Larach, Daniel B; Hancock-Cerutti, William F; Millar, John S; Cuchel, Marina; DerOhannessian, Stephanie; Kontush, Anatol; Surendran, Praveen; Saleheen, Danish; Trompet, Stella; Jukema, J Wouter; De Craen, Anton; Deloukas, Panos; Sattar, Naveed; Ford, Ian; Packard, Chris; Majumder, Abdullah al Shafi; Alam, Dewan S; Di Angelantonio, Emanuele; Abecasis, Goncalo; Chowdhury, Rajiv; Erdmann, Jeanette; Nordestgaard, Børge G; Nielsen, Sune F; Tybjærg-Hansen, Anne; Schmidt, Ruth Frikke; Kuulasmaa, Kari; Liu, Dajiang J; Perola, Markus; Blankenberg, Stefan; Salomaa, Veikko; Männistö, Satu; Amouyel, Philippe; Arveiler, Dominique; Ferrieres, Jean; Müller-Nurasyid, Martina; Ferrario, Marco; Kee, Frank; Willer, Cristen J; Samani, Nilesh; Schunkert, Heribert; Butterworth, Adam S; Howson, Joanna M M; Peloso, Gina M; Stitziel, Nathan O; Danesh, John; Kathiresan, Sekar; Rader, Daniel J
Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).
Nicod, Nathalie; Parker, Robert S; Giordano, Elena; Maestro, Virginia; Davalos, Alberto; Visioli, Francesco
High-density lipoproteins (HDLs) are atheroprotective because of their role in reverse cholesterol transport. The intestine is involved in this process because it synthesizes HDL, removes cholesterol from plasma and excretes it into the lumen. We investigated the role of selected dietary fatty acids on intestinal cholesterol uptake and HDL functionality. Caco-2 monolayers grown on Transwells were supplemented with either palmitic, palmitoleic, oleic, linoleic, docosahexaenoic, eicosapentaenoic, arachidonic or conjugated linoleic acids (CLAs): c9,t11-CLA; t9,t11-CLA; c10,t12-CLA. Cells synthesized HDL in the basolateral compartment for 24 h in the absence or presence of an antibody to SR-BI (aSR-BI), which inhibits its interaction with HDL. Free cholesterol (FC) accumulated to a greater extent in the presence than in the absence of aSR-BI, indicating net uptake of FC by SR-BI. Uptake's efficiency was significantly decreased when cells were treated with c9,t11-CLA relative to the other fatty acids. These differences were associated with lower HDL functionality, since neither SR-BI protein expression nor expression and alternative splicing of other genes involved lipid metabolism were affected. Only INSIG2 expression was decreased, with no increase of its target genes. Increasing pre-β-HDL synthesis, by inducing ABCA1 and adding APOA1, resulted in reduced uptake of FC by SR-BI after c9,t11-CLA treatment, indicating reduced functionality of pre-β-HDL. Conversely, treatment with c9,t11-CLA resulted in a greater uptake of FC and esterified cholesterol from mature HDL. Therefore, Caco-2 monolayers administered c9,t11-CLA produced a nonfunctional pre-β-HDL but took up cholesterol more efficiently via SR-BI from mature HDL.
Vaziri, N D; Liang, K
Chronic renal failure (CRF) is associated with increased risk of arteriosclerotic cardiovascular disease and profound alteration of plasma lipid profile. Uremic dyslipidemia is marked by increased plasma concentration of ApoB-containing lipoproteins and impaired high-density lipoprotein (HDL)-mediated reverse cholesterol transport. These abnormalities are, in part, due to acquired LCAT deficiency and upregulation of hepatic acyl-CoA:cholesterol acyltransferase (ACAT). ACAT catalyzes intracellular esterification of cholesterol, thereby promoting hepatic production of ApoB-containing lipoproteins and constraining HDL-mediated cholesterol uptake in the peripheral tissues. In view of the above considerations, we tested the hypothesis that pharmacological inhibition of ACAT may ameliorate CRF-induced dyslipidemia. 5/6 Nephrectomized rats were treated with either ACAT inhibitor IC-976 (30 mg.kg(-1).day(-1)) or placebo for 6 wk. Sham-operated rats served as controls. Key cholesterol-regulating enzymes, plasma lipids, and creatinine clearance were measured. The untreated CRF rats exhibited increased plasma low-density lipoprotein (LDL) and very LDL (VLDL) cholesterol, unchanged plasma HDL cholesterol, elevated total cholesterol-to-HDL cholesterol ratio, reduced liver microsomal free cholesterol, and diminished creatinine clearance. This was accompanied by reduced plasma LCAT, increased hepatic ACAT-2 mRNA, ACAT-2 protein and ACAT activity, and unchanged hepatic HMG-CoA reductase and cholesterol 7alpha-hydroxylase. ACAT inhibitor raised plasma HDL cholesterol, lowered LDL and VLDL cholesterol, and normalized total cholesterol-to-HDL cholesterol ratio without changing total cholesterol concentration (hence, a shift from ApoB-containing lipoproteins to HDL). This was accompanied by normalizations of hepatic ACAT activity and plasma LCAT. In conclusion, inhibition of ACAT reversed LCAT deficiency and improved plasma HDL level in CRF rats. Future studies are needed to explore
... and proteins. These are called – no big surprise – lipoproteins. Two types of lipoproteins carry cholesterol to and from cells. One is low-density lipoprotein, or LDL. The other is high-density lipoprotein, ...
Asztalos, Bela F; Horvath, Katalin V; Mehan, Michael; Yokota, Yuya; Schaefer, Ernst J
It has been reported that low cell-cholesterol efflux capacity (CEC) of HDL is an independent risk factor for CVD. To better understand CEC regulation, we measured ABCA1- and scavenger receptor class B type I (SR-BI)-dependent cell-cholesterol efflux, HDL anti-oxidative capacity, HDL particles, lipids, and inflammatory- and oxidative-stress markers in 122 subjects with elevated plasma levels of triglyceride (TG), serum amyloid A (SAA), fibrinogen, myeloperoxidase (MPO), or β-sitosterol and in 146 controls. In controls, there were strong positive correlations between ABCA1-dependent cholesterol efflux and small preβ-1 concentrations (R(2) = 0.317) and SR-BI-dependent cholesterol efflux and large (α-1 + α-2) HDL particle concentrations (R(2) = 0.774). In high-TG patients, both the concentration and the functionality (preβ-1 concentration-normalized ABCA1 efflux) of preβ-1 particles were significantly elevated compared with controls; however, though the concentration of large particles was significantly decreased, their functionality (large HDL concentration-normalized SR-BI efflux) was significantly elevated. High levels of SAA or MPO were not associated with decreased functionality of either the small (preβ-1) or the large (α-1 + α-2) HDL particles. HDL anti-oxidative capacity was negatively influenced by high plasma β-sitosterol levels, but not by the concentrations of HDL particles, TG, SAA, fibrinogen, or MPO. Our data demonstrate that under certain conditions CEC is influenced not only by quantitative (concentration), but also by qualitative (functional) properties of HDL particles. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.
The cis-9,trans-11 isomer of conjugated linoleic acid (CLA) lowers plasma triglyceride and raises HDL cholesterol concentrations but does not suppress aortic atherosclerosis in diabetic apoE-deficient mice.
Nestel, Paul; Fujii, Akihiko; Allen, Terri
Reduction in atherosclerosis has been reported in experimental animals fed mixtures of conjugated linoleic acid (CLA). In this study, the major naturally occurring CLA isomer (cis-9,trans-11) was tested in an atherosclerosis-prone mouse model. In a model of insulin deficient apoE deficient mice, 16 animals were fed for 20 weeks with supplemental CLA (09.%, w/w) and compared with a similar number of mice of this phenotype. A control comparison was made of metabolic changes in non-diabetic apoE deficient mice that develop little atherosclerosis over 20 weeks. At 20 weeks, plasma lipids were measured and aortic atherosclerosis quantified by Sudan staining in the arch, thoracic and abdominal segments. The diabetic apoE deficient mice developed marked dyslipidemia, primarily as cholesterol-enriched chylomicron and VLDL-sized lipoproteins and atherosclerosis in the aortic arch. However, there were no significant differences between CLA fed and non-CLA fed mice in either phenotype in plasma cholesterol concentration (in diabetic: 29.4+/-7.7 and 29.5+/-5.9 mmol/L, respectively) or in the area of aortic arch atherosclerosis (in diabetic: 24.8+/-10.3 and 27.6+/-7.7%, respectively). However, among diabetic mice the triglyceride concentration in triglyceride-rich lipoproteins was significantly lower in those fed CLA (for plasma 2.2+/-0.8 to 1.1+/-0.3 mmol/L; P<0.001), a significant difference that was seen also in the non-diabetic mice in which HDL cholesterol increased significantly with CLA (0.35+/-0.12-0.56+/-0.15 mmol/L). In this atherosclerosis-prone model, the diabetic apoE deficient mouse, supplemental 0.9% CLA (cis-9,trans-11) failed to reduce the severity of aortic atherosclerosis, although plasma triglyceride concentration was substantially lowered and HDL cholesterol raised.
Omidi, Arash; Ansari nik, Hossein; Ghazaghi, Mahmood
Ten blue-neck male ostriches (Struthio camelus) were fed Prosopis farcta beans throughout a 30-day experiment. Blood samples were collected from ostriches on days 0 and 30 to measure levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, total serum protein, albumin, globulin, cholesterol, calcium, inorganic phosphorus, the activity of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transferase (γ-GT). From days 0 to 30, HDL cholesterol, total protein, and globulins levels increased significantly whereas LDL cholesterol, inorganic phosphorus, and γ-GT activity decreased significantly.
Storey, Stephen M; McIntosh, Avery L; Huang, Huan; Landrock, Kerstin K; Martin, Gregory G; Landrock, Danilo; Payne, H Ross; Atshaves, Barbara P; Kier, Ann B; Schroeder, Friedhelm
A major gap in our knowledge of rapid hepatic HDL cholesterol clearance is the role of key intracellular factors that influence this process. Although the reverse cholesterol transport pathway targets HDL to the liver for net elimination of free cholesterol from the body, molecular details governing cholesterol uptake into hepatocytes are not completely understood. Therefore, the effects of sterol carrier protein (SCP)-2 and liver fatty acid-binding protein (L-FABP), high-affinity cholesterol-binding proteins present in hepatocyte cytosol, on HDL-mediated free cholesterol uptake were examined using gene-targeted mouse models, cultured primary hepatocytes, and 22-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol). While SCP-2 overexpression enhanced NBD-cholesterol uptake, counterintuitively, SCP-2/SCP-x gene ablation also 1) enhanced the rapid molecular phase of free sterol uptake detectable in <1 min and initial rate and maximal uptake of HDL free cholesterol and 2) differentially enhanced free cholesterol uptake mediated by the HDL3, rather than the HDL2, subfraction. The increased HDL free cholesterol uptake was not due to increased expression or distribution of the HDL receptor [scavenger receptor B1 (SRB1)], proteins regulating SRB1 [postsynaptic density protein (PSD-95)/Drosophila disk large tumor suppressor (dlg)/tight junction protein (ZO1) and 17-kDa membrane-associated protein], or other intracellular cholesterol trafficking proteins (steroidogenic acute response protein D, Niemann Pick C, and oxysterol-binding protein-related proteins). However, expression of L-FABP, the single most prevalent hepatic cytosolic protein that binds cholesterol, was upregulated twofold in SCP-2/SCP-x null hepatocytes. Double-immunogold electron microscopy detected L-FABP sufficiently close to SRB1 for direct interaction, similar to SCP-2. These data suggest a role for L-FABP in HDL cholesterol uptake, a finding confirmed with SCP-2
Storey, Stephen M.; McIntosh, Avery L.; Huang, Huan; Landrock, Kerstin K.; Martin, Gregory G.; Landrock, Danilo; Payne, H. Ross; Atshaves, Barbara P.; Kier, Ann B.
A major gap in our knowledge of rapid hepatic HDL cholesterol clearance is the role of key intracellular factors that influence this process. Although the reverse cholesterol transport pathway targets HDL to the liver for net elimination of free cholesterol from the body, molecular details governing cholesterol uptake into hepatocytes are not completely understood. Therefore, the effects of sterol carrier protein (SCP)-2 and liver fatty acid-binding protein (L-FABP), high-affinity cholesterol-binding proteins present in hepatocyte cytosol, on HDL-mediated free cholesterol uptake were examined using gene-targeted mouse models, cultured primary hepatocytes, and 22-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-amino]-23,24-bisnor-5-cholen-3β-ol (NBD-cholesterol). While SCP-2 overexpression enhanced NBD-cholesterol uptake, counterintuitively, SCP-2/SCP-x gene ablation also 1) enhanced the rapid molecular phase of free sterol uptake detectable in <1 min and initial rate and maximal uptake of HDL free cholesterol and 2) differentially enhanced free cholesterol uptake mediated by the HDL3, rather than the HDL2, subfraction. The increased HDL free cholesterol uptake was not due to increased expression or distribution of the HDL receptor [scavenger receptor B1 (SRB1)], proteins regulating SRB1 [postsynaptic density protein (PSD-95)/Drosophila disk large tumor suppressor (dlg)/tight junction protein (ZO1) and 17-kDa membrane-associated protein], or other intracellular cholesterol trafficking proteins (steroidogenic acute response protein D, Niemann Pick C, and oxysterol-binding protein-related proteins). However, expression of L-FABP, the single most prevalent hepatic cytosolic protein that binds cholesterol, was upregulated twofold in SCP-2/SCP-x null hepatocytes. Double-immunogold electron microscopy detected L-FABP sufficiently close to SRB1 for direct interaction, similar to SCP-2. These data suggest a role for L-FABP in HDL cholesterol uptake, a finding confirmed with SCP-2
Mondul, Alison M; Weinstein, Stephanie J; Virtamo, Jarmo; Albanes, Demetrius
Studies suggest a decreased risk of high-grade prostate cancer in men with lower circulating total cholesterol and that statins may protect against aggressive disease. Confirmation in additional populations and examination of associations for lipoprotein subfractions are needed. We examined prostate cancer risk and serum total and HDL cholesterol in the ATBC Study cohort (n = 29,093). Cox proportional hazards models were used to estimate the relative risk of total (n = 2,041), non-aggressive (n = 829), aggressive (n = 461), advanced (n = 412), and high-grade (n = 231) prostate cancer by categories of total and HDL cholesterol. After excluding the first 10 years of follow-up, men with higher serum total cholesterol were at increased risk of overall (≥240 vs. <200 mg/dl: HR = 1.22, 95% CI 1.03-1.44, p-trend = 0.01) and advanced (≥240 vs. <200 mg/dl: HR = 1.85, 95% CI 1.13-3.03, p-trend = 0.05) prostate cancer. Higher HDL cholesterol was suggestively associated with a decreased risk of prostate cancer regardless of stage or grade. In this population of smokers, high serum total cholesterol was associated with higher risk of advanced prostate cancer, and high HDL cholesterol suggestively reduced the risk of prostate cancer overall. These results support previous studies and, indirectly, support the hypothesis that statins may reduce the risk of advanced prostate cancer by lowering cholesterol.
de Oliveira, Wilson Pascoalino Camargo; Tavoni, Thauany Martins; Freitas, Fatima Rodrigues; Silva, Bruna Miranda Oliveira; Maranhão, Raul Cavalcante
Plasma lipids have been extensively studied in sedentary and in subjects practicing exercise training, but not in extreme inactivity as occurs in bedridden patients. This is important for the care of bedridden patients and understanding the overall plasma lipid regulation. Here, we investigated plasma lipids, lipid transfers to HDL and inflammatory markers in bedridden patients. Fasting blood samples were collected from 23 clinically stable bedridden patients under long-term care (>90 days) and 26 normolipidemic sedentary subjects, paired for age and gender. In vitro transfer of four lipids to HDL was performed by incubating plasma with donor nanoparticles containing radioactive lipids. Total (193 ± 36 vs 160 ± 43, p = 0.005), LDL (124 ± 3 vs 96 ± 33 p = 0.003) and HDL-cholesterol (45 ± 10 vs 36 ± 13, p = 0.008), apolipoprotein A-I (134 ± 20 vs 111 ± 24, p = 0.001) and oxidized LDL (53 ± 13 vs 43 ± 12, p = 0.011) were lower in bedridden patients, whereas triglycerides, apolipoprotein B, CETP and LCAT were equal in both groups. Transfers of all lipids, namely unesterified cholesterol, cholesterol esters, triglycerides and phospholipids, to HDL were lower in bedridden patients, probably due to their lower HDL-cholesterol levels. Concentrations of IL-1β, IL-6, IL-8, HGF and NGF were higher in bedridden patients compared to sedentary subjects. In conclusion, inactivity had great impact on HDL, by lowering HDL-cholesterol, apolipoprotein A-I and thereby cholesterol transfers to the lipoprotein, which suggests that inactivity may deteriorate HDL protection beyond the ordinary sedentary condition.
Huang, LinZhang; Fan, BaoYan; Ma, Ang; Shaul, Philip W; Zhu, HaiBo
ABCA1 plays a key role in the initial lipidation of apoA-I, which generates circulating HDL cholesterol. Whereas it is known that the transcriptional upregulation of ABCA1 promotes HDL formation and reverse cholesterol transport (RCT), it is not known how the inhibition of ABCA1 protein degradation impacts HDL function. Employing the small molecule triacetyl-3-hydroxyphenyladenosine (IMM-H007), we determined how the attenuation of ABCA1 protein degradation affects HDL cholesterol efflux capacity, RCT, and atherosclerotic lesion formation. Pulse-chase analysis revealed that IMM-H007 inhibits ABCA1 degradation and facilitates its cell-surface localization in macrophages, and additional studies in macrophages showed that IMM-H007 thereby promotes cholesterol efflux. IMM-H007 treatment of Paigen diet-fed mice caused an increase in circulating HDL level, it increased the cholesterol efflux capacity of HDL, and it enhanced in vivo RCT from macrophages to the plasma, liver, and feces. Furthermore, ABCA1 degradation suppression by IMM-H007 reduced atherosclerotic plaque formation in apoE(-/-) mice. Thus, via effects on both ABCA1-expressing cells and circulating HDL function, the inhibition of ABCA1 protein degradation by IMM-H007 promotes HDL cholesterol efflux capacity and RCT and attenuates atherogenesis. IMM-H007 potentially represents a lead compound for the development of agents to augment HDL function. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.
Background Altered lipid profile, and in particular low HDL and high triglyceride (TG) plasma levels, are within the major determinants of cardiovascular diseases. The identification of quantitative trait loci (QTL) affecting these lipid levels is a relevant issue for predictive purposes. The WWOX gene has been recently associated with HDL levels. This gene is located at chromosome 16q23, a region previously linked to familial combined hyperlipidemia (FCHL) and HDL. Our objective is to perform a genetic association analysis at the WWOX gene region with HDL, TG and TG/HDL ratio. Methods A quantitative association analysis performed in 801 individuals selected from the Spanish general population. Results For HDL levels, two regions of intron 8 display clustering of positive signals (p < 0.05) but none of them was associated in the haplotypic analysis (0.07 ≤ p ≤ 0.165). For TG levels not only intron 8 but also a 27 kb region spanning from the promoter region to intron 4 are associated in this study. For the TG/HDL genetic association analysis, positive signals are coincident with those of the isolated traits. Interestingly, haplotypic analysis at the 5' region showed that variation in this region modified both HDL and TG levels, especially the latter (p = 0.003). Conclusions Our results suggest that WWOX is a QTL for both TG and HDL. PMID:20942981
Fernández-Castillejo, Sara; Rubió, Laura; Hernáez, Álvaro; Catalán, Úrsula; Pedret, Anna; Valls, Rosa-M; Mosele, Juana I; Covas, Maria-Isabel; Remaley, Alan T; Castañer, Olga; Motilva, Maria-José; Solá, Rosa
Cholesterol efflux capacity of HDL (CEC) is inversely associated with cardiovascular risk. HDL composition, fluidity, oxidation, and size are related with CEC. We aimed to assess which HDL parameters were CEC determinants after virgin olive oil (VOO) ingestion. Post-hoc analyses from the VOHF study, a crossover intervention with three types of VOO. We assessed the relationship of 3-week changes in HDL-related variables after intervention periods with independence of the type of VOO. After univariate analyses, mixed linear models were fitted with variables related with CEC and fluidity. Fluidity and Apolipoprotein (Apo)A-I content in HDL was directly associated, and HDL oxidative status inversely, with CEC. A reduction in free cholesterol, an increase in triglycerides in HDL, and a decrease in small HDL particle number or an increase in HDL mean size, were associated to HDL fluidity. HDL fluidity, ApoA-I concentration, and oxidative status are major determinants for CEC after VOO. The impact on CEC of changes in free cholesterol and triglycerides in HDL, and those of small HDL or HDL mean size, could be mechanistically linked through HDL fluidity. Our work points out novel therapeutic targets to improve HDL functionality in humans through nutritional or pharmacological interventions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Després, J P; Lemieux, I; Dagenais, G R; Cantin, B; Lamarche, B
Primary as well as secondary prevention trials have shown the relevance of lowering LDL-cholesterol to reduce coronary heart disease (CHD) risk. However, although the association between LDL-cholesterol and CHD is well recognized, there is a considerable overlap in the distribution of plasma LDL-cholesterol levels between CHD patients and healthy subjects. The objective of the present review article is to use data from the Quebec cardiovascular study to demonstrate that in men, a low HDL-cholesterol may be even more of a risk factor and a target for therapy than a high LDL-cholesterol. Results of the Quebec cardiovascular study, a prospective study of 2103 middle-aged men followed for a period of 5 years, have confirmed results of previous studies in showing that plasma HDL-cholesterol concentration was an independent predictor of a first ischemic heart disease (IHD) event which included typical effort angina, coronary insufficiency, nonfatal myocardial infarction and coronary death. In addition, a reduced plasma HDL-cholesterol concentration was found to have a greater impact than raised LDL-cholesterol on the atherogenic index (total cholesterol/HDL-cholesterol ratio), this ratio being the best variable of the traditional lipid profile for the prediction of IHD events in the Quebec cardiovascular study. However, a low HDL-cholesterol concentration is not often observed as an isolated disorder but also includes hypertriglyceridemia, elevated apo B concentration, and an increased proportion of small, dense LDL particles. These abnormalities are features of an insulin resistant-hyperinsulinemic state resulting from abdominal obesity. It is therefore recommended that we need to go beyond LDL-cholesterol measurement lowering therapy for the optimal management of CHD risk. Raising plasma HDL-cholesterol through weight loss and a healthy diet, by an increased physical activity and, if required, by proper pharmacotherapy is therefore a legitimate therapeutic target for
Fulks, Michael; Stout, Robert L; Dolan, Vera F
Determine the relationship between various lipid tests and all-cause mortality in life insurance applicants stratified by age and sex. By use of the Social Security Death Master File, mortality was determined in 1,488,572 life insurance applicants from whom blood samples were submitted to Clinical Reference Laboratory. There were 41,020 deaths observed in this healthy adult population during a median follow-up of 12 years (range 10 to 14 years). Results were stratified by 4 age-sex subpopulations: females, ages 20 to 59 or 60+; and males, ages 20 to 59 or 60+. Those with serum albumin < 3.6 mg/dL or fructosamine > or = 2.1 mmol/L were excluded. The middle 50% of lipid values specific to each of these 4 age-sex subpopulations was used as the reference band. The mortality rates in bands representing other percentiles of lipid values were compared with the mortality rate in the reference band within each age-sex subpopulation. In contrast to some published findings from general populations, lipid test results are only moderately predictive of all-cause mortality risk in a life insurance applicant population and that risk is dependent on age and sex. At ages below 60, HDL values are associated with a "J" shaped mortality curve and at ages 60+, total cholesterol is associated with a "U" shaped curve. The total cholesterol/HDL ratio may serve as a useful single measure to predict mortality risk, but only if stratified by age and sex, and only if high HDL values at younger ages and lower total cholesterol values at ages 60+ are recognized as being associated with increased risk as well. Using LDL or non-HDL cholesterol instead of total cholesterol does not improve mortality risk discrimination; neither does using total cholesterol or triglyceride values in addition to the total cholesterol/HDL ratio. The total cholesterol/HDL ratio is the best single measure of all-cause mortality risk among the various lipid tests but is useful only if viewed on an age- and sex
Andersen, Catherine J; Blesso, Christopher N; Lee, Jiyoung; Barona, Jacqueline; Shah, Dharika; Thomas, Michael J; Fernandez, Maria Luz
We recently demonstrated that daily whole egg consumption during moderate carbohydrate restriction leads to greater increases in plasma HDL-cholesterol (HDL-C) and improvements in HDL profiles in metabolic syndrome (MetS) when compared to intake of a yolk-free egg substitute. We further investigated the effects of this intervention on HDL composition and function, hypothesizing that the phospholipid species present in egg yolk modulate HDL lipid composition to increase the cholesterol-accepting capacity of subject serum. Men and women classified with MetS were randomly assigned to consume either three whole eggs (EGG, n = 20) per day or the equivalent amount of egg substitute (SUB, n = 17) throughout a 12-week moderate carbohydrate-restricted (25-30 % of energy) diet. Relative to other HDL lipids, HDL-cholesteryl ester content increased in all subjects, with greater increases in the SUB group. Further, HDL-triacylglycerol content was reduced in EGG group subjects with normal baseline plasma HDL-C, resulting in increases in HDL-CE/TAG ratios in both groups. Phospholipid analysis by mass spectrometry revealed that HDL became enriched in phosphatidylethanolamine in the EGG group, and that EGG group HDL better reflected sphingomyelin species present in the whole egg product at week 12 compared to baseline. Further, macrophage cholesterol efflux to EGG subject serum increased from baseline to week 12, whereas no changes were observed in the SUB group. Together, these findings suggest that daily egg consumption promotes favorable shifts in HDL lipid composition and function beyond increasing plasma HDL-C in MetS.
Andersen, Catherine J.; Blesso, Christopher N.; Lee, Jiyoung; Barona, Jacqueline; Shah, Dharika; Thomas, Michael J.
We recently demonstrated that daily whole egg consumption during moderate carbohydrate restriction leads to greater increases in plasma HDL-cholesterol (HDL-C) and improvements in HDL profiles in metabolic syndrome (MetS) when compared to intake of a yolk-free egg substitute. We further investigated the effects of this intervention on HDL composition and function, hypothesizing that the phospholipid species present in egg yolk modulate HDL lipid composition to increase the cholesterol-accepting capacity of subject serum. Men and women classified with MetS were randomly assigned to consume either three whole eggs (EGG, n = 20) per day or the equivalent amount of egg substitute (SUB, n = 17) throughout a 12-week moderate carbohydrate-restricted (25–30 % of energy) diet. Relative to other HDL lipids, HDL-cholesteryl ester content increased in all subjects, with greater increases in the SUB group. Further, HDL-triacylglycerol content was reduced in EGG group subjects with normal baseline plasma HDL-C, resulting in increases in HDL-CE/TAG ratios in both groups. Phospholipid analysis by mass spectrometry revealed that HDL became enriched in phosphatidylethanolamine in the EGG group, and that EGG group HDL better reflected sphingomyelin species present in the whole egg product at week 12 compared to baseline. Further, macrophage cholesterol efflux to EGG subject serum increased from baseline to week 12, whereas no changes were observed in the SUB group. Together, these findings suggest that daily egg consumption promotes favorable shifts in HDL lipid composition and function beyond increasing plasma HDL-C in MetS. PMID:23494579
Ciprofibrate therapy in patients with hypertriglyceridemia and low high density lipoprotein (HDL)-cholesterol: greater reduction of non-HDL cholesterol in subjects with excess body weight (The CIPROAMLAT study)
Aguilar-Salinas, Carlos A; Assis-Luores-Vale, Andréia; Stockins, Benjamín; Rengifo, Hector Mario; Filho, José Dondici; Neto, Abrahão Afiune; Rabelo, Lísia Marcílio; Torres, Kerginaldo Paulo; Oliveira, José Egídio Paulo de; Machado, Carlos Alberto; Reyes, Eliana; Saavedra, Victor; Florenzano, Fernando; Hernández, Ma Victoria; Jiménez, Sergio Hernandez; Ramírez, Erika; Vazquez, Cuauhtémoc; Salinas, Saul; Hernández, Ismael; Medel, Octavio; Moreno, Ricardo; Lugo, Paula; Alvarado, Ricardo; Mehta, Roopa; Gutierrez, Victor; Gómez Pérez, Francisco J
Background Hypertriglyceridemia in combination with low HDL cholesterol levels is a risk factor for cardiovascular disease. Our objective was to evaluate the efficacy of ciprofibrate for the treatment of this form of dyslipidemia and to identify factors associated with better treatment response. Methods Multicenter, international, open-label study. Four hundred and thirty seven patients were included. The plasma lipid levels at inclusion were fasting triglyceride concentrations between 1.6–3.9 mM/l and HDL cholesterol ≤ 1.05 mM/l for women and ≤ 0.9 mM/l for men. The LDL cholesterol was below 4.2 mM/l. All patients received ciprofibrate 100 mg/d. Efficacy and safety parameters were assessed at baseline and at the end of the treatment. The primary efficacy parameter of the study was percentage change in triglycerides from baseline. Results After 4 months, plasma triglyceride concentrations were decreased by 44% (p < 0.001). HDL cholesterol concentrations were increased by 10% (p < 0.001). Non-HDL cholesterol was decreased by 19%. A greater HDL cholesterol response was observed in lean patients (body mass index < 25 kg/m2) compared to the rest of the population (8.2 vs 19.7%, p < 0.001). In contrast, cases with excess body weight had a larger decrease in non-HDL cholesterol levels (-20.8 vs -10.8%, p < 0.001). There were no significant complications resulting from treatment with ciprofibrate. Conclusions Ciprofibrate is efficacious for the correction of hypertriglyceridemia / low HDL cholesterol. A greater decrease in non-HDL cholesterol was found among cases with excess body weight. The mechanism of action of ciprofibrate may be influenced by the pathophysiology of the disorder being treated. PMID:15272932
Monette, Jeffrey S.; Hutchins, Patrick M.; Ronsein, Graziella E.; Wimberger, Jake; Irwin, Angela D.; Tang, Chongren; Sara, Jaskanwal D.; Shao, Baohai; Vaisar, Tomas; Lerman, Amir; Heinecke, Jay W.
Rationale Coronary endothelial dysfunction (ED)–an early marker of atherosclerosis–increases the risk of cardiovascular events. Objective We tested the hypothesis that cholesterol efflux capacity and HDL particle concentration predict coronary ED better than HDL-cholesterol (HDL-C). Methods and Results We studied 80 subjects with non-obstructive (<30% stenosis) coronary artery disease. ED was defined as <50% change in coronary blood flow in response to intra-coronary infusions of acetylcholine during diagnostic coronary angiography. Cholesterol efflux capacity and HDL particle concentration (HDL-PIMA) were assessed with validated assays. Cholesterol efflux capacity and HDL-PIMA were both strong, inverse predictors of ED (P<0.001 and 0.005, respectively). In contrast, HDL-C and other traditional lipid risk factors did not differ significantly between control and ED subjects. Large HDL particles were markedly decreased in ED subjects (33%; P=0.005). After correction for HDL-C, both efflux capacity and HDL-PIMA remained significant predictors of ED status. HDL-PIMA explained cholesterol efflux capacity more effectively than HDL-C (r=0.54 and 0.36, respectively). The efflux capacities of isolated HDL and serum HDL correlated strongly (r=0.49). Conclusions Cholesterol efflux capacity and HDL-PIMA are reduced in subjects with coronary ED, independently of HDL-C. Alterations in HDL-PIMA and HDL itself account for a much larger fraction of the variation in cholesterol efflux capacity than does HDL-C. A selective decrease in large HDL particles may contribute to impaired cholesterol efflux capacity in ED subjects. These observations support a role for HDL size, concentration and function as markers—and perhaps mediators—of coronary atherosclerosis in humans. PMID:27114438
Madden, Jacqueline; Carrero, Juan J; Brunner, Andreas; Dastur, Neville; Shearman, Cliff P; Calder, Philip C; Grimble, Robert F
Five SNPs in the CD36 gene, 25444G>A, 27645del>ins, 30294G>C, -31118G>A and -33137A>G in haplotypic combinations, link to fasting plasma NEFA concentrations. Fish oil lowers TAG concentrations. The influence of CD36 SNPs on hypotriglyceridemic effects is unknown. The study examines how four of the SNPs modify the effects of fish oil on fasting plasma TAG, NEFA, glucose LDL and HDL cholesterol concentrations in 111 healthy, middle-aged, Caucasian men. Subjects consumed habitual diets while taking 6g MaxEPA daily for 12 weeks. TAG decreased from 1.48 mol/l to 0.11 mmol/l, and glucose and HDL rose from 5.92 to 0.15 mmol/l and from 1.27 to 0.04 mmol/l, respectively, irrespective of genotype. NEFA was unaffected. Significant falls in TAG only occurred in individuals with the GG variant of the 25444, 30294, -31118 or -33137 SNPs. The TAG-lowering effects may be via stimulation of CD36 activity in extrahepatic tissue in individuals with the GG variants of these SNPs.
Background: ATP-binding cassette transporters G5/G8 have shown an association with HDL-C. One of the most likely mechanisms to explain those associations is through ABCA1. Objective: To assess whether the effect of ABCG5/G8 polymorphisms on HDL-C is dependent on ABCA1, we studied potential interacti...
Adu, Patrick; Ake, Edem; Agbodzakey, Hope; Adoba, Prince; Cudjoe, Obed; Agoni, Clement
Background. Abnormal lipid homeostasis in sickle cell disease (SCD) is characterized by defects in plasma and erythrocyte lipids and may increase the risk of cardiovascular disease. This study assessed the lipid profile and non-HDL cholesterol level of SCD patients. Methods. A hospital-based cross-sectional study was conducted in 50 SCD patients, in the steady state, aged 8–28 years, attending the SCD clinic, and 50 healthy volunteers between the ages of 8–38 years. Serum lipids were determined by enzymatic methods and non-HDL cholesterol calculated by this formula: non-HDL-C = TC-HDL-C. Results. Total cholesterol (TC) (p = 0.001) and high-density lipoprotein cholesterol (HDL-C) (p < 0.0001) were significantly decreased in cases compared to controls. The levels of non-HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were similar among the participants. The levels of decrease in TC and HDL were associated with whether a patient was SCD-SS or SCD-SC. Systolic blood pressure and diastolic blood pressure were each significantly associated with increased VLDL [SBP, p = 0.01, OR: 0.74 (CI: 0.6–0.93); DBP, p = 0.023, OR: 1.45 (CI: 1.05–2.0)]. Conclusion. Dyslipidemia is common among participants in this study. It was more pronounced in the SCD-SS than in SCD-SC. This dyslipidemia was associated with high VLDL as well as increased SBP and DBP. PMID:28078142
Fernandez, Maria Luz; Jones, Jennifer J; Ackerman, Daniela; Barona, Jacqueline; Calle, Mariana; Comperatore, Michael V; Kim, Jung-Eun; Andersen, Catherine; Leite, Jose O; Volek, Jeff S; McIntosh, Mark; Kalynych, Colleen; Najm, Wadie; Lerman, Robert H
Both metabolic syndrome (MetS) and elevated LDL cholesterol (LDL-C) increase the risk for cardiovascular disease (CVD). We hypothesized that low HDL cholesterol (HDL-C) would further increase CVD risk in women having both conditions. To assess this, we recruited 89 women with MetS (25-72 y) and LDL-C ≥ 2.6 mmol/L. To determine whether plasma HDL-C concentrations were associated with dietary components, circulating atherogenic particles, and other risk factors for CVD, we divided the subjects into two groups: high HDL-C (H-HDL) (≥ 1.3 mmol/L, n = 32) and low HDL-C (L-HDL) (< 1.3 mmol/L, n = 57). Plasma lipids, insulin, adiponectin, apolipoproteins, oxidized LDL, Lipoprotein(a), and lipoprotein size and subfractions were measured, and 3-d dietary records were used to assess macronutrient intake. Women with L-HDL had higher sugar intake and glycemic load (P < 0.05), higher plasma insulin (P < 0.01), lower adiponectin (P < 0.05), and higher numbers of atherogenic lipoproteins such as large VLDL (P < 0.01) and small LDL (P < 0.001) than the H-HDL group. Women with L-HDL also had larger VLDL and both smaller LDL and HDL particle diameters (P < 0.001). HDL-C was positively correlated with LDL size (r = 0.691, P < 0.0001) and HDL size (r = 0.606, P < 0.001), and inversely correlated with VLDL size (r = -0.327, P < 0.01). We concluded that L-HDL could be used as a marker for increased numbers of circulating atherogenic lipoproteins as well as increased insulin resistance in women who are already at risk for CVD.
Jones, Jennifer J; Ackerman, Daniela; Barona, Jacqueline; Calle, Mariana; Comperatore, Michael V; Kim, Jung-Eun; Andersen, Catherine; Leite, Jose O; Volek, Jeff S; McIntosh, Mark; Kalynych, Colleen; Najm, Wadie; Lerman, Robert H
Both metabolic syndrome (MetS) and elevated LDL cholesterol (LDL-C) increase the risk for cardiovascular disease (CVD). We hypothesized that low HDL cholesterol (HDL-C) would further increase CVD risk in women having both conditions. To assess this, we recruited 89 women with MetS (25-72 y) and LDL-C ≥ 2.6 mmol/L. To determine whether plasma HDL-C concentrations were associated with dietary components, circulating atherogenic particles, and other risk factors for CVD, we divided the subjects into two groups: high HDL-C (H-HDL) (≥ 1.3 mmol/L, n = 32) and low HDL-C (L-HDL) (< 1.3 mmol/L, n = 57). Plasma lipids, insulin, adiponectin, apolipoproteins, oxidized LDL, Lipoprotein(a), and lipoprotein size and subfractions were measured, and 3-d dietary records were used to assess macronutrient intake. Women with L-HDL had higher sugar intake and glycemic load (P < 0.05), higher plasma insulin (P < 0.01), lower adiponectin (P < 0.05), and higher numbers of atherogenic lipoproteins such as large VLDL (P < 0.01) and small LDL (P < 0.001) than the H-HDL group. Women with L-HDL also had larger VLDL and both smaller LDL and HDL particle diameters (P < 0.001). HDL-C was positively correlated with LDL size (r = 0.691, P < 0.0001) and HDL size (r = 0.606, P < 0.001), and inversely correlated with VLDL size (r = -0.327, P < 0.01). We concluded that L-HDL could be used as a marker for increased numbers of circulating atherogenic lipoproteins as well as increased insulin resistance in women who are already at risk for CVD. PMID:21286407
Bhatt, Anish; Rohatgi, Anand
Low high-density lipoprotein cholesterol (HDL-C) levels are associated with incident cardiovascular events; however, many therapies targeting increases in HDL-C have failed to show consistent clinical benefit. Thus, focus has recently shifted toward measuring high-density lipoprotein (HDL) function. HDL is the key mediator of reverse cholesterol transport, the process of cholesterol extraction from foam cells, and eventual excretion into the biliary system. Cholesterol efflux from peripheral macrophages to HDL particles has been associated with atherosclerosis in both animals and humans. We review the mechanism of cholesterol efflux and the emerging evidence on the association between cholesterol efflux capacity and cardiovascular disease in human studies. We also focus on the completed and ongoing trials of novel therapies targeting different aspects of HDL cholesterol efflux.
Auton, Matthew; Bassett, G. Randall; Gillard, Baiba K.; Pownall, Henry J.
Reassembled high density lipoproteins (rHDL) of various sizes and compositions containing apo A-I or apo A-II as their sole protein, dimyristoyl phosphatidylcholine (DMPC), and various amounts of free cholesterol (FC) have been isolated and analyzed by differential scanning calorimetry (DSC) and by circular dichroism to determine their stability and the temperature dependence of their helical content. Our data show that the multiple rHDL species obtained at each mol% FC usually do not have the same mole% FC as the starting mixture and that the size of the multiple species increases in a quantized way with their respective mol% FC. DSC studies reveal multiple phases or domains that can be classified as virtual DMPC, which contains a small amount of DMPC that slightly reduces the melting temperature Tm, a boundary phase that is adjacent to the apo A-I or apo A-II that circumscribes the discoidal rHDL, and a mixed FC + DMPC phase that has a Tm that increases with mol% FC. Only the large rHDL contain virtual DMPC whereas all contain boundary phase and various amounts of mixed FC + DMPC according to increasing size and mol% FC. As reported by others, FC stabilizes the rHDL. For rHDL (apo A-II) compared to rHDL (apo A-I), this occurs in spite of the reduced number of helical regions that mediate binding to the DMPC surface. This effect is attributed to the very high lipophilicity of apo A-II and the reduction in the polarity of the interface between DMPC and the aqueous phase with increasing mol% FC, an effect that is expected to increase the hydrophobic associations with the non polar face of the amphipathic helices of apo A-II. These data are relevant to the differential effects of FC and apolipoprotein species on intracellular and plasma membrane nascent HDL assembly and subsequent remodeling by plasma proteins. PMID:23721456
Bulum, T; Kolaric, B; Duvnjak, L
Previous studies have suggested a positive association between dyslipidemia and chronic kidney disease, but sparse data are available on the relation of lipids and urinary albumin excretion rate (UAE) in normoalbuminuric patients with normal renal function. The aim of this study was to evaluate the associations of serum lipids, including total, LDL, HDL, HDL2, HDL3 cholesterol, and triglyceride levels with UAE in normoalbuminuric Type 1 diabetic (T1D) patients. Study included 313 normoalbuminuric T1D patients with normal renal function and before any interventions with statins, ACE inhibitors or angiotensin II receptor blockers. Subjects were classified as low-normoalbuminuric (UAE<11.0 mg/24h) or high-normoalbuminuric (UAE≥11.0 mg/24h) based on median UAE of at least two 24- h urine collections. Correlations and multiple linear regressions analysis were performed to identify relationships between serum lipids and UAE in normoalbuminuric subjects. Total HDL (p=0.02) and HDL3 cholesterol (p=0.01) levels were higher in low-normoalbuminuric subjects compared to high-normoalbuminuric subjects. In logistic regression analysis, after adjustment for age, sex, BMI, duration of diabetes and HbA1c, lower total HDL and HDL3 cholesterol levels were significantly associated with risk of higher UAE in our normoalbuminuric subjects (p≤0.01), with odds ratios of 0.34 to 0.43. Elevated total HDL and HDL3 cholesterol levels are associated with lower UAE in normoalbuminuric T1D patients. However, whether the detection of elevated total HDL and HDL3 cholesterol levels in T1D patients has protective value for development of microalbuminuria needs to be assessed in further follow-up studies.
Borja, Mark S.; Ng, Kit F.; Irwin, Angela; Hong, Jaekyoung; Wu, Xing; Isquith, Daniel; Zhao, Xue-Qiao; Prazen, Bryan; Gildengorin, Virginia; Oda, Michael N.; Vaisar, Tomáš
HDL is the primary mediator of cholesterol mobilization from the periphery to the liver via reverse cholesterol transport (RCT). A critical first step in this process is the uptake of cholesterol from lipid-loaded macrophages by HDL, a function of HDL inversely associated with prevalent and incident cardiovascular disease. We hypothesized that the dynamic ability of HDL to undergo remodeling and exchange of apoA-I is an important and potentially rate-limiting aspect of RCT. In this study, we investigated the relationship between HDL-apoA-I exchange (HAE) and serum HDL cholesterol (HDL-C) efflux capacity. We compared HAE to the total and ABCA1-specific cholesterol efflux capacity of 77 subjects. We found that HAE was highly correlated with both total (r = 0.69, P < 0.0001) and ABCA1-specific (r = 0.47, P < 0.0001) efflux, and this relationship remained significant after adjustment for HDL-C or apoA-I. Multivariate models of sterol efflux capacity indicated that HAE accounted for approximately 25% of the model variance for both total and ABCA1-specific efflux. We conclude that the ability of HDL to exchange apoA-I and remodel, as measured by HAE, is a significant contributor to serum HDL efflux capacity, independent of HDL-C and apoA-I, indicating that HDL dynamics are an important factor in cholesterol efflux capacity and likely RCT. PMID:26254308
Krikken, J A; Waanders, F; Dallinga-Thie, G M; Dikkeschei, L D; Vogt, L; Navis, G J; Dullaart, R P F
Dyslipidemia contributes to increased cardiovascular risk in nephrotic syndrome. We questioned whether reduction in proteinuria not only lowers low-density lipoprotein cholesterol (LDL-C), but also high-density lipoprotein cholesterol (HDL-C) and cholesteryl ester transfer protein (CETP) mass and whether changes in HDL-C were related to changes in plasma adiponectin. Thirty-two non-diabetic proteinuric patients (12 on statin therapy), were followed during two double blind 6-week periods of placebo and treatment (low sodium + 100mg losartan + 25 mg hydrochlorothiazide). With placebo HDL-C was lower but LDL-C and CETP were not different in proteinuric patients compared with matched controls. LDL-C, HDL-C and CETP decreased upon proteinuria reduction. The decrease in LDL-C correlated with the drop in CETP and the degree of proteinuria reduction. HDL-C also decreased in proportion to proteinuria lowering. Individual changes in HDL-C were correlated with changes in adiponectin. LDL-C lowering upon robust reduction of proteinuria may be affected by changes in plasma CETP mass, but this treatment also decreases HDL-C in relation to the degree of proteinuria reduction. This adverse effect on HDL-C may in part be attributable to changes in adiponectin.
Masson, David; Koseki, Masahiro; Ishibashi, Minako; Larson, Christopher J; Miller, Stephen G; King, Bernard D; Tall, Alan R
Increasing HDL levels is a potential strategy for the treatment of atherosclerosis. ITX5061, a molecule initially characterized as a p38 MAPK inhibitor, increased HDL-C levels by 20% in a human population of hypertriglyceridemic subjects with low HDL levels. ITX5061 also moderately increased apoA-I but did not affect VLDL/LDL cholesterol or plasma triglyceride concentrations. ITX5061 increased HDL-C in WT and human apoA-I transgenic mice, and kinetic experiments showed that ITX5061 decreased the fractional catabolic rate of HDL-CE and reduced its hepatic uptake. In transfected cells, ITX5061 inhibited SR-BI-dependent uptake of HDL-CE. Moreover, ITX5061 failed to increase HDL-C levels in SR-BI(-/-) mice. To assess effects on atherosclerosis, ITX5061 was given to atherogenic diet-fed Ldlr(+/-) mice with or without CETP expression for 18 weeks. In both the control and CETP-expressing groups, ITX5061-treated mice displayed reductions of early atherosclerotic lesions in the aortic arch -40%, P<0.05), and a nonsignificant trend to reduced lesion area in the proximal aorta. Our data indicate that ITX5061 increases HDL-C levels by inhibition of SR-BI activity. This suggests that pharmacological inhibition of SR-BI has the potential to raise HDL-C and apoA-I levels without adverse effects on VLDL/LDL cholesterol levels in humans.
Puhkala, Jatta; Luoto, Riitta; Ahotupa, Markku; Raitanen, Jani; Vasankari, Tommi
Oxidized LDL lipids (ox-LDL) are associated with lifestyle diseases such as cardiovascular diseases, metabolic syndrome and type 2 diabetes. The present study investigated how postpartum weight retention effects on ox-LDL and serum lipids. The study is a nested comparative research of a cluster-randomized controlled trial, NELLI (lifestyle and counselling during pregnancy). During early pregnancy (8-12 weeks) and 1 year postpartum, 141 women participated in measurements for determining of plasma lipids: total cholesterol (T-C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triacylglycerols (TAG) and ox-LDL. Subjects were stratified into tertiles (weight loss, unaltered weight and weight gain groups) based on their weight change from baseline to follow-up. Ox-LDL was determined by baseline level of conjugated dienes in LDL lipids. Among the group of weight gainers, concentration of TAG reduced less (-0.14 vs. -0.33, p = 0.002), HDL-C reduced more (-0.31 vs. -0.16, p = 0.003) and ox-LDL/HDL-C ratio increased (3.0 vs. -0.2, p = 0.003) when compared to group of weight loss. Both T-C and LDL-C elevated more (0.14 vs. -0.21, p = 0.008; 0.31 vs. 0.07, p = 0.015) and TAG and ox-LDL reduced less (-0.33 vs. 0.20, p = 0.033; -3.33 vs. -0.68, p = 0.026) in unaltered weight group compared to weight loss group. The women who gained weight developed higher TAG and ox-LDL/HDL-C ratio as compared to those who lost weight. Postpartum weight retention of 3.4 kg or more is associated with atherogenic lipid profile.
Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial.
Brousseau, Margaret E; O'Connor, John J; Ordovas, Jose M; Collins, Dorothea; Otvos, James D; Massov, Tatyana; McNamara, Judith R; Rubins, Hanna B; Robins, Sander J; Schaefer, Ernst J
We have previously reported that genetic variation at the cholesteryl ester transfer protein (CETP) TaqIB locus is correlated with plasma lipid levels and coronary heart disease (CHD) risk in the Framingham Offspring Study (FOS). In FOS, the B2 allele was associated with increased levels of high density lipoprotein (HDL) cholesterol (HDL-C), decreased CETP activity, and reduced CHD risk for men having the B2B2 genotype. The present study was undertaken to further define the relationship between this polymorphism and CHD risk at the population level. We tested for associations between the CETP TaqIB genotype and plasma lipoprotein levels, response to gemfibrozil therapy, and CHD end points in 852 men participating in the Veterans Affairs HDL-C Intervention Trial (VA-HIT), a study designed to explore the potential benefits of raising HDL levels in men having established CHD with low HDL-C (< or =40 mg/dL) as their primary lipid abnormality. In VA-HIT, 13.9% of the men had the B2B2 genotype relative to 19.1% of the men in FOS (-27%, P<0.03), whereas more men in VA-HIT had the B1B1 genotype (15%, P<0.05). Similar to our finding in FOS, B2B2 men in VA-HIT had the highest mean level of HDL-C (32.6+/-4.8 mg/dL), followed by B1B2 men (32.0+/-5.3 mg/dL), and, last, by B1B1 men (30.9+/-4.9 mg/dL). Interestingly, B1B1 men, who had the least favorable plasma lipid profile at baseline, had the greatest triglyceride-lowering response to gemfibrozil (-34%, P=0.006). CETP TaqIB genotype was also associated with the risk of CHD end points in VA-HIT, with an adjusted risk ratio of 0.52 for B2B2 men (P=0.08). Our data demonstrate that in men with CHD and HDL deficiency, the CETP TaqI B2B2 genotype is (1) significantly reduced and (2) associated with higher levels of plasma HDL-C and lower CHD risk. Together with our earlier report, these results support the concept that increased HDL-C levels, resulting from reduced CETP activity, are associated with decreased CHD risk.
Ma, Weilie; Lin, Margarita; Ding, Hang; Lin, Guorong; Zhang, Zhizhen
Objective HDL and its apolipoproteins protect against atherosclerotic disease partly by removing excess cholesterol from macrophage foam cells. But the underlying mechanisms of cholesterol clearance are still not well defined. We investigated roles of vesicle trafficking of coatomer β-COP in delivering cholesterol to the cell surface during apoA-1 and apoE-mediated lipid efflux from fibroblasts and THP-1 macrophages. Methods shRNA knockout, confocal and electron microscopy and biochemical analysis were used to investigate the roles of β-COP in apolipoprotein-mediated cholesterol efflux in fibroblasts and THP-1 macrophages. Results We showed that β-COP knockdown by lentiviral shRNA resulted in reduced apoA-1-mediated cholesterol efflux, while increased cholesterol accumulation and formation of larger vesicles were observed in THP-1 macrophages by laser scanning confocal microscopy. Immunogold electron microscopy showed that β-COP appeared on the membrane protrusion complexes and colocalized with apoA-1 or apoE during cholesterol efflux. This was associated with releasing heterogeneous sizes of small particles into the culture media of THP-1 macrophage. Western blotting also showed that apoA-1 promotes β-COP translocation to the cell membrane and secretion into culture media, in which a total of 17 proteins were identified by proteomics. Moreover, β-COP exclusively associated with human plasma HDL fractions. Conclusion ApoA-1 and apoE promoted transport vesicles consisting of β-COP and other candidate proteins to exocytose cholesterol, forming the protrusion complexes on cell surface, which were then released from the cell membrane as small particles to media. PMID:26986486
Weiss, Ram; Nassar, Hisham; Sinnreich, Ronit; Kark, Jeremy D.
Aims To evaluate differences in the triglyceride to HDL-cholesterol ratio (TG/HDL), thought to be a proxy measure of insulin resistance, between Palestinian and Israeli adults in view of the greater incidence of coronary heart disease and high prevalence of diabetes in Palestinian Arabs. Research Methods A population-based observational prevalence study of cardiovascular and diabetes risk factors in Jerusalem. Participants (968 Palestinians, 707 Israelis, sampled at ages 25-74 years) underwent fasting and 2h post-75g oral challenge plasma glucose determinations. Metabolic risk was assessed using the surrogate index TG/HDL. Sex-specific comparisons were stratified by categories of body mass index and sex-specific waist circumference quartiles, adjusted by regression for age, glucose tolerance status and use of statins. Results Prevalence of overweight and obesity was substantially larger in Palestinians (p = 0.005). Prevalence of diabetes was 2.4 and 4 fold higher among Palestinian men and women, respectively (p<0.001). Adjusted TG/HDL was higher in Palestinians than Israelis across BMI and waist circumference categories (p<0.001 for both). Higher TG/HDL in Palestinians persisted in analyses restricted to participants with normal glucose tolerance and off statins. Notably, higher TG/HDL among Palestinians prevailed at a young age (25-44 years) and in normal weight individuals of both sexes. Conclusions Palestinians have a higher TG/HDL ratio than Israelis. Notably, this is evident also in young, healthy and normal weight participants. These findings indicate the need to study the determinants of this biomarker and other measures of insulin resistance in urban Arab populations and to focus research attention on earlier ages: childhood and prenatal stages of development. PMID:25635396
Li, Tricia Y; Zhang, Cuilin; Asselbergs, Folkert W; Qi, Lu; Rimm, Eric; Hunter, David J; Hu, Frank B
A low plasma HDL-cholesterol concentration is a major characteristic of diabetic dyslipidemia. HDL concentrations are determined by both environmental factors and genetic factors. Cholesterol ester transfer protein (CETP) plays an important role in the regulation of HDL metabolism, and the TaqIB polymorphism of the CETP gene has been associated with elevated HDL concentrations. We examined the association between the CETP TaqIB polymorphism and plasma HDL concentrations and evaluated whether this association was modified by dietary fat intake. We followed 780 diabetic men aged 40-75 y who participated in the Health Professionals Follow-Up Study since its initiation in 1986. The participants had confirmed type 2 diabetes and were free of cardiovascular disease at the time blood was drawn. After adjustment for age, smoking, alcohol consumption, fasting status, hemoglobin A(1c), physical activity, total energy intake, and body mass index, HDL concentrations were significantly higher in men with the B2B2 or B1B2 genotype than in those with the B1B1 genotype (adjusted x +/- SE: 37.9 +/- 0.02, 40.3 +/- 0.01, and 42.6 +/- 0.02 mg/dL for B1B1, B1B2, and B2B2, respectively; P for trend = 0.0004). This inverse association of the B1 allele with plasma HDL concentrations existed for those with a high consumption of animal fat (P for interaction = 0.02), saturated fat (P for interaction = 0.02), and monounsaturated fat (P for interaction = 0.04). These data confirmed a significant effect of the CETP Taq1 gene on HDL concentrations and suggested a potential interaction between the CETP TaqIB polymorphism and intake of dietary fat on plasma HDL concentration.
Tsaoussis, V; Vakirtzi-Lemonias, C
The PAF acetylhydrolase (PAF-AH) of mouse plasma was characterised as to its lipoprotein subclass and apolipoprotein association. Association with plasma lipoproteins was established by cholesteryl-hemisuccinate agarose affinity chromatography while electrophoretic and electrofocusing studies demonstrated almost exclusive association with the HDL-VHDL. Fractionation of [4-14C]cholesterol-labelled plasma on a Bio-Gel A-5m column established that 1% of the enzymic activity was associated with the VLDL-LDL, 4.5% with the HDL1, 80% with the HDL2-HDL3 and 15% with the VHDL. Electrophoresis of the solubilised, HDL2-HDL3 bound enzyme gave two peaks of activity with mobilities of 0.29 and 0.49 and a distribution of the recovered activity of 78 and 22%, respectively. The VHDL associated activity on similar analysis gave a 25 and 75% distribution. These findings showed that two enzymes, both associated with the HDL and VHDL fractions, constitute the PAF-AH activity of mouse plasma. Further fractionation of the HDL2-HDL3 bound activity on heparin-agarose established that 70% of the recovered activity was bound to the apo-E containing HDL.
Eliasson, B; Gudbjörnsdottir, S; Zethelius, B; Eeg-Olofsson, K; Cederholm, J
We assessed the association between different blood lipid measures and risk of fatal/nonfatal coronary heart disease (CHD), which has been less analysed previously in type 2 diabetes. Observational study of 46,786 patients with type 2 diabetes, aged 30-70 years, from the Swedish National Diabetes Register, followed for a mean of 5.8 years until 2009. Baseline and updated mean low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-, non-HDL-cholesterol, and non-HDL-to-HDL-cholesterol ratio were measured. Hazard ratios (HR) for CHD with quartiles 2-4 of baseline lipid measures, with lowest quartile 1 as reference: 1.03-1.29-1.63 for LDL; 1.23-1.41-1.95 for non-HDL; 1.29-1.39-1.57 for HDL; and 1.31-1.67-2.01 for non-HDL:HDL, all p < 0.001 except for quartile 2 of LDL, when adjusted for clinical characteristics and nonlipid risk factors. A similar picture was seen with updated mean values. Splines with absolute 6-year CHD rates in a Cox model showed decreasing rates only down to around 3 mmol/l for LDL, with linearly decreasing rates to the lowest level of non-HDL:HDL. Non-HDL and HDL were independent additive risk factors for CHD risk. HRs per 1 SD continuous decrease in baseline or updated mean HDL were 1.14-1.17 when fully adjusted as above, and 1.08-1.13 when also adjusted for non-HDL (p < 0.001). HRs were 1.13-1.16 adjusted for LDL, and 1.22-1.26 adjusted for total cholesterol and triglycerides (p < 0.001). Splines showed progressively increasing 6-year CHD rates with lower HDL down to 0.5 mmol/l. This study suggests that lower levels of non-HDL:HDL are a better risk marker for CHD than LDL-cholesterol below 3 mmol/l. © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
Luthi, Andrea J.; Zhang, Heng; Kim, Dongwoo; Giljohann, David A.; Mirkin, Chad A.; Thaxton, C. Shad
Gold nanoparticles (Au NPs) were employed as templates to synthesize spherical, high-density lipoprotein (HDL) biomimics (HDL Au NPs) of different sizes and surface chemistries. The effect of size and surface chemistry on the cholesterol binding properties and the ability of the HDL Au NPs to efflux cholesterol from macrophage cells were measured. Results demonstrate that Au NPs may be utilized as templates to generate nanostructures with different physical characteristics that mimic natural HDL. Furthermore, the properties of the HDL Au NPs may be tailored to modulate the ability to bind cholesterol in solution and efflux cholesterol from macrophages. From the conjugates tested, the optimum size and surface chemistry for preparing functional Au NP-templated HDL biomimics were identified. PMID:22117189
Mietus-Snyder, Michele L.; Shigenaga, Mark K.; Suh, Jung H.; Shenvi, Swapna V.; Lal, Ashutosh; McHugh, Tara; Olson, Don; Lilienstein, Joshua; Krauss, Ronald M.; Gildengoren, Ginny; McCann, Joyce C.; Ames, Bruce N.
Dietary intake modulates disease risk, but little is known how components within food mixtures affect pathophysiology. A low-calorie, high-fiber, fruit-based nutrient-dense bar of defined composition (e.g., vitamins and minerals, fruit polyphenolics, β-glucan, docosahexaenoic acid) appropriate for deconstruction and mechanistic studies is described and evaluated in a pilot trial. The bar was developed in collaboration with the U.S. Department of Agriculture. Changes in cardiovascular disease and diabetes risk biomarkers were measured after 2 wk twice-daily consumption of the bar, and compared against baseline controls in 25 healthy adults. Plasma HDL-cholesterol (HDL-c) increased 6.2% (P=0.001), due primarily to a 28% increase in large HDL (HDL-L; P<0.0001). Total plasma homocysteine (Hcy) decreased 19% (P=0.017), and glutathione (GSH) increased 20% (P=0.011). The changes in HDL and Hcy are in the direction associated with decreased risk of cardiovascular disease and cognitive decline; increased GSH reflects improved antioxidant defense. Changes in biomarkers linked to insulin resistance and inflammation were not observed. A defined food-based supplement can, within 2 wk, positively impact metabolic biomarkers linked to disease risk. These results lay the groundwork for mechanistic/deconstruction experiments to identify critical bar components and putative synergistic combinations responsible for observed effects.—Mietus-Snyder, M. L., Shigenaga, M. K., Suh, J. H., Shenvi, S. V., Lal, A., McHugh, T., Olson, D., Lilienstein, J., Krauss, R. M., Gildengoren, G., McCann, J. C., Ames, B. N. A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial. PMID:22549511
Mazer, Norman A.; Giulianini, Franco; Paynter, Nina P.; Jordan, Paul; Mora, Samia
Background HDL size and composition vary among individuals and may be associated with cardiovascular disease and diabetes. We investigated the theoretical relationship between HDL size and composition using an updated version of the spherical model of lipoprotein structure proposed by Shen et al. and compared its predictions with experimental data from the Women’s Health Study (WHS). Methods The Shen model was updated to predict the relationship between HDL diameter and the ratio of HDL-cholesterol (HDL-C) to apolipoprotein A-I (ApoA-I) plasma concentrations, i.e., the HDL-C/ApoA-I ratio. In WHS (n=26,772), NMR spectroscopy was used to measure the average HDL diameter (davg,NMR) and particle concentration (HDL-P); HDL-C and ApoA-I (mg/dL) were measured by standardized assays. Results The updated Shen model predicts a quasi-linear increase of HDL diameter with the HDL-C/ApoA-I ratio, consistent with the measured davg,NMR values from WHS, which ranged between 8.0 and 10.8 nm and correlated positively with the HDL-C/ApoA-I ratio (r=0.608, p<2.2×10−16). The WHS data were further described by a linear regression equation: dWHS (nm) = 4.66 + 12.31 HDL-C/ApoA-I. The validity of this equation for estimating HDL size was assessed with data from CETP deficiency and pharmacologic inhibition. We also illustrate how HDL-P can be estimated from the HDL size and ApoA-I level. Conclusions This study provides a large-scale experimental examination of the updated Shen model, offers new insights into HDL structure, composition and remodeling, and suggests that the HDL-C/ApoA-I ratio could be a readily available biomarker for estimating HDL size and HDL-P. PMID:23426429
Wang, Jing; Bie, Jinghua; Ghosh, Shobha
While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 (FABP1)] not only facilitate CE hydrolase-mediated hydrolysis of HDL-CEs, but also enhance elimination of cholesterol into bile. Adenovirus-mediated overexpression of FABP1 or SCP2 in primary hepatocytes significantly increased hydrolysis of HDL-[3H]CE, reduced resecretion of HDL-CE-derived FC as nascent HDL, and increased its secretion as bile acids. Consistently, the flux of [3H]cholesterol from HDL-[3H]CE to biliary bile acids was increased by overexpression of SCP2 or FABP1 in vivo and reduced in SCP2−/− mice. Increased flux of HDL-[3H]CE to biliary FC was noted with FABP1 overexpression and in SCP2−/− mice that have increased FABP1 expression. Lack of a significant decrease in the flux of HDL-[3H]CE to biliary FC or bile acids in FABP1−/− mice indicates the likely compensation of its function by an as yet unidentified mechanism. Taken together, these studies demonstrate that FABP1 and SCP2 facilitate the preferential movement of HDL-CEs to bile for final elimination. PMID:27381048
Jia, Lianqun; Bai, Huai; Fu, Mingde; Xu, Yanhua; Yang, Yuye; Long, Shiyin
It is generally accepted that apolipoprotein (apo) A-I is the dominant structural apolipoprotein of HDL particles and different HDL subclasses have distinct but interrelated metabolic functions. HDL is known to directly affect the atherogenic process hence changes in HDL subclasses distribution may be related to the incidence and prevalence of atherosclerosis. The ApoA-I contents (mg/l) of plasma HDL subclasses were determined by 2-dimensional gel electrophoresis coupled with immunodetection and apoA-I genotypes were assayed by PCR-RFLP in 307 Chinese subjects (169 males, 138 females). The G/G and C/C genotypes were the most frequent at -78 bp and +83 bp of apoA-I gene, respectively. There were no significant differences in the frequencies of rare A allele at -78 bp and rare T allele at +83 bp between males and females. Compared with the G/G carriers, G/A and A/A carriers had significantly higher plasma concentrations of TG, apoC-II, apoC-III, apoA-I contents of prebeta(1)-HDL, HDL(3a) and TG/HDL-C ratio. And in addition, A/A carriers had significantly lower apoA-I contents of HDL(2a) and HDL(2b). Females had increased plasma concentrations of apoA-I, HDL-C, apoA-I contents of HDL(2a) and HDL(2b) while decreased apoA-I contents of prebeta(1)-HDL, HDL(3b) and TG/HDL-C ratio as compared to males carrying the same genotype. No significant differences were demonstrated on the concentrations of plasma lipids, lipoproteins, apolipoproteins and apoA-I contents of plasma HDL subclasses between the C/C and C/T subjects. The G/A polymorphism at -78 bp of apoA-I gene was associated with changes of HDL subclasses distribution. There was a general shift towards smaller-sized HDL, which, in turn, indicated that reverse cholesterol transport (RCT) might be weakened and HDL maturation might be abnormal in the subjects with G/A mutation.
Kannisto, Kristina; Gåfvels, Mats; Jiang, Zhao-Yan; Slätis, Katharina; Hu, Xiaoli; Jorns, Carl; Steffensen, Knut R; Eggertsen, Gösta
We investigated whether: (1) liver X receptor (LXR)-driven induction of high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on cholesterol metabolism depend on intestinal cholesterol absorption; and (2) combined treatment with the LXR agonist GW3965 and the cholesterol absorption inhibitor ezetimibe results in synergistic effects on cholesterol metabolism that could be beneficial for treatment of atherosclerosis. Mice were fed 0.2 % cholesterol and treated with GW3965+ezetimibe, GW3965 or ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and Apolipoprotein (Apo) AI, effectively reduced the intestinal cholesterol absorption and increased the excretion of faecal neutral sterols. No changes in intestinal ATP-binding cassette (ABC) A1 or ABCG5 protein expression were observed, despite increased mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal cholesterol levels. GW3965 did not affect the intestinal cholesterol absorption, but increased serum HDL-C and ApoAI levels. GW3965 also increased Apoa1 mRNA levels in primary mouse hepatocytes and HEPA1-6 cells. Ezetimibe reduced the intestinal cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of cholesterol via NPC1L1 and/or low levels of intracellular cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased mRNA levels. Combined LXR activation and blocked intestinal cholesterol absorption induced effective faecal elimination of cholesterol.
Vaisar, Tomáš; Tang, Chongren; Babenko, Ilona; Hutchins, Patrick; Wimberger, Jake; Suffredini, Anthony F.; Heinecke, Jay W.
Recent studies demonstrate that HDL’s ability to promote cholesterol efflux from macrophages associates strongly with cardioprotection in humans independently of HDL-cholesterol (HDL-C) and apoA-I, HDL’s major protein. However, the mechanisms that impair cholesterol efflux capacity during vascular disease are unclear. Inflammation, a well-established risk factor for cardiovascular disease, has been shown to impair HDL’s cholesterol efflux capacity. We therefore tested the hypothesis that HDL’s impaired efflux capacity is mediated by specific changes of its protein cargo. Humans with acute inflammation induced by low-level endotoxin had unchanged HDL-C levels, but their HDL-C efflux capacity was significantly impaired. Proteomic analyses demonstrated that HDL’s cholesterol efflux capacity correlated inversely with HDL content of serum amyloid A (SAA)1 and SAA2. In mice, acute inflammation caused a marked impairment of HDL-C efflux capacity that correlated with a large increase in HDL SAA. In striking contrast, the efflux capacity of mouse inflammatory HDL was preserved with genetic ablation of SAA1 and SAA2. Our observations indicate that the inflammatory impairment of HDL-C efflux capacity is due in part to SAA-mediated remodeling of HDL’s protein cargo. PMID:25995210
Borja, Mark S; Ng, Kit F; Irwin, Angela; Hong, Jaekyoung; Wu, Xing; Isquith, Daniel; Zhao, Xue-Qiao; Prazen, Bryan; Gildengorin, Virginia; Oda, Michael N; Vaisar, Tomáš
HDL is the primary mediator of cholesterol mobilization from the periphery to the liver via reverse cholesterol transport (RCT). A critical first step in this process is the uptake of cholesterol from lipid-loaded macrophages by HDL, a function of HDL inversely associated with prevalent and incident cardiovascular disease. We hypothesized that the dynamic ability of HDL to undergo remodeling and exchange of apoA-I is an important and potentially rate-limiting aspect of RCT. In this study, we investigated the relationship between HDL-apoA-I exchange (HAE) and serum HDL cholesterol (HDL-C) efflux capacity. We compared HAE to the total and ABCA1-specific cholesterol efflux capacity of 77 subjects. We found that HAE was highly correlated with both total (r = 0.69, P < 0.0001) and ABCA1-specific (r = 0.47, P < 0.0001) efflux, and this relationship remained significant after adjustment for HDL-C or apoA-I. Multivariate models of sterol efflux capacity indicated that HAE accounted for approximately 25% of the model variance for both total and ABCA1-specific efflux. We conclude that the ability of HDL to exchange apoA-I and remodel, as measured by HAE, is a significant contributor to serum HDL efflux capacity, independent of HDL-C and apoA-I, indicating that HDL dynamics are an important factor in cholesterol efflux capacity and likely RCT. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.
De Pergola, Giovanni; Triggiani, Vincenzo; Bartolomeo, Nicola; Nardecchia, Adele; Giagulli, Vito Angelo; Bruno, Irene; Caccavo, Domenico; Silvestris, Franco
Osteocalcin, a protein synthesized by osteoblasts during the bone formation phase of bone remodeling, is used as a biomarker for the bone production process, and its serum levels are positively correlated with bone mineral density during treatment with anabolic bone drugs for osteoporosis. Higher fat mass has been shown to be a risk factor for osteoporosis and fragility fractures and body fat and bone interplay through several adipokines and bone-derived molecules, regulating bone remodeling, adipogenesis, body weight control, and glucose homeostasis. The aim of this study was to evaluate the relationship between total osteocalcin levels and obesity, hypertension and type 2 diabetes. The present study was performed in a cohort of 298 patients including a) 121 overweight and obese patients, unaffected by hypertension or type 2 diabetes, b) 129 subjects affected by hypertension and not by type 2 diabetes, and c) 48 subjects affected by both hypertension and type 2 diabetes. No subject of the group of overweight and obese patients was taking any kind of drug. All patients affected by hypertension, with or without type 2 diabetes, were taking drugs for hypertension. Examining only patients affected by type 2 diabetes (n: 48), 43 (90% of all) were taking drugs to reduce blood glucose levels, 26 (54% of all) were taking drugs to reduce cholesterol levels (statins and/or ezetimide, etc), and 4 (8% of all) were taking ω-3 for hypertriglyceridemia. Each patient was evaluated for anthropometric measurements as well as for serum osteocalcin and uric acid, and plasma glucose, HbA1c, and lipid determination. Osteocalcin levels were significantly and negatively associated with BMI, waist circumference, and HbA1c, and significantly and positively correlated with HDL-cholesterol and systolic blood pressure in the whole population. Osteocalcin levels did maintain an independent negative association with BMI, and HbA1c, and positive association with HDL cholesterol and systolic
Ahn, Nayoung; Kim, Kijin
Decreases in high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of coronary artery disease (CAD), whereas increased HDL-C levels are related to a decreased risk of CAD and myocardial infarction. Although HDL prevents the oxidation of low-density lipoprotein under normal conditions, it triggers a structural change, inhibiting antiarteriosclerotic and anti-inflammatory functions, under pathological conditions such as oxidative stress, inflammation, and diabetes. HDL can transform into various structures based on the quantitative reduction and deformation of apolipoprotein A1 and is the primary cause of increased levels of dysfunctional HDL, which can lead to an increased risk of CAD. Therefore, analyzing the structure and components of HDL rather than HDL-C after the application of an exercise training program may be useful for understanding the effects of HDL.
Fadini, Gian Paolo; Iori, Elisabetta; Marescotti, Maria Cristina; Vigili de Kreutzenberg, Saula; Avogaro, Angelo
Type 2 diabetes (T2D) is characterized by low HDL cholesterol (HDL-C) and HDL dysfunction. We herein tested whether lowering HbA1c affects HDL-C and reverse cholesterol transport (RCT). Forty-two uncontrolled T2D patients initiating basal insulin were included. HbA1c, HDL-C and RCT were assessed at baseline and after 6 months. At baseline, HDL-C and RCT were directly correlated (r = 0.50; p < 0.001). After 6 months of insulin therapy, HbA1c dropped from 8.8 ± 0.16% to 7.1 ± 0.1%, while average HDL-C and RCT did not change. Follow-up HDL-C and RCT were still correlated (r = 0.31; p = 0.033) and ΔHDL-C correlated with ΔRCT (r = 0.32; p = 0.029). ΔHbA1c correlated with ΔHDL-C (r = 0.43, p = 0.001), but not with ΔRCT. In patients with ΔHbA1c above the median value (1.3%), HDL-C (but not RCT) increased significantly. In conclusion, glucose control correlates with increased HDL-C, but not with improved RCT. Thus, persistent HDL dysfunction despite improved HbA1c and HDL-C can contribute to residual cardiovascular risk in T2D. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Brouwer, Ingeborg A.; Wanders, Anne J.; Katan, Martijn B.
Background Trans fatty acids are produced either by industrial hydrogenation or by biohydrogenation in the rumens of cows and sheep. Industrial trans fatty acids lower HDL cholesterol, raise LDL cholesterol, and increase the risk of coronary heart disease. The effects of conjugated linoleic acid and trans fatty acids from ruminant animals are less clear. We reviewed the literature, estimated the effects trans fatty acids from ruminant sources and of conjugated trans linoleic acid (CLA) on blood lipoproteins, and compared these with industrial trans fatty acids. Methodology/Principal Findings We searched Medline and scanned reference lists for intervention trials that reported effects of industrial trans fatty acids, ruminant trans fatty acids or conjugated linoleic acid on LDL and HDL cholesterol in humans. The 39 studies that met our criteria provided results of 29 treatments with industrial trans fatty acids, 6 with ruminant trans fatty acids and 17 with CLA. Control treatments differed between studies; to enable comparison between studies we recalculated for each study what the effect of trans fatty acids on lipoprotein would be if they isocalorically replaced cis mono unsaturated fatty acids. In linear regression analysis the plasma LDL to HDL cholesterol ratio increased by 0.055 (95%CI 0.044–0.066) for each % of dietary energy from industrial trans fatty acids replacing cis monounsaturated fatty acids The increase in the LDL to HDL ratio for each % of energy was 0.038 (95%CI 0.012–0.065) for ruminant trans fatty acids, and 0.043 (95% CI 0.012–0.074) for conjugated linoleic acid (p = 0.99 for difference between CLA and industrial trans fatty acids; p = 0.37 for ruminant versus industrial trans fatty acids). Conclusions/Significance Published data suggest that all fatty acids with a double bond in the trans configuration raise the ratio of plasma LDL to HDL cholesterol. PMID:20209147
Contreras, Freddy; Lares, Mary; Castro, Jorge; Velasco, Manuel; Rojas, Joselyn; Guerra, Xavier; Chacín, Maricarmen; Dowling, Victoria; Bermúdez, Valmore
Recently, it has been suggested that non-high-density lipoprotein (non-HDL) cholesterol measure is a useful evaluation tool to assess heart disease death risk. The non-HDL cholesterol is defined as the value between total cholesterol and HDL - total cholesterol, and it involves the different fractions of lipoproteins: low-density lipoprotein, intermediate-density lipoprotein, and very low density lipoprotein, including highly atherogenic lipoproteins as very low density lipoprotein remnants. The purpose of this study was to compare the values of non-HDL cholesterol as a cardiovascular risk marker in a control population, and one diabetic and hypertensive. It was demonstrated that the mean values of non-HDL cholesterol in the diseased groups were higher than the values from the control group, whereas the low-density lipoprotein showed no marked difference in high-risk patients. Non-HDL cholesterol has shown to be a quick and simple way to estimate the risk of developing cardiovascular disease.
Mora, Samia; Glynn, Robert J.; Ridker, Paul M
Background Chemically-measured high-density lipoprotein cholesterol (HDL-C) may not be the best clinical measure of HDL. Little is known about alternative HDL meassures such as HDL size or particle number (HDL-P) as determinants of residual risk after potent statin therapy. Methods and Results In JUPITER, HDL size and HDL-P were measured by nuclear magnetic resonance spectroscopy, and HDL-C and apolipoprotein A-I (apoA-I) were chemically assayed in 10,886 participants without cardiovascular disease (CVD) before and after random allocation to rosuvastatin 20 mg/day or placebo. Levels were examined with first CVD (N=234). HDL-P correlated better with apoA-I (Spearman r=0.69, p<0.0001) than with HDL-C (r=0.55, p<0.0001). Rosuvastatin lowered LDL cholesterol (49%) and raised HDL-C (6.1%), apoA-I (2.1%), HDL-P (3.8%) and HDL size (1.2%); all p<0.0001. Among placebo-allocated individuals, on-treatment HDL-C, apoA-I, and HDL-P had similar inverse associations with CVD (risk factor-adjusted hazard ratio and 95% CI per 1-SD: 0.79 [0.63–0.98], 0.75 [0.62–0.92], and 0.81 [0.67–0.97], respectively). Among rosuvastatin-allocated individuals, on-treatment HDL-P had a statistically significant and somewhat stronger association with CVD (0.73, 0.57–0.93, p=0.01) than HDL-C (0.82, 0.63–1.08, p=0.16) or apoA-I (0.86, 0.67–1.10, p=0.22). Among rosuvastatin-allocated individuals, on-treatment HDL-P remained significant (0.72, 0.53–0.97, p=0.03) after additionally adjusting for HDL-C. In risk factor-adjusted models, HDL size showed no significant association with CVD. Conclusions In the setting of potent statin therapy, HDL particle number may be a better marker of residual risk than chemically-measured HDL-C or apoA-I. This has potential implications for evaluating novel therapies targeting HDL. Clinical Trial Registration ClinicalTrials.gov; NCT00239681 PMID:24002795
Quintanilla-Cantú, Armando; Peña-de-la-Sancha, Paola; Flores-Castillo, Cristobal; Mejía-Domínguez, Ana María; Posadas-Sánchez, Rosalinda; Pérez-Hernández, Nonanzit; Bautista-Pérez, Rocío; Enriquez-Calderón, Reyna Esmeralda; Juárez-Oropeza, Marco Antonio; Fragoso, José Manuel; Vargas-Alarcón, Gilberto; Pérez-Méndez, Oscar
Postprandial triglyceridemia may transitory affect the structure of HDL subclasses and probably their antiatherogenic properties but little is known in this field. We analyzed the HDL subclasses lipid content along postprandial period. Fifteen metabolic syndrome (MS) patients and 15 healthy controls were enrolled. HDL were isolated from plasma samples obtained at fasting and every 2-h up to 8-h, after a 75-g fat meal. Cholesterol (C), triglycerides (TAG), and phospholipid (Ph) plasma concentrations of five HDL subclasses were determined by densitometry of electrophoresis gels enzymatically stained. The increase of postprandial triglyceridemia expressed as the incremental area under the curve (iAUC) was twice in MS patients than in controls. Only large HDL2b-TAG were higher in MS than controls at 4, 6 and 8h after meal intake, whereas cholesterol of HDL2a, 3a and 3b were lower at 8h. HDL size distribution shifted towards large HDL and HDL3a-, 3b- and 3c-subclasses had a lower content of cholesterol (estimated by the C-to-Ph ratio) in subjects whose iAUC>289.5mgh/dl (n=15) in comparison with those subjects with iAUC below this cutoff point (n=15), independently of the MS status and fasting TAG. Triglycerides content of HDL subclasses changed only discreetly along the postprandial period, whereas paraoxonase-1 remained unchanged. A high postprandial triglyceridemia conditions the shift of HDL size distribution towards large particles and the decrease of cholesterol in HDL3 subclasses. These data demonstrate that postprandial hypertriglyceridemia contributes to a transitory hypoalphalipoproteinemia that may increase the risk of cardiovascular disease. Copyright © 2016 Elsevier B.V. All rights reserved.
Leduc, Magalie S; Lyons, Malcolm; Darvishi, Katayoon; Walsh, Kenneth; Sheehan, Susan; Amend, Sarah; Cox, Allison; Orho-Melander, Marju; Kathiresan, Sekar; Paigen, Beverly; Korstanje, Ron
Genome-wide association (GWA) studies represent a powerful strategy for identifying susceptibility genes for complex diseases in human populations but results must be confirmed and replicated. Because of the close homology between mouse and human genomes, the mouse can be used to add evidence to genes suggested by human studies. We used the mouse quantitative trait loci (QTL) map to interpret results from a GWA study for genes associated with plasma HDL cholesterol levels. We first positioned single nucleotide polymorphisms (SNPs) from a human GWA study on the genomic map for mouse HDL QTL. We then used mouse bioinformatics, sequencing, and expression studies to add evidence for one well-known HDL gene (Abca1) and three newly identified genes (Galnt2, Wwox, and Cdh13), thus supporting the results of the human study. For GWA peaks that occur in human haplotype blocks with multiple genes, we examined the homologous regions in the mouse to prioritize the genes using expression, sequencing, and bioinformatics from the mouse model, showing that some genes were unlikely candidates and adding evidence for candidate genes Mvk and Mmab in one haplotype block and Fads1 and Fads2 in the second haplotype block. Our study highlights the value of mouse genetics for evaluating genes found in human GWA studies.
Hutchins, Patrick M.; Matthews, Karen A.; Brooks, Maria M.; Orchard, Trevor J.; Ronsein, Graziella E.; Heinecke, Jay W.
Context: Growing evidence challenges the concept that high-density lipoprotein-cholesterol (HDL-C) is cardioprotective after menopause. HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) might be better predictors of cardiovascular risk. Objective: Quantify alterations in HDL-P and CEC during menopause, correlating those changes with alterations in estradiol (E2) and FSH. Design: Longitudinal study of HDL metrics before and after menopause as indexed by the final menstrual period (FMP). Participants: Forty-six women, mean baseline age 47.1 years, 33% black, 67% white. Main Outcomes and Measures: HDL-P concentration (HDL-PIMA) by calibrated ion mobility analysis (IMA); macrophage CEC with cAMP-stimulated macrophages; ATP-binding cassette transporter A1 (ABCA1)-specific CEC with BHK cells expressing human ABCA1. Results: After a median of 2.1 years since FMP, both HDL-C (P = .03) and HDL-PIMA (P = .01) increased, with a selective increase in large HDL-PIMA (P = .01), whereas sizes of medium and small HDL-PIMA were decreased (P < .05). These changes were independent of race, body mass index, and time difference. Macrophage CEC and ABCA1-specific CEC increased after FMP (both P < .001). Greater declines in E2 correlated with larger increases in small HDL-PIMA (P = .01), whereas greater increases in FSH associated with greater reductions in the size of medium HDL-PIMA (P = .04). Macrophage CEC and ABCA1-specific CEC correlated positively with E2 levels only before menopause (P = .04 and .009, respectively). Conclusions: Large HDL-PIMA and CEC increased significantly in the early phase of the menopausal transition. Whether patterns of these alterations differ in late postmenopause is unknown. Further exploration is needed to assess that and to determine whether the reported changes in HDL metrics associate with increased cardiovascular risk after menopause. PMID:27399353
Rana, Jamal S; Boekholdt, S Matthijs; Kastelein, John J P; Shah, Prediman K
Despite aggressive lipid-lowering therapy, patients continue to be at significant risk of coronary heart disease (CHD). Assessment of non-high-density lipoprotein cholesterol (non-HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the third Adult Treatment Panel (ATP III) guidelines of the US National Cholesterol Education Program, non-HDL-C was introduced as a secondary target of therapy in persons with triglycerides ≥200 mg/dL. A recent meta-analysis of the relationship between non-HDL-C reduction and CHD risk showed non-HDL-C as an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have a 1:1 relationship between percent non-HDL-C lowering and percent CHD reduction. In the EPIC-Norfolk prospective population study, 21,448 participants without diabetes or CHD between 45 and 79 years of age were followed for 11.0 years. Participants with high non-HDL-C levels were at increased CHD risk independently of their LDL-C levels. Also, compared to apolipoprotein B, non-HDL-C appears to be a better choice given the fact that no additional tests or costs are needed and established cut points are already available. Future guidelines should emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies with an increased need to have non-HDL-C reported on routine lipid panels.
Dullaart, Robin P F; Otvos, James D; James, Richard W
We determined relationships of the anti-oxidative enzyme, paraoxonase-1 (PON-1), with high density lipoprotein (HDL) subfractions, and tested whether these relationships are stronger than those with HDL cholesterol and apolipoprotein A-I (apoA-I) in subjects with and without type 2 diabetes mellitus (T2DM). Serum PON-1 (arylesterase activity) and HDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 67 T2DM patients and in 56 non-diabetic subjects. PON-1 activity, HDL cholesterol and apoA-I were decreased in T2DM (all p<0.05). The HDL particle concentration was unaltered, but large HDL particles, medium HDL particles and HDL particle size were decreased, whereas small HDL particles were increased in T2DM (all p<0.05). PON-1 was more closely related to HDL cholesterol than to apoA-I (p=0.001). In turn, the positive relationship of PON-1 with the HDL particle concentration and with large HDL particles was stronger than that with HDL cholesterol (both p<0.01). The inverse relationship of PON-1 with T2DM was only modestly attenuated by HDL cholesterol or HDL particle characteristics. PON-1 activity is more closely related to the HDL particle concentration or large HDL particles than to HDL cholesterol. Impaired PON-1 activity in T2DM is not to a considerable extent explained by altered HDL subfraction levels. Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Ali, K Mahdy; Wonnerth, A; Huber, K; Wojta, J
Since the first discovery of an inverse correlation between high-density lipoprotein-cholesterol (HDL-C) levels and coronary heart disease in the 1950s the life cycle of HDL, its role in atherosclerosis and the therapeutic modification of HDL-C levels have been major research topics. The Framingham study and others that followed could show that HDL-C is an independent cardiovascular risk factor and that the increase of HDL-C of only 10 mg·L−1 leads to a risk reduction of 2–3%. While statin therapy and therefore low-density lipoprotein-cholesterol (LDL-C) reduction could lower coronary heart disease considerably; cardiovascular morbidity and mortality still occur in a significant portion of subjects already receiving therapy. Therefore, new strategies and therapies are needed to further reduce the risk. Raising HDL-C was thought to achieve this goal. However, established drug therapies resulting in substantial HDL-C increase are scarce and their effect is controversial. Furthermore, it is becoming increasingly evident that HDL particle functionality is at least as important as HDL-C levels since HDL particles not only promote reverse cholesterol transport from the periphery (mainly macrophages) to the liver but also exert pleiotropic effects on inflammation, haemostasis and apoptosis. This review deals with the biology of HDL particles, the established and future therapeutic options to increase HDL-C and discusses the results and conclusions of the most important studies published in the last years. Finally, an outlook on future diagnostic tools and therapeutic opportunities regarding coronary artery disease is given. PMID:22725625
Iqbal, Fatima; Baker, Wendy S; Khan, Madiha I; Thukuntla, Shwetha; McKinney, Kevin H; Abate, Nicola; Tuvdendorj, Demidmaa
Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Inflammatory processes arising from metabolic abnormalities are known to precipitate the development of CVD. Several metabolic and inflammatory markers have been proposed for predicting the progression of CVD, including high density lipoprotein cholesterol (HDL-C). For ~50 years, HDL-C has been considered as the atheroprotective 'good' cholesterol because of its strong inverse association with the progression of CVD. Thus, interventions to increase the concentration of HDL-C have been successfully tested in animals; however, clinical trials were unable to confirm the cardiovascular benefits of pharmaceutical interventions aimed at increasing HDL-C levels. Based on these data, the significance of HDL-C in the prevention of CVD has been called into question. Fundamental in vitro and animal studies suggest that HDL-C functionality, rather than HDL-C concentration, is important for the CVD-preventive qualities of HDL-C. Our current review of the literature positively demonstrates the negative impact of systemic and tissue (i.e. adipose tissue) inflammation in the healthy metabolism and function of HDL-C. Our survey indicates that HDL-C may be a good marker of adipose tissue health, independently of its atheroprotective associations. We summarize the current findings on the use of anti-inflammatory drugs to either prevent HDL-C clearance or improve the function and production of HDL-C particles. It is evident that the therapeutic agents currently available may not provide the optimal strategy for altering HDL-C metabolism and function, and thus, further research is required to supplement this mechanistic approach for preventing the progression of CVD.
Zhou, Quan; Wu, Jiang; Tang, Jie; Wang, Jia-Ji; Lu, Chu-Hong; Wang, Pei-Xi
Research has shown that high-dose supplemental dietary fiber intake has beneficial effects on cardiovascular risk factors. To clarify such a relationship, we examined the association between daily dietary fiber intake and plasma lipids using a cross-sectional design including 1034 (M 502, F 532) rural-to-urban workers in China. We found a dose-response relationship between increased dietary fiber intakes and increase of HDL cholesterol in male workers. There was also a dose-response relationship between increased dietary fiber intake and decreased total cholesterol to HDL cholesterol (TC/HDL-C) ratio in both male and female workers, after adjusting for potential confounders (p for trend, all p < 0.05). When the average dietary fiber intake increased from less than 18 g/day to over 30 g/day, the average HDL cholesterol level increased by 10.1%, and the TC/HDL-C ratio decreased by 14.4% for males (p = 0.020) and by 11.1% for females (p = 0.048). In conclusion, higher daily dietary fiber consumption is associated with beneficial effect on cholesterol for rural-to-urban workers in China, suggesting its potential beneficial effect on decreasing the risk of cardiovascular diseases.
Zhou, Quan; Wu, Jiang; Tang, Jie; Wang, Jia-Ji; Lu, Chu-Hong; Wang, Pei-Xi
Research has shown that high-dose supplemental dietary fiber intake has beneficial effects on cardiovascular risk factors. To clarify such a relationship, we examined the association between daily dietary fiber intake and plasma lipids using a cross-sectional design including 1034 (M 502, F 532) rural-to-urban workers in China. We found a dose-response relationship between increased dietary fiber intakes and increase of HDL cholesterol in male workers. There was also a dose-response relationship between increased dietary fiber intake and decreased total cholesterol to HDL cholesterol (TC/HDL-C) ratio in both male and female workers, after adjusting for potential confounders (p for trend, all p < 0.05). When the average dietary fiber intake increased from less than 18 g/day to over 30 g/day, the average HDL cholesterol level increased by 10.1%, and the TC/HDL-C ratio decreased by 14.4% for males (p = 0.020) and by 11.1% for females (p = 0.048). In conclusion, higher daily dietary fiber consumption is associated with beneficial effect on cholesterol for rural-to-urban workers in China, suggesting its potential beneficial effect on decreasing the risk of cardiovascular diseases. PMID:25938914
Dang, Xiao-yong; Chu, Wei-wei; Shi, Heng-chuan; Yu, Shi-gang; Han, Hai-yin; Gu, Shu-Hua; Chen, Jie
Excess accumulation of cholesterol in plasma may result in coronary artery disease. Numerous studies have demonstrated that ATP-binding cassette protein A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to apolipoproteins, a process necessary for plasma high density lipoprotein (HDL) formation. Higher plasma levels of HDL are associated with lower risk for cardiovascular disease. Studies of human disease and animal models had shown that an increased hepatic ABCA1 activity relates to an enhanced plasma HDL level. In this study, we hypothesized that functional mutations in the ABCA1 promoter in pigs may affect gene transcription activity, and consequently the HDL level in plasma. The promoter region of ABCA1 was comparatively scanned by direct sequencing with pool DNA of high- and low-HDL groups (n=30 for each group). Two polymorphisms, c. - 608A>G and c. - 418T>A, were revealed with reverse allele distribution in the two groups. The two polymorphisms were completely linked and formed only G-A or A-T haplotypes when genotyped in a larger population (n=526). Furthermore, we found that the G-A/G-A genotype was associated with higher HDL and ABCA1 mRNA level than A-T/A-T genotype. Luciferase assay also revealed that G-A haplotype promoter had higher activity than A-T haplotype. Single-nucleotide mutant assay showed that c.-418T>A was the causal mutation for ABCA1 transcription activity alteration. Conclusively, we identified two completely linked SNPs in porcine ABCA1 promoter region which have influence on the plasma HDL level by altering ABCA1 gene transcriptional activity.
Postmus, Iris; Warren, Helen R; Trompet, Stella; Arsenault, Benoit J; Avery, Christy L; Bis, Joshua C; Chasman, Daniel I; de Keyser, Catherine E; Deshmukh, Harshal A; Evans, Daniel S; Feng, QiPing; Li, Xiaohui; Smit, Roelof A J; Smith, Albert V; Sun, Fangui; Taylor, Kent D; Arnold, Alice M; Barnes, Michael R; Barratt, Bryan J; Betteridge, John; Boekholdt, S Matthijs; Boerwinkle, Eric; Buckley, Brendan M; Chen, Y-D Ida; de Craen, Anton J M; Cummings, Steven R; Denny, Joshua C; Dubé, Marie Pierre; Durrington, Paul N; Eiriksdottir, Gudny; Ford, Ian; Guo, Xiuqing; Harris, Tamara B; Heckbert, Susan R; Hofman, Albert; Hovingh, G Kees; Kastelein, John J P; Launer, Leonore J; Liu, Ching-Ti; Liu, Yongmei; Lumley, Thomas; McKeigue, Paul M; Munroe, Patricia B; Neil, Andrew; Nickerson, Deborah A; Nyberg, Fredrik; O'Brien, Eoin; O'Donnell, Christopher J; Post, Wendy; Poulter, Neil; Vasan, Ramachandran S; Rice, Kenneth; Rich, Stephen S; Rivadeneira, Fernando; Sattar, Naveed; Sever, Peter; Shaw-Hawkins, Sue; Shields, Denis C; Slagboom, P Eline; Smith, Nicholas L; Smith, Joshua D; Sotoodehnia, Nona; Stanton, Alice; Stott, David J; Stricker, Bruno H; Stürmer, Til; Uitterlinden, André G; Wei, Wei-Qi; Westendorp, Rudi G J; Whitsel, Eric A; Wiggins, Kerri L; Wilke, Russell A; Ballantyne, Christie M; Colhoun, Helen M; Cupples, L Adrienne; Franco, Oscar H; Gudnason, Vilmundur; Hitman, Graham; Palmer, Colin N A; Psaty, Bruce M; Ridker, Paul M; Stafford, Jeanette M; Stein, Charles M; Tardif, Jean-Claude; Caulfield, Mark J; Jukema, J Wouter; Rotter, Jerome I; Krauss, Ronald M
In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Julia, Zélie; Duchene, Emilie; Fournier, Natalie; Bellanger, Natacha; Chapman, M John; Le Goff, Wilfried; Guerin, Maryse
Lipid and cholesterol metabolism in the postprandial phase is associated with both quantitative and qualitative remodeling of HDL particle subspecies that may influence their anti-atherogenic functions in the reverse cholesterol transport pathway. We evaluated the capacity of whole plasma or isolated HDL particles to mediate cellular free cholesterol (FC) efflux, cholesteryl ester transfer protein (CETP)-mediated cholesteryl ester (CE) transfer, and selective hepatic CE uptake during the postprandial phase in subjects displaying type IIB hyperlipidemia (n = 16). Postprandial, large HDL2 displayed an enhanced capacity to mediate FC efflux via both scavenger receptor class B type I (SR-BI)-dependent (+12%; P < 0.02) and ATP binding cassette transporter G1 (ABCG1)-dependent (+31%; P < 0.008) pathways in in vitro cell systems. In addition, the capacity of whole postprandial plasma (4 h and 8 h postprandially) to mediate cellular FC efflux via the ABCA1-dependent pathway was significantly increased (+19%; P < 0.0003). Concomitantly, postprandial lipemia was associated with elevated endogenous CE transfer rates from HDL2 to apoB lipoproteins and with attenuated capacity (-17%; P < 0.02) of total HDL to deliver CE to hepatic cells. Postprandial lipemia enhanced SR-BI and ABCG1-dependent efflux to large HDL2 particles. However, postprandial lipemia is equally associated with deleterious features by enhancing formation of CE-enriched, triglyceride-rich lipoprotein particles through the action of CETP and by reducing the direct return of HDL-CE to the liver.
Langlois, Michel R; Blaton, Victor H
High-density lipoprotein cholesterol (HDL-C) comprises a family of particles with differing physicochemical characteristics. Continuing progress in improving HDL-C analysis has originated from two separate fields-one clinical, reflecting increased attention to HDL-C in estimating risk for coronary heart disease (CHD), and the other analytical, reflecting increased emphasis on finding more reliable and cost-effective HDL-C assays. Epidemiologic and prospective studies established the inverse association of HDL-C with CHD risk, a relationship that is consistent with protective mechanisms demonstrated in basic research and animal studies. Atheroprotective and less atheroprotective HDL subpopulations have been described. Guidelines on primary and secondary CHD prevention, which increased the workload in clinical laboratories, have led to a revolution in HDL-C assay technology. Many analytical techniques including ultracentrifugation, electrophoresis, chromatography, and polyanion precipitation methods have been developed to separate and quantify HDL-C and HDL subclasses. More recently developed homogeneous assays enable direct measurement of HDL-C on an automated analyzer, without the need for manual pretreatment to separate non-HDL. Although homogeneous assays show improved accuracy and precision in normal serum, discrepant results exist in samples with atypical lipoprotein characteristics. Hypertriglyceridemia and monoclonal paraproteins are important interfering factors. A novel approach is nuclear magnetic resonance spectroscopy that allows rapid and reliable analysis of lipoprotein subclasses, which may improve the identification of individuals at increased CHD risk. Apolipoprotein A-I, the major protein of HDL, has been proposed as an alternative cardioprotective marker avoiding the analytical limitations of HDL-C.
Crichton, Georgina E; Elias, Merrill F; Davey, Adam; Sullivan, Kevin J; Robbins, Michael A
Few studies have examined associations between different subcategories of cholesterol and cognitive function. We examined relationships between total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride levels and cognitive performance in the Maine-Syracuse Longitudinal Study, a community-based study of cardiovascular risk factors. Cross-sectional analyses were undertaken on data from 540 participants, aged 60 to 98 years, free of dementia and stroke. TC, HDL, LDL, and triglyceride levels were obtained. Cognitive function was assessed using a thorough neuropsychological test battery, including domains of cognitive function indexed by multiple cognitive tests. The cognitive outcomes studied were as follows: Visual-Spatial Memory and Organization, Verbal and Working Memory, Scanning and Tracking, Abstract Reasoning, a Global Composite score, and the Mini-Mental State Examination (MMSE). Significant positive associations were observed between HDL-cholesterol and the Global Composite score, Working Memory, and the MMSE after adjustment for demographic and cardiovascular risk factors. Participants with desirable levels of HDL (≥60 mg/dL) had the highest scores on all cognitive outcomes. There were no significant associations observed between TC, LDL, or triglyceride concentrations and cognition. In older individuals, HDL-cholesterol was related to a composite of Working Memory tests and for general measures of cognitive ability when adjusted for cardiovascular variables. We speculate that persons over 60 are survivors and thus less likely to show cognitive deficit in relation to TC, LDL-cholesterol, and triglycerides. Longitudinal studies are needed to examine relations between specific cognitive abilities and the different subcategories of cholesterol.
Sasamoto, Kenta; Hirayama, Satoshi; Kon, Mika; Seino, Utako; Ueno, Tsuyoshi; Nagao, Yuki; Hirayama, Akiko; Isshiki, Miwa; Idei, Mayumi; Yano, Kouji; Miida, Takashi
High-density lipoprotein-cholesterol (HDL-C) is generally measured using several homogeneous assays. We aimed to clarify whether apolipoprotein E-containing HDL (apoE-HDL) subfractions are altered during storage, and if so, whether such changes affect the HDL-C concentration measured using homogeneous assays. We stored serum from normolipidemic (n=32) and dyslipidemic (n=17) subjects at 4°C for up to 7days. ApoE-HDL subfractions were analyzed using native 2-dimensional gel (native 2D-gel) electrophoresis. HDL-C concentrations were determined using 2 precipitation and 4homogeneous assays. Native 2D-gel electrophoresis revealed variously sized apoE-HDL subfractions. After 4h incubation at 37°C, subfractions of smaller particles were converted into larger particles by lecithin:cholesterol acyltransferase (LCAT) activity. After 7days storage at 4°C, the smaller subfractions were decreased in the normolipidemic group, accompanying increases in larger subfractions, whereas changes in the respective subfractions varied among individuals in the dyslipidemic group. HDL-C concentrations were significantly lower after storage at 4°C in all assays, except that using Sekisui Medical's reagent. Therefore, changes in HDL-C concentration and apoE-HDL subfractions were independent of each other. ApoE-HDL subfractions change during storage, but these changes are not linked to those in HDL-C concentration measured using homogeneous assays. Copyright © 2017 Elsevier B.V. All rights reserved.
Welty, Francine K
This review article summarizes recent research into the mechanisms as to how elevated levels of triglyceride (TG) and low levels of high- density- lipoprotein cholesterol (HDL-C) contribute to inflammation and atherosclerosis. Evidence supports the role of TG-rich lipoproteins in signaling mechanisms via apolipoproteins C-III and free fatty acids leading to activation of NFKβ, VCAM-1 and other inflammatory mediators which lead to fatty streak formation and advanced atherosclerosis. Moreover, the cholesterol content in TG-rich lipoproteins has been shown to predict CAD risk better than LDL-C. In addition to reverse cholesterol transport, HDL has many other cardioprotective effects which include regulating immune function. The "functionality" of HDL appears more important than the level of HDL-C. Insulin resistance and central obesity underlie the pathophysiology of elevated TG and low HDL-C in metabolic syndrome and type 2 diabetes. Lifestyle recommendations including exercise and weight loss remain first line therapy in ameliorating insulin resistance and the adverse signaling processes from elevated levels of TG-rich lipoproteins and low HDL-C.
Welty, Francine K.
This review article summarizes recent research into the mechanisms as to how elevated levels of triglyceride (TG) and low levels of high- density- lipoprotein cholesterol (HDL-C) contribute to inflammation and atherosclerosis. Evidence supports the role of TG-rich lipoproteins in signaling mechanisms via apolipoproteins C-III and free fatty acids leading to activation of NFKβ, VCAM-1 and other inflammatory mediators which lead to fatty streak formation and advanced atherosclerosis. Moreover, the cholesterol content in TG-rich lipoproteins has been shown to predict CAD risk better than LDL-C. In addition to reverse cholesterol transport, HDL has many other cardioprotective effects which include regulating immune function. The “functionality” of HDL appears more important than the level of HDL-C. Insulin resistance and central obesity underlie the pathophysiology of elevated TG and low HDL-C in metabolic syndrome and type 2 diabetes. Lifestyle recommendations including exercise and weight loss remain first line therapy in ameliorating insulin resistance and the adverse signaling processes from elevated levels of TG-rich lipoproteins and low HDL-C. PMID:23881582
Bertato, Marina P; Oliveira, Carolina P; Wajchenberg, Bernardo L; Lerario, Antonio C; Maranhão, Raul C
OBJECTIVE: Glucose intolerance is frequently associated with an altered plasma lipid profile and increased cardiovascular disease risk. Nonetheless, lipid metabolism is scarcely studied in normolipidemic glucose-intolerant patients. The aim of this study was to investigate whether important lipid metabolic parameters, such as the kinetics of LDL free and esterified cholesterol and the transfer of lipids to HDL, are altered in glucose-intolerant patients with normal plasma lipids. METHODS: Fourteen glucose-intolerant patients and 15 control patients were studied; none of the patients had cardiovascular disease manifestations, and they were paired for age, sex, race and co-morbidities. A nanoemulsion resembling a LDL lipid composition (LDE) labeled with 14C-cholesteryl ester and 3H-free cholesterol was intravenously injected, and blood samples were collected over a 24-h period to determine the fractional clearance rate of the labels by compartmental analysis. The transfer of free and esterified cholesterol, triglycerides and phospholipids from the LDE to HDL was measured by the incubation of the LDE with plasma and radioactivity counting of the supernatant after chemical precipitation of non-HDL fractions. RESULTS: The levels of LDL, non-HDL and HDL cholesterol, triglycerides, apo A1 and apo B were equal in both groups. The 14C-esterified cholesterol fractional clearance rate was not different between glucose-intolerant and control patients, but the 3H-free- cholesterol fractional clearance rate was greater in glucose-intolerant patients than in control patients. The lipid transfer to HDL was equal in both groups. CONCLUSION: In these glucose-intolerant patients with normal plasma lipids, a faster removal of LDE free cholesterol was the only lipid metabolic alteration detected in our study. This finding suggests that the dissociation of free cholesterol from lipoprotein particles occurs in normolipidemic glucose intolerance and may participate in atherogenic
Rotzsch, W; Richter, V; Rassoul, F; Walper, A
Postprandial Lipaemia under Treatment with Allium sativum/Controlled double-blind study in healthy volunteers with reduced HDL2-cholesterol levels. The effectiveness of a standardized garlic powder preparation (Sapec, Kwai) on alimentary hypertriglyceridaemia after intake of a standardized fatty test meal containing 100 g butter was analyzed in a randomized placebo-controlled double-blind study. 24 volunteers with HDL2-cholesterol concentrations in plasma of less than 10 mg/dl (men) respectively 15 mg/dl (women) participated in the study. The volunteers received 3 times 1 tablet daily over a period of 6 weeks equivalent to a daily dosage of 900 mg garlic powder in the active treated group. Control measurements were made on the 1st, 22nd and 43rd day of treatment and 0, 3 and 5 h after intake of the meal. The postprandial increase of triglycerides was clearly reduced under garlic medication as compared to placebo treatment. The determined AUC-values for the triglycerides were up to 35% lower in the garlic group compared to the placebo group. The regular intake of the garlic preparation over the period of 6 weeks showed a significant lowering of the fasting values of triglycerides in comparison to placebo. Under garlic medication HDL2-cholesterol increased more than under placebo in tendency.
Nakamura, Yasushi; Kotite, Leila; Gan, Yonghong; Spencer, Thomas A; Fielding, Christopher J; Fielding, Phoebe E
A 70-75 kDa high-density lipoprotein (HDL) particle with pre-beta-electrophoretic migration (pre-beta(1)-HDL) has been identified in several studies as an early acceptor of cell-derived cholesterol. However, the further metabolism of this complex has not been determined. Here we sought to identify the mechanism by which cell-derived cholesterol was esterified and converted to mature HDL as part of reverse cholesterol transport (RCT). Human plasma selectively immunodepleted of pre-beta(1)-HDL was used to study factors regulating pre-beta(1)-HDL production. A major role for phospholipid transfer protein (PLTP) in the recycling of pre-beta(1)-HDL was identified. Cholesterol binding, esterification by lecithin/cholesterol acyltransferase (LCAT) and transfer by cholesteryl ester transfer protein (CETP) were measured using (3)H-cholesterol-labeled cell monolayers. LCAT bound to (3)H-free cholesterol (FC)-labeled pre-beta(1)-HDL generated cholesteryl esters at a rate much greater than the rest of HDL. The cholesteryl ester produced in pre-beta(1)-HDL in turn became the preferred substrate of CETP. Selective LCAT-mediated reactivity with pre-beta(1)-HDL represents a novel mechanism increasing the efficiency of RCT.
Gilmore, L Anne; Walzem, Rosemary L; Crouse, Stephen F; Smith, Dana R; Adams, Thaddeus H; Vaidyanathan, Vidya; Cao, Xiaojuan; Smith, Stephen B
On the basis of previous results from this laboratory, this study tested the hypothesis that ground beef high in MUFA and low in SFA would increase the HDL-cholesterol (HDL-C) concentration and LDL particle diameter. In a crossover dietary intervention, 27 free-living normocholesterolemic men completed treatments in which five 114-g ground beef patties/wk were consumed for 5 wk with an intervening 4-wk washout period. Patties contained 24% total fat with a MUFA:SFA ratio of either 0.71 (low MUFA, from pasture-fed cattle) or 1.10 (high MUFA, from grain-fed cattle). High-MUFA ground beef provided 3.21 g more 18:1(n-9), 1.26 g less 18:0, 0.89 g less 16:0, and 0.36 g less 18:1(trans) fatty acids per patty than did the low-MUFA ground beef. Both ground beef interventions decreased plasma insulin and HDL(2) and HDL(3) particle diameters and increased plasma 18:0 and 20:4(n-6) (all P ≤ 0.05) relative to baseline values. Only the high-MUFA ground beef intervention increased the HDL-C concentration from baseline (P = 0.02). The plasma TG concentration was positively correlated with the plasma insulin concentration (r = 0.40; P < 0.001) and negatively correlated with HDL-C (r = -0.47; P < 0.001) and plasma 18:0 (r = -0.24; P < 0.01). Plasma insulin and HDL diameters were not correlated (r = 0.01; P > 0.50), indicating that reductions in these measures were not coordinately regulated. The data indicate that dietary beef interventions have effects on risk factors for cardiovascular disease that are independent (insulin, HDL diameters) and dependent (HDL-C) on beef fatty acid composition.
Peres, Rogerio Correa; Gollücke, Andrea Pitelli Boiago; Soares, Clayton; Machado, Patricia; Viveiros Filho, Vitor; Rocha, Silvana; Morais, Damila Rodrigues; Bataglion, Giovana Anceski; Eberlin, Marcos Nogueira; Ribeiro, Daniel Araki
The aim of this study was to investigate the phenolic composition of a natural food colourant (G8000™) as well as its effects on plasma markers after 28-day consumption by healthy individuals at a dietary dose (70 g). Parameters of total cholesterol and its fractions, triglycerides and plasma enzymes biomarkers of muscle injury were measured. Major compounds identified in G8000™ by ESI-MS showed the presence of anthocyanins, organic acids, phenolic acids as well as monosaccharides. HDL levels significantly increased from 43 ± 10.2 mg/dL to 95 ± 16.9 mg/dL. LDL levels significantly decreased from 110 ± 40.9 mg/dL to 69 ± 39 mg/dL (p < 0.001). No significant statistical differences (p > 0.05) were observed for total cholesterol, triglycerides and VLDL. After the intake, plasma enzyme CK-MB decreased from 20 ± 12.1 U/L to 10 ± 1.9 U/L while LDH levels increased from 275 ± 124.4 U/L to 317 ± 114.7 U/L (p < 0.005). No significant differences were observed for CK levels. Taken together, dietary intake of natural colourant G8000™ was able to exert beneficial effects on atherosclerosis biomarkers.
Cai, Anping; Li, Xida; Zhong, Qi; Li, Minming; Wang, Rui; Liang, Yingcong; Chen, Wenzhong; Huang, Tehui; Li, Xiaohong; Zhou, Yingling; Li, Liwen
The aim of the present study was to evaluate the association between HDL cholesterol level and all-cause mortality in patients with ejection fraction reduced heart failure (EFrHF) complicating coronary heart disease (CHD).A total of 323 patients were retrospectively recruited. Patients were divided into low and high HDL cholesterol groups. Between-group differences and associations between HDL cholesterol level and all-cause mortality were assessed.Patients in the high HDL cholesterol group had higher HDL cholesterol level and other lipid components (P <0.05 for all comparison). Lower levels of alanine aminotransferase (ALT), high-sensitivity C-reactive protein (Hs-CRP), and higher albumin (ALB) level were observed in the high HDL cholesterol group (P <0.05 for all comparison). Although left ventricular ejection fraction (LVEF) were comparable (28.8 ± 4.5% vs 28.4 ± 4.6%, P = 0.358), mean mortality rate in the high HDL cholesterol group was significantly lower (43.5% vs 59.1%, P = 0.007). HDL cholesterol level was positively correlated with ALB level, while inversely correlated with ALT, Hs-CRP, and NYHA classification. Logistic regression analysis revealed that after extensively adjusted for confounding variates, HDL cholesterol level remained significantly associated with all-cause mortality although the magnitude of association was gradually attenuated with odds ratio of 0.007 (95% confidence interval 0.001-0.327, P = 0.012).Higher HDL cholesterol level is associated with better survival in patients with EFrHF complicating CHD, and future studies are necessary to demonstrate whether increasing HDL cholesterol level will confer survival benefit in these populations of patients.
Linn, S; Fulwood, R; Carroll, M; Brook, J G; Johnson, C; Kalsbeek, W D; Rifkind, B M
BACKGROUND: Framingham Study findings suggest that total cholesterol (TC):High density lipoprotein cholesterol (HDL-C) ratio is a useful summary of the joint contribution of TC and HDL-C to coronary heart disease (CHD) risk. Information on the distribution of TC:HDL-C in the US population is limited to selected populations and the relationship of the ratio distribution and its correlates has received little attention. METHOD: TC/HDL-C ratios were examined in a representative sample of the United States adult population ages 20 to 74 years, between February 1976 and February 1980 during NHANES II, using stratification and multivariate regression analyses. RESULTS: Age-adjusted mean ratios were higher in men compared with women and were higher in Whites compared with Blacks. White men had the highest TC/HDL-C mean ratios. These relationships remained after stratification by age, education, body mass index, alcohol use, cigarette smoking, and physical activity. Using multivariate analyses, the ratios were positively related to BMI, age, and smoking; and negatively related to female sex, alcohol use, being Black, and physical activity. CONCLUSIONS: Using a ratio reference point of greater than or equal to 4.5 from the Framingham study, at least an estimated 44 million persons ages 25 to 74 years in the US were found to be at higher risk of developing coronary heart disease. PMID:1853996
Genoux, Annelise; Pons, Véronique; Radojkovic, Claudia; Roux-Dalvai, Florence; Combes, Guillaume; Rolland, Corinne; Malet, Nicole; Monsarrat, Bernard; Lopez, Frédéric; Ruidavets, Jean-Bernard; Perret, Bertrand; Martinez, Laurent O.
Background Mitochondrial ATP synthase is expressed as a plasma membrane receptor for apolipoprotein A-I (apoA-I), the major protein component in High Density Lipoproteins (HDL). On hepatocytes, apoA-I binds to cell surface ATP synthase (namely ecto-F1-ATPase) and stimulates its ATPase activity, generating extracellular ADP. This production of extracellular ADP activates a P2Y13-mediated HDL endocytosis pathway. Conversely, exogenous IF1, classically known as a natural mitochondrial specific inhibitor of F1-ATPase activity, inhibits ecto-F1-ATPase activity and decreases HDL endocytosis by both human hepatocytes and perfused rat liver. Methodology/Principal Findings Since recent reports also described the presence of IF1 at the plasma membrane of different cell types, we investigated whether IF1 is present in the systemic circulation in humans. We first unambiguously detected IF1 in human serum by immunoprecipitation and mass spectrometry. We then set up a competitive ELISA assay in order to quantify its level in human serum. Analyses of IF1 levels in 100 normolipemic male subjects evidenced a normal distribution, with a median value of 0.49 µg/mL and a 95% confidence interval of 0.22–0.82 µg/mL. Correlations between IF1 levels and serum lipid levels demonstrated that serum IF1 levels are positively correlated with HDL-cholesterol and negatively with triglycerides (TG). Conclusions/Significance Altogether, these data support the view that, in humans, circulating IF1 might affect HDL levels by inhibiting hepatic HDL uptake and also impact TG metabolism. PMID:21935367
Pamir, Nathalie; Hutchins, Patrick; Ronsein, Graziella; Vaisar, Tomas; Reardon, Catherine A.; Getz, Godfrey S.; Lusis, Aldons J.; Heinecke, Jay W.
Cholesterol efflux capacity associates strongly and negatively with the incidence and prevalence of human CVD. We investigated the relationships of HDL’s size and protein cargo with its cholesterol efflux capacity using APOB-depleted serum and HDLs isolated from five inbred mouse strains with different susceptibilities to atherosclerosis. Like humans, mouse HDL carried >70 proteins linked to lipid metabolism, the acute-phase response, proteinase inhibition, and the immune system. HDL’s content of specific proteins strongly correlated with its size and cholesterol efflux capacity, suggesting that its protein cargo regulates its function. Cholesterol efflux capacity with macrophages strongly and positively correlated with retinol binding protein 4 (RBP4) and PLTP, but not APOA1. In contrast, ABCA1-specific cholesterol efflux correlated strongly with HDL’s content of APOA1, APOC3, and APOD, but not RBP4 and PLTP. Unexpectedly, APOE had a strong negative correlation with ABCA1-specific cholesterol efflux capacity. Moreover, the ABCA1-specific cholesterol efflux capacity of HDL isolated from APOE-deficient mice was significantly greater than that of HDL from wild-type mice. Our observations demonstrate that the HDL-associated APOE regulates HDL’s ABCA1-specific cholesterol efflux capacity. These findings may be clinically relevant because HDL’s APOE content associates with CVD risk and ABCA1 deficiency promotes unregulated cholesterol accumulation in human macrophages. PMID:26673204
Hafiane, Anouar; Bielicki, John K.; Johansson, Jan O.; ...
Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from themore » carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are
Hafiane, Anouar; Bielicki, John K.; Johansson, Jan O.; Genest, Jacques
Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are
Hafiane, Anouar; Bielicki, John K; Johansson, Jan O; Genest, Jacques
Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These mechanisms are
Kushwaha, Rampratap S.
The present studies were conducted to determine whether a synthetic truncated apoC-I peptide that inhibits CETP activity in baboons would raise plasma HDL cholesterol levels in nonhuman primates with low HDL levels. We used 2 cynomolgus monkeys and 3 baboons fed a cholesterol- and fat-enriched diet. In cynomolgus monkeys, we injected synthetic truncated apoC-I inhibitor peptide at a dose of 20 mg/kg and, in baboons, at doses of 10, 15, and 20 mg/kg at weekly intervals. Blood samples were collected 3 times a week and VLDL + LDL and HDL cholesterol concentrations were measured. In cynomolgus monkeys, administration of the inhibitor peptide caused a rapid decrease in VLDL + LDL cholesterol concentrations (30%–60%) and an increase in HDL cholesterol concentrations (10%–20%). VLDL + LDL cholesterol concentrations returned to baseline levels in approximately 15 days. In baboons, administration of the synthetic inhibitor peptide caused a decrease in VLDL + LDL cholesterol (20%–60%) and an increase in HDL cholesterol (10%–20%). VLDL + LDL cholesterol returned to baseline levels by day 21, whereas HDL cholesterol concentrations remained elevated for up to 26 days. ApoA-I concentrations increased, whereas apoE and triglyceride concentrations decreased. Subcutaneous and intravenous administrations of the inhibitor peptide had similar effects on LDL and HDL cholesterol concentrations. There was no change in body weight, food consumption, or plasma IgG levels of any baboon during the study. These studies suggest that the truncated apoC-I peptide can be used to raise HDL in humans. PMID:15467157
Lim, Soo; Park, Yae Min; Sakuma, Ichiro; Koh, Kwang Kon
Lowering low-density lipoprotein-cholesterol (LDL-C) is the primary target in the management of dyslipidemia in patients at high risk of cardiovascular disease. However, patients who have achieved LDL-C levels below the currently recommended targets may still experience cardiovascular events. This may result, in part, from elevated triglyceride (TG) levels and low levels of high-density lipoprotein-cholesterol (HDL-C). Low HDL-C and high TG levels are common and are recognized as independent risk factors for cardiovascular morbidity and mortality. Furthermore, atherogenic dyslipidemia, characterized by low levels of HDL-C, high TG, and small, dense LDL particles, is a typical phenotype of dyslipidemia in subjects with insulin resistance and metabolic syndrome. Therefore, to reduce further the risk of coronary heart disease (CHD), raising HDL-C and lowering TG may be the secondary therapeutic target for patients who achieve LDL-C levels below the currently recommended targets but are still at risk of CHD. However, whether increasing HDL-C levels alone reduces CHD has not yet been confirmed in large randomized clinical trials, and whether functional HDL is more important than HDL-C in reducing CHD remains controversial. Large CHD endpoint trials that include many patients with diabetes are underway to compare combination treatments with statin and niacin, fibrates, or cholesteryl ester transfer protein inhibitors with statin alone treatments. In this review, we discuss the rationale and importance of increasing HDL-C levels with and without lowering TG levels in the treatment and prevention of cardiovascular events. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Masson, Walter; Siniawski, Daniel; Lobo, Martín; Molinero, Graciela; Huerín, Melina
The triglyceride/HDL cholesterol ratio, as a surrogate marker of insulin resistance, may be associated to presence of subclinical carotid atherosclerosis in postmenopausal women. The aim of this study was to explore this association. Women (last menstrual period≥2 years) in primary prevention up to 65 years of age were recruited. Association between the triglyceride/HDL cholesterol (HDL-C) ratio and presence of carotid plaque, assessed by ultrasonography, was analyzed. ROC analysis was performed, determining the precision of this ratio to detect carotid plaque. A total of 332 women (age 57±5 years) were recruited. Triglyceride/HDL-C ratio was 2.35±1.6. Prevalence of carotid plaque was 29%. Women with carotid plaque had higher triglyceride/HDL-C ratios (3.33±1.96 vs. 2.1±1.2, P<.001) than women with no carotid plaque. A positive relationship was seen between quintiles of this ratio and prevalence of carotid plaque (p<.001). Regardless of other risk factors, women with higher triglyceride/HDL-C ratios were more likely to have carotid plaque (odds ratio 1.47, 95% confidence interval 1.20-1.79, P<.001). The area under the curve of the triglyceride/HDL-C ratio to detect carotid plaque was .71 (95% confidence interval .65 to .76), and the optimal cut-off point was 2.04. In postmenopausal women in primary prevention, insulin resistance, estimated from the triglyceride/HDL-C ratio, was independently associated to a greater probability of carotid plaque. A value of such ratio greater than 2 may be used for assessing cardiovascular risk in this particular group of women. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.
Vanstone, C A.; Raeini-Sarjaz, M; Jones, P J.H.
Although plant sterols are known to suppress intestinal cholesterol absorption, whether plasma and hepatic lipid levels are influenced through non-gut related internal mechanisms has not been established. To examine this question 50 male hamsters were divided into 5 groups and fed semi-purified diets containing 20% energy as fat and 0.25% (w/w) cholesterol ad libitum for 60 days. The control group (i) received diet alone, while four additional groups consumed the diet plus one of four equivalent phytosterol mixtures (5 mg/kg/day) given either as (ii) tall oil phytosterols/stanols mixed with diet (oralSA), (iii) tall oil phytosterols/stanols subcutaneously injected (subSA), (iv) soybean oil phytosterols alone mixed with diet (oralSE), or (v) soybean oil subcutaneous injected phytosterols alone (subSE). The control group and both orally supplemented groups also received placebo subcutaneous sham injections. Neither food consumption, body weight, nor liver weight differed across treatment groups. Subcutaneous administration of SA and SE decreased plasma total cholesterol levels by 21% and 23% (p < 0.0001) and non-apolipoprotein-A cholesterol concentrations by 22% and 15% (p < 0.0002), respectively, compared to control. HDL cholesterol and TG concentrations remained unchanged across all groups, except for a decline of 25% (p < 0.0001) in HDL concentration in the subSE group versus control. Plasma campesterol levels were lower (p < 0.05) in the subSA group relative to all other groups. Plasma campesterol:cholesterol and campesterol:sitosterol ratios were, however, higher (p < 0.0001) for both the oral and subSE groups. Hepatic cholesterol levels were higher (p < 0.0001) in the oral and subSE phytosterol groups by 30% and 31%, respectively, relative to control. We conclude that low doses of subcutaneously administered plant sterols reduce circulating cholesterol levels through mechanisms other than inhibiting intestinal cholesterol absorption.
Mulay, Vishwaroop; Wood, Peta; Rentero, Carles; Enrich, Carlos; Grewal, Thomas
Binding of High Density Lipoprotein (HDL) and its major apolipoprotein A-I (apoA-I) to cell surface receptors is believed to initiate a plethora of signaling cascades that promote atheroprotective cell behavior, including the removal of excess cholesterol from lipid-loaded macrophages. More specifically, HDL and apoA-I binding to scavenger receptor BI (SR-BI) and ATP-binding cassette (ABC) transporter A1 has been shown to activate protein kinase A and C (PKA, PKC), Rac/Rho GTPases, Janus Kinase 2 (JAK2), calmodulin as well as mitogen-activated protein kinases (MAPK). Some of these signaling events upregulate mobilization of cholesterol from cellular pools, while others promote efflux pathways through increased expression, stability, and cell surface localization of SR-BI and ABCA1. This review aims to summarize the current knowledge of HDL- and apoA-I -induced signal transduction pathways that are linked to cholesterol efflux and discusses the underlying mechanisms that could couple ligand binding to SR-BI and ABCA1 with signaling and cholesterol export. Additional focus is given on the potential of pharmacological intervention to modulate the activity of signaling cascades for the inhibition or regression of cholesterol accumulation in atherosclerotic lesions.
Anderson, Josephine L.C.; Gautier, Thomas; Nijstad, Niels; Tölle, Markus; Schuchardt, Mirjam; van der Giet, Markus; Tietge, Uwe J.F.
Atherosclerotic cardiovascular disease (CVD) represents the largest cause of mortality in end-stage renal disease (ESRD). CVD in ESRD is not explained by classical CVD risk factors such as HDL cholesterol mass levels making functional alterations of lipoproteins conceivable. HDL functions in atheroprotection by promoting reverse cholesterol transport (RCT), comprising cholesterol efflux from macrophage foam cells, uptake into hepatocytes and final excretion into the feces. ESRD-HDL (n = 15) were compared to healthy control HDL (n = 15) for their capacity to promote in vitro (i) cholesterol efflux from THP-1 macrophage foam cells and (ii) SR-BI-mediated selective uptake into ldla[SR-BI] cells as well as (iii) in vivo RCT. Compared with HDL from controls, ESRD-HDL displayed a significant reduction in mediating cholesterol efflux (p < 0.001) and SR-BI-mediated selective uptake (p < 0.01), two key steps in RCT. Consistently, also the in vivo capacity of ESRD-HDL to promote RCT when infused into wild-type mice was significantly impaired (p < 0.01). In vitro oxidation of HDL from healthy controls with hypochloric acid was able to fully mimic the impaired biological activities of ESRD-HDL. In conclusion, we demonstrate that HDL from ESRD patients is dysfunctional in key steps as well as overall RCT, likely due to oxidative modification. PMID:28148911
Anderson, Josephine L C; Gautier, Thomas; Nijstad, Niels; Tölle, Markus; Schuchardt, Mirjam; van der Giet, Markus; Tietge, Uwe J F
Atherosclerotic cardiovascular disease (CVD) represents the largest cause of mortality in end-stage renal disease (ESRD). CVD in ESRD is not explained by classical CVD risk factors such as HDL cholesterol mass levels making functional alterations of lipoproteins conceivable. HDL functions in atheroprotection by promoting reverse cholesterol transport (RCT), comprising cholesterol efflux from macrophage foam cells, uptake into hepatocytes and final excretion into the feces. ESRD-HDL (n = 15) were compared to healthy control HDL (n = 15) for their capacity to promote in vitro (i) cholesterol efflux from THP-1 macrophage foam cells and (ii) SR-BI-mediated selective uptake into ldla[SR-BI] cells as well as (iii) in vivo RCT. Compared with HDL from controls, ESRD-HDL displayed a significant reduction in mediating cholesterol efflux (p < 0.001) and SR-BI-mediated selective uptake (p < 0.01), two key steps in RCT. Consistently, also the in vivo capacity of ESRD-HDL to promote RCT when infused into wild-type mice was significantly impaired (p < 0.01). In vitro oxidation of HDL from healthy controls with hypochloric acid was able to fully mimic the impaired biological activities of ESRD-HDL. In conclusion, we demonstrate that HDL from ESRD patients is dysfunctional in key steps as well as overall RCT, likely due to oxidative modification.
Nettleton, Jennifer A; Steffen, Lyn M; Ballantyne, Christie M; Boerwinkle, Eric; Folsom, Aaron R
Polymorphisms in genes involved in HDL-cholesterol (HDL-C) metabolism influence plasma HDL-C concentrations. We examined whether dietary fat intake modified relations between HDL-C and polymorphisms in hepatic lipase (LIPC-514C-->T), cholesteryl ester transfer protein (CETP TaqIB), and lipoprotein lipase (LPL S447X) genes. Diet (food frequency questionnaire), plasma lipids, and LIPC, CETP, and LPL genotypes were assessed in approximately 12,000 White and African American adults. In both races and all genotypes studied, minor allele homozygotes had highest HDL-C concentrations compared to the other genotypes (P<0.001). However, main effects were modified by usual dietary fat intake. In African Americans - women somewhat more strongly than men -LIPC TT homozygotes with fat intake >or=33.2% of energy had approximately 3-4 mg/dL higher HDL-C concentrations than CC and CT genotypes. In contrast, when fat intake was <33.2% of energy, TT homozygotes had HDL-C concentrations approximately 3.5mg/dL greater than those with the CC genotype but not different from those with the CT genotype (P(interaction)=0.013). In Whites, LPLGG homozygotes had greatest HDL-C at lower total, saturated, and monounsaturated fat intakes but lowest HDL-C at higher intakes of these fats (P(interaction)
Chang, Yu-Hung; Lin, Kun-Cheng; Chang, Dao-Ming; Hsieh, Chang-Hsun; Lee, Yau-Jiunn
OBJECTIVES: There is extensive but controversial evidence on the diverse effects of statins on the level of high-density lipoprotein cholesterol (HDL-C). Some of these effects may limit the benefits of statins in terms of cardiovascular risk reduction. To identify the conditions for beneficial effects, this study investigated the response to atorvastatin and simvastatin treatment in type 2 diabetic patients with elevated low-density lipoprotein cholesterol (LDL-C). METHODS: 2,872 subjects with type 2 diabetes from a disease management program were investigated. Patients with LDL-C ≥130 mg/dl or total cholesterol ≥200 mg/dl were put onto statin therapy by the National Health Insurance system in Taiwan. RESULTS: 1,080 patients who completed 1 year of statin treatment were analyzed. There were significant reductions in LDL-C in both the atorvastatin (37.1%) and simvastatin (34.3%) group after one year of treatment compared with baseline levels. Unexpectedly, the majority of diabetic patients who received atorvastatin or simvastatin did not show an increase in HDL-C levels. 59.8% of patients had a significant HDL-C reduction (ΔHDL-C ≤ -3%) after atorvastatin treatment. Multivariate logistic regression analysis showed that the following patients were at higher risk of HDL-C reduction after 12 months: (i) patients in whom statin therapy was initiated aged <65 years and who had a BMI ≥24 kg/m2, (ii) male patients with a baseline HDL-C >40 mg/dl, and (iii) female patients with a baseline HDL-C >50 mg/dl. However, diabetic patients with severe atherogenic dyslipidemia (LDL-C ≥130, TG ≥204, and HDL-C ≤34 mg/dl) obtained more benefits in terms of HDL-C change after statin therapy. CONCLUSIONS: Diabetic patients, except those with severe atherogenic dyslipidemia, are prone to a decrease in serum HDL-C level after statin treatment, particularly after atorvastatin treatment. PMID:24380094
Chang, Yu-Hung; Lin, Kun-Cheng; Chang, Dao-Ming; Hsieh, Chang-Hsun; Lee, Yau-Jiunn
There is extensive but controversial evidence on the diverse effects of statins on the level of high-density lipoprotein cholesterol (HDL-C). Some of these effects may limit the benefits of statins in terms of cardiovascular risk reduction. To identify the conditions for beneficial effects, this study investigated the response to atorvastatin and simvastatin treatment in type 2 diabetic patients with elevated low-density lipoprotein cholesterol (LDL-C). 2,872 subjects with type 2 diabetes from a disease management program were investigated. Patients with LDL-C ≥130 mg/dl or total cholesterol ≥200 mg/dl were put onto statin therapy by the National Health Insurance system in Taiwan. 1,080 patients who completed 1 year of statin treatment were analyzed. There were significant reductions in LDL-C in both the atorvastatin (37.1%) and simvastatin (34.3%) group after one year of treatment compared with baseline levels. Unexpectedly, the majority of diabetic patients who received atorvastatin or simvastatin did not show an increase in HDL-C levels. 59.8% of patients had a significant HDL-C reduction (ΔHDL-C ≤ -3%) after atorvastatin treatment. Multivariate logistic regression analysis showed that the following patients were at higher risk of HDL-C reduction after 12 months: (i) patients in whom statin therapy was initiated aged <65 years and who had a BMI ≥24 kg/m(2), (ii) male patients with a baseline HDL-C >40 mg/dl, and (iii) female patients with a baseline HDL-C >50 mg/dl. However, diabetic patients with severe atherogenic dyslipidemia (LDL-C ≥130, TG ≥204, and HDL-C ≤34 mg/dl) obtained more benefits in terms of HDL-C change after statin therapy. Diabetic patients, except those with severe atherogenic dyslipidemia, are prone to a decrease in serum HDL-C level after statin treatment, particularly after atorvastatin treatment.
Paragh, György; Harangi, Mariann; László, Márk
Previous epidemiological studies have demonstrated the low level of high-density lipoprotein (HDL) cholesterol as an independent risk factor for cardiovascular diseases, the increase of which is one of the cornerstones of preventive cardiovascular care. In addition to its major role in reverse cholesterol transport, HDL-C has other biological activities that may contribute to its protective effects against atherosclerosis. These include antioxidant, anti-inflammatory, antithrombotic/profibrinolytic and vasoprotective effects. Current guidelines recommend aggressive lifestyle modifications, niacin, fibrate, statin or a combination of these to increase HDL-cholesterol levels. In addition, several novel HDL-based therapeutic strategies have been or are currently being tested. These include newer formulations of nicotinic acid/receptor agonists, CETP inhibitors, cannabinoid-1 receptor antagonists, PPAR agonists, liver X receptor/farnesoid X receptor agonists, and apoA-I and/or phospholipid-derived therapies. In this article previous clinical trials, epidemiological observations, basic science studies and the most important trials of novel agents are reviewed.
Lilja, Heidi E; Suviolahti, Elina; Soro-Paavonen, Aino; Hiekkalinna, Tero; Day, Aaron; Lange, Kenneth; Sobel, Eric; Taskinen, Marja-Riitta; Peltonen, Leena; Perola, Markus; Pajukanta, Päivi
Decreased HDL-cholesterol (HDL-C) and familial combined hyperlipidemia (FCHL) are the two most common familial dyslipidemias predisposing to premature coronary heart disease (CHD). These dyslipidemias share many phenotypic features, suggesting a partially overlapping molecular pathogenesis. This was supported by our previous pooled data analysis of the genome scans for low HDL-C and FCHL, which identified three shared chromosomal regions for a qualitative HDL-C trait on 8q23.1, 16q23.3, and 20q13.32. This study further investigates these regions as well as two other loci we identified earlier for premature CHD on 2q31 and Xq24 and a locus for high serum triglycerides (TGs) on 10q11. We analyzed 67 microsatellite markers in an extended study sample of 1,109 individuals from 92 low HDL-C or FCHL families using both qualitative and quantitative lipid phenotypes. These analyses provided evidence for linkage (a logarithm of odds score of 3.2) on 10q11 using a quantitative HDL-C trait. Importantly, this region, previously linked to TGs, body mass index, and obesity, provided evidence for association for quantitative TGs (P = 0.0006) and for a combined trait of HDL-C and TGs (P = 0.008) with marker D10S546. Suggestive evidence for linkage also emerged for HDL-C on 2q31 and for TGs on 20q13.32. Finnish families ascertained for dyslipidemias thus suggest that 10q11, 2q31, and 20q13.32 harbor loci for HDL-C and TGs.
Ray, Kausik; Wainwright, Nick W J; Visser, Loes; Witteman, Jacqueline; Breteler, Monique; Ambegaonkar, Baishali; Hofman, Albert; Stricker, Bruno; Wareham, Nick; Khaw, Kay Tee; Sandhu, Manjinder
Lipid modification therapy (LMT) produces cardiovascular benefits principally through reductions in low density lipoprotein cholesterol. While recent evidence, using data from 454 participants in the Framingham Offspring Study, has suggested that increases in high density lipoprotein cholesterol (HDL-C) are also associated with a reduction in cardiovascular outcomes, independently of changes in low density lipoprotein cholesterol, replication of this finding is important. The authors therefore present further results using data from the EPIC-Norfolk (UK) and Rotterdam (The Netherlands) prospective cohort studies. A total of 1148 participants, 446 from the EPIC-Norfolk and 702 from the Rotterdam study, were assessed for lipids before and after starting LMT. Subsequent risk of cardiovascular events, ascertained through linkage with mortality records and hospital databases, was investigated using Cox proportional hazards regression. Random effects meta-analysis was used to combine results across studies. Based on combined data from the EPIC-Norfolk and Rotterdam studies there was some evidence that change in HDL-C resulting from LMT was associated with reduced cardiovascular risk (HR per pooled SD (=0.34 mmol/l) increase=0.74, 95% CI 0.56 to 0.99, adjusted for age, sex and baseline HDL-C). However, this association was attenuated and was not (statistically) significant with further adjustments for non-HDL-C and for cigarette smoking history, prevalent diabetes, systolic blood pressure, body mass index, use of antihypertensive medication, previous myocardial infarction, prevalent angina and previous stroke (0.92, 0.701.20). Following adjustment for conventional non-lipid risk factors of cardiovascular disease, this study provides no evidence to support a significant benefit from increasing HDL-C independent of the effect of lowering non-HDL-C.
Schwendeman, Anna; Sviridov, Denis O.; Yuan, Wenmin; Guo, Yanhong; Morin, Emily E.; Yuan, Yue; Stonik, John; Freeman, Lita; Ossoli, Alice; Thacker, Seth; Killion, Salena; Pryor, Milton; Chen, Y. Eugene; Turner, Scott; Remaley, Alan T.
The goal of this study was to understand how the reconstituted HDL (rHDL) phospholipid (PL) composition affects its cholesterol efflux and anti-inflammatory properties. An ApoA-I mimetic peptide, 5A, was combined with either SM or POPC. Both lipid formulations exhibited similar in vitro cholesterol efflux by ABCA1, but 5A-SM exhibited higher ABCG1- and SR-BI-mediated efflux relative to 5A-POPC (P < 0.05). Injection of both rHDLs in rats resulted in mobilization of plasma cholesterol, although the relative potency was 3-fold higher for the same doses of 5A-SM than for 5A-POPC. Formation of preβ HDL was observed following incubation of rHDLs with both human and rat plasma in vitro, with 5A-SM inducing a higher extent of preβ formation relative to 5A-POPC. Both rHDLs exhibited anti-inflammatory properties, but 5A-SM showed higher inhibition of TNF-α, IL-6, and IL-1β release than did 5A-POPC (P < 0.05). Both 5A-SM and 5A-POPC showed reduction in total plaque area in ApoE−/− mice, but only 5A-SM showed a statistically significant reduction over placebo control and baseline (P < 0.01). The type of PL used to reconstitute peptide has significant influence on rHDL’s anti-inflammatory and anti-atherosclerosis properties. PMID:26117661
Yassine, Hussein N; Belopolskaya, Alexandra; Schall, Christina; Stump, Craig S; Lau, Serrine S; Reaven, Peter D
Our objective was to examine the role of hypertriglyceridemia on the capacity of HDL to facilitate ABCA-1 mediated cholesterol efflux in type 2 diabetes (T2DM). HDL mediated cholesterol efflux through the ABCA-1 transporter was measured using BHK cell lines in samples of 71 participants with T2DM in the presence or absence of high triglyceride levels (TG). Additionally, HDL mediated efflux was measured in 13 diabetic and non-diabetic participants fasting and four hours after a high-fat test challenge. HDL mediated cholesterol efflux function was increased in participants with T2DM with hypertriglyceridemia when compared to participants with T2DM without hypertriglyceridemia (efflux ratio mean±standard deviation (SD), T2DM+TG: 1.17±0.25 vs. T2DM - TG: 1.03±0.19, p=0.0098). In the fat challenge study, we observed a significant increase in ABCA-1 mediated cholesterol efflux capacity following an ingestion of high-fat test meal by participants in both groups of T2DM (n=6, efflux ratio, mean±SD, pre: 0.86±0.4 vs. post: 1.34±0.6, p=0.01) and non-diabetic participants (n=7, efflux ratio mean±SD pre: 1.24±0.31 vs. post: 1.39±0.42, p=0.04) that was partly explained by the difference in CETP activity (r=0.6, p=0.03). Our study suggests that high triglyceride levels facilitate ABCA-1 mediated efflux function of HDL in part by activating CETP. Copyright © 2014 Elsevier Inc. All rights reserved.
Bechor, Sapir; Zolberg Relevy, Noa; Harari, Ayelet; Almog, Tal; Kamari, Yehuda; Ben-Amotz, Ami; Harats, Dror; Shaish, Aviv
Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-β-carotene (9-cis-βc) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-βc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with βc from the alga Dunaliella led to βc accumulation in peritoneal macrophages. 9-cis-βc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from βc in RAW264.7 macrophages. Furthermore, 9-cis-βc, as well as all-trans-βc, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-βc augmented cholesterol efflux from macrophages ex vivo. 9-cis-βc increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE) and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-βc from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of βc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages.
Bechor, Sapir; Zolberg Relevy, Noa; Harari, Ayelet; Almog, Tal; Kamari, Yehuda; Ben-Amotz, Ami; Harats, Dror; Shaish, Aviv
Cholesterol efflux from macrophages is a key process in reverse cholesterol transport and, therefore, might inhibit atherogenesis. 9-cis-β-carotene (9-cis-βc) is a precursor for 9-cis-retinoic-acid (9-cis-RA), which regulates macrophage cholesterol efflux. Our objective was to assess whether 9-cis-βc increases macrophage cholesterol efflux and induces the expression of cholesterol transporters. Enrichment of a mouse diet with βc from the alga Dunaliella led to βc accumulation in peritoneal macrophages. 9-cis-βc increased the mRNA levels of CYP26B1, an enzyme that regulates RA cellular levels, indicating the formation of RA from βc in RAW264.7 macrophages. Furthermore, 9-cis-βc, as well as all-trans-βc, significantly increased cholesterol efflux to high-density lipoprotein (HDL) by 50% in RAW264.7 macrophages. Likewise, food fortification with 9-cis-βc augmented cholesterol efflux from macrophages ex vivo. 9-cis-βc increased both the mRNA and protein levels of ABCA1 and apolipoprotein E (APOE) and the mRNA level of ABCG1. Our study shows, for the first time, that 9-cis-βc from the diet accumulates in peritoneal macrophages and increases cholesterol efflux to HDL. These effects might be ascribed to transcriptional induction of ABCA1, ABCG1, and APOE. These results highlight the beneficial effect of βc in inhibition of atherosclerosis by improving cholesterol efflux from macrophages. PMID:27447665
Manco, Melania; Grugni, Graziano; Di Pietro, Mario; Balsamo, Antonio; Di Candia, Stefania; Morino, Giuseppe Stefano; Franzese, Adriana; Di Bonito, Procolo; Maffeis, Claudio; Valerio, Giuliana
To identify metabolic phenotypes at increased risk of impaired glucose tolerance (IGT) in Italian overweight/obese children (n = 148, age 5-10 years) and adolescents (n = 531, age 10-17.9 year). Phenotypes were defined as follows: obesity by the 95th cut-points of the Center for Disease Control body mass index reference standards, impaired fasting glucose (fasting plasma glucose ≥100 mg/dl), high circulating triglycerides (TG), TG/HDL cholesterol ≥2.2, waist-to-height ratio (WTHR) >0.6, and combination of the latter with high TG or TG/HDL cholesterol ≥2.2. In the 148 obese children, TG/HDL-C ≥ 2.2 (OR 20.19; 95 % CI 2.50-163.28, p = 0.005) and the combination of TG/HDL-C ≥ 2.2 and WTHR > 0.60 (OR 14.97; 95 % CI 2.18-102.76, p = 0.006) were significantly associated with IGT. In the 531 adolescents, TG/HDL-C ≥ 2.2 (OR 1.991; 95 % CI 1.243-3.191, p = 0.004) and the combination with WTHR > 0.60 (OR 2.24; 95 % CI 1.29-3.87, p = 0.004) were associated with significantly increased risk of IGT. In the whole sample, having high TG levels according to the NIH National Heart, Lung and Blood Institute Expert Panel was not associated with an increased risk of presenting IGT. TG/HDL-C ratio can be useful, particularly in children, to identify obese young patients at risk of IGT. Its accuracy as screening tool in a general population needs to be verified. The combination of TG/HDL-C ratio and WTHR > 0.6 did not improve prediction. Having high TG according to the NIH definition was not associated with increased risk of developing IGT.
Yamamoto, K; Kamo-Yamada, F; Cho, S; Sugano, M
Cholesterol esterification and cholesterol ester hydrolysis in dog plasma were investigated. Esterification proceeded linearly for 60 min, and the amounts of cholesterol esterified were in the range of 0.13-0.18 mumol/ml/h. No change of acyl composition had occurred in newly formed cholesterol esters during incubation. With the addition of Na taurocholate (10 mM), complete inhibition of the esterifying activity and maximal activation of the hydrolase activity were observed. Approximately 50% of cholesterol esters present in plasma was hydrolyzed in 10 min of incubation, and the reaction was completed within 60 min. The maximal rate of hydrolysis was estimated to be 4.0-5.4 mumol/ml/h, and polyunsaturated esters were hydrolyzed more rapidly than saturated ones. The esterifying activity was detected in high density (HDL) and very high density lipoproteins (VHDL), while the hydrolytic activity was found only in VHDL. Each lipoprotein fraction served as a good substrate for hydrolysis, while HDL was the sole substrate for esterification. The optimal pH of the hydrolytic activity in VHDL lay in a broad range between 6.8 and 7.2 and the apparent Km was determined as 12.5 x 10(-3) mM for cholesteryl oleate.
Almasy, L; Hixson, J E; Rainwater, D L; Cole, S; Williams, J T; Mahaney, M C; VandeBerg, J L; Stern, M P; MacCluer, J W; Blangero, J
Common disorders with genetic susceptibilities involve the action of multiple genes interacting with each other and with environmental factors, making it difficult to localize the specific genetic loci responsible. An important route to the disentangling of this complex inheritance is through the study of normal physiological variation in quantitative risk factors that may underlie liability to disease. We present an analysis of HDL-cholesterol (HDL-C), which is inversely correlated with risk of heart disease. A variety of HDL subphenotypes were analyzed, including HDL particle-size classes and the concentrations and proportions of esterified and unesterified HDL-C. Results of a complete genomic screen in large, randomly ascertained pedigrees implicated two loci, one on chromosome 8 and the other on chromosome 15, that influence a component of HDL-C-namely, unesterified HDL2a-C. Multivariate analyses of multiple HDL phenotypes and simultaneous multilocus analysis of the quantitative-trait loci identified permit further characterization of the genetic effects on HDL-C. These analyses suggest that the action of the chromosome 8 locus is specific to unesterified cholesterol levels, whereas the chromosome 15 locus appears to influence both HDL-C concentration and distribution of cholesterol among HDL particle sizes. PMID:10330356
Morton, Jamie; Zoungas, Sophia; Li, Qiang; Patel, Anushka A; Chalmers, John; Woodward, Mark; Celermajer, David S; Beulens, Joline W J; Stolk, Ronald P; Glasziou, Paul; Ng, Martin K C
Although low HDL cholesterol (HDL-C) is an established risk factor for atherosclerosis, data on HDL-C and the risk of microvascular disease are limited. We tested the association between HDL-C and microvascular disease in a cohort of patients with type 2 diabetes. A total of 11,140 patients with type 2 diabetes and at least one additional vascular risk factor were followed a median of 5 years. Cox proportional hazards models were used to assess the association between baseline HDL-C and the development of new or worsening microvascular disease, defined prospectively as a composite of renal and retinal events. The mean baseline HDL-C level was 1.3 mmol/L (SD 0.45 mmol/L [range 0.1-4.0]). During follow-up, 32% of patients developed new or worsening microvascular disease, with 28% experiencing a renal event and 6% a retinal event. Compared with patients in the highest third, those in the lowest third had a 17% higher risk of microvascular disease (adjusted hazard ratio 1.17 [95% CI 1.06-1.28], P = 0.001) after adjustment for potential confounders and regression dilution. This was driven by a 19% higher risk of renal events (1.19 [1.08-1.32], P = 0.0005). There was no association between thirds of HDL-C and retinal events (1.01 [0.82-1.25], P = 0.9). In patients with type 2 diabetes, HDL-C level is an independent risk factor for the development of microvascular disease affecting the kidney but not the retina.
Qiang, Zhiyi; Lee, Sun-Ok; Ye, Zhong; Wu, Xianai; Hendrich, Suzanne
A study was conducted in hamsters to determine if artichoke leaf extract (ALE) could lower plasma total and non-HDL cholesterol by increasing fecal excretion of neutral bile acids and sterols. Sixty-four Golden Syrian hamsters (8 week old) were fed control diet or a similar diet containing ALE (4.5 g/kg diet) for 6 weeks. No significant changes for total cholesterol, HDL, non-HDL cholesterol triglycerides or fecal neutral sterols and bile acids were found after 21 days for ALE-fed animals compared with controls. But after 42 days, ALE-fed male hamsters had significantly lower total cholesterol (15%), non-HDL cholesterol (30%) and triglycerides (22%) and female hamsters fed ALE showed reductions of 15% for total cholesterol, 29% for non-HDL cholesterol and 29% for triglycerides compared with controls. Total neutral sterol and bile acids concentrations increased significantly by 50% and 53% in fecal samples of ALE fed males, and 82.4% and 25% in ALE fed females compared with controls. The ALE lowered hamster plasma cholesterol levels by a mechanism involving the greater excretion of fecal bile acids and neutral sterols after feeding for 42 days. Copyright © 2011 John Wiley & Sons, Ltd.
Singer, P; Hoffmann, P; Beitz, J; Förster, W; Wirth, M; Gödicke, W
Spontaneously hypertensive rats (SHR) were fed diets enriched with evening primrose (EPO), sunflower (SO) and linseed oils (LO) as well as palm kernel fat (PKF), the latter being deficient in polyunsarated fatty acids (PUFA). In SHR fed EPO serum triglycerides were lowest and HDL1 cholesterol was highest as compared to the other groups of animals. Total cholesterol was not different. The data suggest that - as with blood pressure - serum lipids and lipoproteins might be influenced most effectively by EPO in comparison to other polyunsaturated fats.
Kuburovic, Vladimir; Vekic, Jelena; Zeljkovic, Aleksandra; Carrie, Alain; Kotur-Stevuljevic, Jelena; Bojanin, Dragana; Kosutic, Jovan; Spasojevic-Kalimanovska, Vesna; Miljkovic, Milica; Kuburovic, Nina; Couvert, Philippe
Plasma high-density lipoprotein cholesterol (HDL-C) level is a strong inverse predictor of cardiovascular disease (CVD) development. Tangier disease, a consequence of mutations in the ATP binding cassette transporter 1 (ABCA1) gene, is associated with very low HDL-C levels. Still, the relationship between Tangier disease and CVD is not always evident. The study investigates usefulness of lipoprotein subfractions, oxidative stress and paraoxonase 1 (PON1) status assessment for evaluation and management of patient with low HDL-C phenotype. A 12-year-old boy was hospitalised due to hypertension. Laboratory evaluation revealed low HDL-C level, and subsequent molecular diagnostic confirmed Tangier disease. Lipoprotein subfractions were assessed by gradient-gel electrophoresis. Oxidative stress status was estimated by measuring total antioxidative status, total oxidative status, prooxidative-antioxidative balance, malondialdehyde and advanced oxidation protein products levels. Activity of paraoxonase 1 in serum and its distribution within HDL subclasses was also determined (ten healthy boys aged 13.1±3.4years served as the reference group). Analysis of oxidative stress status biomarkers revealed a state of prolonged prooxidants activity. In turn, serum PON1 activity was substantially reduced. The majority of PON1 activity was present on HDL 2 particles. Impaired antioxidative potential of HDL may point toward hidden cardiovascular risk in isolated low HDL-phenotype. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Saleheen, Danish; Scott, Robert; Javad, Sundas; Zhao, Wei; Rodrigues, Amrith; Picataggi, Antonino; Lukmanova, Daniya; Mucksavage, Megan L; Luben, Robert; Billheimer, Jeffery; Kastelein, John J P; Boekholdt, S Matthijs; Khaw, Kay-Tee; Wareham, Nick; Rader, Daniel J
Although HDL cholesterol concentrations are strongly and inversely associated with risk of coronary heart disease, interventions that raise HDL cholesterol do not reduce risk of coronary heart disease. HDL cholesterol efflux capacity-a prototypical measure of HDL function-has been associated with coronary heart disease after adjusting for HDL cholesterol, but its effect on incident coronary heart disease risk is uncertain. We measured cholesterol efflux capacity and assessed its relation with vascular risk factors and incident coronary heart disease events in a nested case-control sample from the prospective EPIC-Norfolk study of 25 639 individuals aged 40-79 years, assessed in 1993-97 and followed up to 2009. We quantified cholesterol efflux capacity in 1745 patients with incident coronary heart disease and 1749 control participants free of any cardiovascular disorders by use of a validated ex-vivo radiotracer assay that involved incubation of cholesterol-labelled J774 macrophages with apoB-depleted serum from study participants. Cholesterol efflux capacity was positively correlated with HDL cholesterol concentration (r=0·40; p<0·0001) and apoA-I concentration (r=0·22; p<0·0001). It was also inversely correlated with type 2 diabetes (r=-0·18; p<0·0001) and positively correlated with alcohol consumption (r=0·12; p<0·0001). In analyses comparing the top and bottom tertiles, cholesterol efflux capacity was significantly and inversely associated with incident coronary heart disease events, independent of age, sex, diabetes, hypertension, smoking and alcohol use, waist:hip ratio, BMI, LDL cholesterol concentration, log-triglycerides, and HDL cholesterol or apoA-I concentrations (odds ratio 0·64, 95% CI 0·51-0·80). After a similar multivariable adjustment the risk of incident coronary heart disease was 0·80 (95% CI 0·70-0·90) for a per-SD change in cholesterol efflux capacity. HDL cholesterol efflux capacity might provide an alternative mechanism for
Tresaco, Beatriz; Moreno, Luis A; Ruiz, Jonatan R; Ortega, Francisco B; Bueno, Gloria; González-Gross, Marcela; Wärnberg, Julia; Gutiérrez, Angel; García-Fuentes, Miguel; Marcos, Ascensión; Castillo, Manuel J; Bueno, Manuel
We examined whether abdominal and truncal adiposity, assessed with simple anthropometric indices, determines serum triglycerides and high-density lipoprotein (HDL)-cholesterol levels independently of total adiposity amount in adolescents. A total of 547 Spanish adolescents (284 males and 263 females) aged 13-18.5 years were included in this study. Measures of truncal adiposity included subscapular to triceps ratio, and trunk-to-total skinfolds ratio (TTS%). Waist circumference was used as a surrogate of abdominal adiposity, and BMI was used as a measure of total adiposity. The results of the regression models indicated that levels of triglycerides were positively associated with waist circumference and TTS% after controlling for age and Tanner stage in both sexes. Once BMI was entered in the model, these associations remained significant for waist circumference in females. HDL-cholesterol levels were negatively associated with waist circumference in both sexes, and with subscapular to triceps ratio and TTS% in males, after controlling for age and Tanner stage. Once BMI was entered in the model, these associations remained significant for subscapular to triceps ratio and for TTS% in males. The results of this study suggest that in male adolescents, truncal adiposity is negatively associated with levels of HDL-cholesterol, whereas in females, abdominal adiposity is positively associated with levels of triglycerides independently of total adiposity. These findings highlight the deleterious effect of both truncal and abdominal fat depots on the lipid profile already from the first decades of life.
Lee, I Te; Wang, Chih-Yuan; Huang, Chien-Ning; Fu, Chen-Chung; Sheu, Wayne H H
Emerging evidence indicates that metabolic syndrome (MetS) predisposes diabetic subjects to nephropathy. Aside from hypertension and hyperglycemia, it is unclear which component of MetS also contributes to increased urinary albumin excretion (UAE). We compared the MetS profiles of subjects divided into two groups based on their UAE. The Asia Pacific Real-Life Effectiveness and Care Patterns of Diabetes Management (AP RECAP-DM) study is a cross-sectional survey in which type 2 diabetic subjects using oral anti-hyperglycemic drugs were enrolled. We analyzed the data of 162 type 2 diabetic subjects with normotension or taking antihypertensive medications. There were 123 subjects with normal UAE (<30 mg/g) and 39 with abnormal UAE (≥30 mg/g). MetS was more prevalent in the abnormal UAE group (79.5%) than in the normal UAE group (58.5%) (P=0.018). Hypertriglyceridemia (odds ratio=8.65, P<0.001) and reduced high-density lipoprotein (HDL) cholesterol (odds ratio=3.27, P=0.022) were both independently associated with abnormal UAE. Using 3.4 as a cut-off value, a high triglyceride-to-HDL cholesterol ratio was a useful marker (odds ratio=15.05, P<0.001) for abnormal UAE. A high triglyceride-to-HDL cholesterol ratio was found to be an important risk factor for nephropathy in type 2 diabetic subjects. Copyright © 2013 Elsevier Inc. All rights reserved.
Belalcazar, L Maria; Lang, Wei; Haffner, Steven M; Hoogeveen, Ron C; Pi-Sunyer, F Xavier; Schwenke, Dawn C; Balasubramanyam, Ashok; Tracy, Russell P; Kriska, Andrea P; Ballantyne, Christie M
Adipose tissue dysfunction plays a key role in the development of the metabolic abnormalities characteristic of type 2 diabetes (T2DM) and participates actively in lipid metabolism. Adiponectin, found abundantly in circulation and a marker of adipose health, is decreased in obese persons with T2DM. We investigated whether the changes in adiponectin with an intensive lifestyle intervention (ILI) for weight loss could potentially mediate the increase in low HDL-cholesterol (HDL-C) with ILI. Adiponectin and its fractions were determined using an ELISA with selective protease treatment in 1,397 participants from Look AHEAD, a trial examining whether ILI will reduce cardiovascular events in overweight/obese subjects with T2DM when compared with a control arm, diabetes support and education (DSE). Multivariable regression and mediational analyses were performed for adiponectin and its high-molecular-weight (HMW) and non-HMW fractions. ILI increased baseline HDL-C by 9.7% and adiponectin by 11.9%; changes with DSE were 1.3% and 0.2%, respectively (P < 0.0001). In a model including changes in weight, fitness, triglycerides, and glucose control and that adjusted for demographics and medical history, adiponectin changes remained significantly associated with HDL-C change. Data supported the contribution of changes in both HMW- and non-HMW-adiponectin to the improvement in HDL-C with ILI.
Rondanelli, Mariangela; Giacosa, Attilio; Morazzoni, Paolo; Guido, Davide; Grassi, Mario; Morandi, Gabriella; Bologna, Chiara; Riva, Antonella; Allegrini, Pietro; Perna, Simone
Background. High HDL-cholesterol (HDL-C) values are negatively correlated with cardiovascular diseases. This review analyses the effect of the supplementation with various Mediterranean diet products (artichoke, bergamot, and olive oil) and Asian diet products (red yeast rice) on the HDL-C value in dyslipidemic subjects. Methods. A systematic review has been done involving all the English written studies published from the 1st of January 1958 to the 31st of March 2016. Results. The results of this systematic review indicate that the dietary supplementation with red yeast rice, bergamot, artichoke, and virgin olive oil has promising effects on the increase of HDL-C serum levels. The artichoke leaf extract and virgin olive oil appear to be particularly interesting, while bergamot extract needs further research and the effect of red yeast rice seems to be limited to patients with previous myocardial infarction. Conclusions. Various MediterrAsian diet products or natural extracts may represent a potential intervention treatment to raise HDL-C in dyslipidemic subjects.
Sánchez Bayle, M; Fernández Ruiz, M L
The purpose of this study was to evaluate HDL-C values and their relationship to high total cholesterol values during childhood. We have studied 4,547 children and adolescents of both sexes between 4 and 6 years of age. We found HDL-C values > 50, 65 and 75 mg/dl in 66.28%, 26.17% and 7.81%, respectively. Of the cases studied, 44.8% had TC > 174.9 mg/dl and 15.17% higher than 199.9 mg/dl. The positive predictive value (PPV) to detect LDL-C > 129.9 mg/dl was 67.1 and 26.4 for values of TC > 199.9 and 174.9, respectively. The PPV to detect a LDL-C/HDL-C > 2.19 of the TC > 199.9 and 174.9 mg/dl was 54.78 and 23.95, respectively. The HDL-C of children and adolescents is often high and this could be responsible for the high TC values. Most of the children with TC values between 174.9 and 199.9 mg/dl have neither an increase in LDL-C nor in the LDL-C/HDL-C ratio.
Giacosa, Attilio; Morazzoni, Paolo; Guido, Davide; Grassi, Mario; Morandi, Gabriella; Bologna, Chiara; Allegrini, Pietro
Background. High HDL-cholesterol (HDL-C) values are negatively correlated with cardiovascular diseases. This review analyses the effect of the supplementation with various Mediterranean diet products (artichoke, bergamot, and olive oil) and Asian diet products (red yeast rice) on the HDL-C value in dyslipidemic subjects. Methods. A systematic review has been done involving all the English written studies published from the 1st of January 1958 to the 31st of March 2016. Results. The results of this systematic review indicate that the dietary supplementation with red yeast rice, bergamot, artichoke, and virgin olive oil has promising effects on the increase of HDL-C serum levels. The artichoke leaf extract and virgin olive oil appear to be particularly interesting, while bergamot extract needs further research and the effect of red yeast rice seems to be limited to patients with previous myocardial infarction. Conclusions. Various MediterrAsian diet products or natural extracts may represent a potential intervention treatment to raise HDL-C in dyslipidemic subjects. PMID:27882320
Ito, Kumie; Yoshida, Hiroshi; Yanai, Hidekatsu; Kurosawa, Hideo; Sato, Ryo; Manita, Daisuke; Hirowatari, Yuji; Tada, Norio
Cholesterol levels of non-high-density lipoprotein (non-HDL), which contains low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), very low-density lipoprotein (VLDL) and chylomicron (CM) remnant, have been proven to perform a significant predictor of coronary heart disease (CHD) better than LDL-cholesterol regardless of triglyceride (TG) levels. The present study investigated the relevance of TG-rich lipoproteins (IDL, VLDL, CM) to Framingham risk score (FRS) predictive of 10-year CHD risk. Lipoprotein profiles (cholesterol levels of HDL, LDL, IDL, VLDL, CM) in Japanese men (n = 487) who underwent medical check-up were determined by using our developed anion-exchange high performance liquid chromatography (AEX-HPLC). Total-cholesterol (TC), TG, fasting blood sugar (FBS) and hemoglobin (Hb) A1c were measured by routine methods. The lipoprotein profiles, non-HDL-cholesterol, TC, and TG were examined on these associations with FRS. The lipid levels except for CM-cholesterol were significantly different between two groups (low FRS, < 10%; high FRS, ≥10%) (P < 0.0001), and body mass index (BMI), TC, TG, IDL-, and VLDL-cholesterol were significantly and positively correlated with FRS. Among them, the significant association of non-HDL-cholesterol to FRS was noted (r = 0.411, P < 0.0001). Multiple stepwise regression analysis shows that, in addition to non-HDL-cholesterol, IDL-cholesterol in TG-rich lipoproteins was significantly correlated with FRS in independently of BMI. These correlation results were similarly found even when the part of the study subjects (n = 348) without the drug therapy for hyperlipidemia, diabetes, and hypertension was investigated. These results suggest that IDL-cholesterol may serve as a useful marker for CHD risk in Japanese men with increased non-HDL-cholesterol. © 2013.
Laguna, S; Andrada, P; Silva, C; Rotellar, F; Valenti, V; Gil, M J; Gómez-Ambrosi, J; Frühbeck, G; Salvador, J
Bariatric surgery has multiple beneficial effects on lipid profile in patients with morbid obesity. However, these changes can be attenuated by weight regain. This retrospective study was designed to assess the effects of gastric bypass(GBP) on different lipid fractions over a 6 year follow-up. We studied 177 patients (135 women)with morbid obesity (BMI 44.2+0.4 kg/m2) aged 42.4+0.9 years before and 3, 6, 9, 12, 24, 36, 48, 60 and 72 months after laparoscopic proximal GBP. Anthropometry, body composition measurement (Bod-Pod) and fasting blood samples were taken in all evaluations to measure total cholesterol (TC),LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides(TG), glucose and insulin. GPB was followed by a significant BMI reduction (nadir BMI at 18 m 28.3+0.4 kg/m2 p<0,001) and fat mass decrease(p<0,001). Maximal percentage of excess BMI lost was 84.1%and that of body fat was 87% 18 months after GBP. These numbers decreased to 65.6% and 38.3% (p<0,005 vs nadir) respectively 72 months after the operation, indicating both weight and fat mass regain. TG and LDL-C values decreased 30% with respect to preoperative levels, while HDL-C increased 97%over initial values. This HDL-C increase was progressive even over the weight regain phase. Both TC/HDL-C and TG/HDL-Cratios normalized after GBP and values were sustained over the weight regain period until the end of the study. These results confirm the beneficial effects of GBP on all lipid fractions, which are maintained over 6 years of follow-up. Globally, the rise in HDL-C seems to be independent of weight or fat mass changes, since it increases even over the weight regain phase, so contributing to a reduction in the prevalence of dyslipidaemia and to cardiovascular risk reduction.
Hojnacki, J.L.; Mulligan, J.J.; Cluette, J.E.; Kew, R.R.; Stack, D.J.; Huber, G.L.
Pigeons were assigned to four treatment groups: 1) Controls fed a chow diet ad libitum and retained in their cages; 2) Sham pigeons fed a cholesterol-saturated fat diet and exposed to fresh air by the Lorillard smoking machine; 3) Low nicotine-low carbon monoxide (LoLo) animals also fed the cholesterol diet and exposed to low concentrations of cigarette smoke; and 4) High nicotine-high carbon monoxide (HiHi) birds fed the cholesterol diet and subjected to high concentrations of inhalants. Plasma very low density (VLDL), low density (LDL), and high density (HDL) lipoproteins were isolated by density gradient ultracentrifugation. Smoke-related differences appeared in HiHi HDL which contained relatively more free and esterified cholesterol and total lipid, but less total protein than HDL from Sham-smoked pigeons. VLDL from birds exposed to cigarette smoke (LoLo and HiHi) contained relatively more total lipid, but less total protein than VLDL from Sham pigeons. Inhalation smoke produced a marked depression in the HDL2/HDL3 ratio resulting from an increased proportion of the HDL3 subfraction relative to HDL2. Pigeons fed the cholesterol-saturated fat diet circulated HDL with greater free and esterified cholesterol mass than Controls. Diet also altered the type of cholesteryl ester present in HDL with cholesteryl linoleate representing the predominant form in Control pigeons and cholesteryl oleate in cholesterol-fed birds. These results demonstrate that cigarette smoking can mediate alterations in lipoprotein composition independent of changes induced by dietary cholesterol and saturated fat.
Ikeda, Toru; Shinohata, Ryoko; Murakami, Masaaki; Hina, Kazuyoshi; Kamikawa, Shigeshi; Hirohata, Satoshi; Kusachi, Shozo; Tamura, Arisa; Usui, Shinichi
High-density lipoprotein (HDL) containing apolipoprotein E (apoE-rich HDL) represents only a small portion of plasma HDL. Reliable methods for determining and isolating apoE-rich HDL have not been well studied. We established a novel analytical method for apoE-rich HDL using polyethylene glycol and a cation-exchange column (PEG-column method). Furthermore, we examined biochemical correlates of apoE-rich HDL-cholesterol (HDL-C) in 36 patients who underwent coronary computed tomographic angiography. Our PEG-column method demonstrated high reproducibility (coefficient of variation <3.52%) and linearity up to 15mg/dl for apoE-rich HDL-C concentrations. Isolated apoE-rich HDL exhibited a larger diameter (14.8nm) than apoE-poor HDL (10.8nm) and contained both apoE and apoA-I. ApoE-rich HDL-C concentrations correlated significantly with triglycerides (rs=-0.646), LDL size (rs=0.472), adiponectin (rs=0.476), and other lipoprotein components. No significant correlation was obtained with the coronary calcium score. Multiple regression analysis revealed that plasma triglycerides and adiponectin concentrations remained significant independent predictors of apoE-rich (adjusted R(2)=0.486) but not apoE-poor HDL-C. The PEG-column method demonstrated, to various degrees, significant correlations between HDL subfractions and several lipid-related biomarkers involved in an atherogenic lipoprotein profile. Our separation technique for apoE-rich HDL is useful to clarify the role of apoE-rich HDL in atherosclerosis. Copyright © 2016 Elsevier B.V. All rights reserved.
Cao, Guoqing; Beyer, Thomas P.; Zhang, Youyan; Schmidt, Robert J.; Chen, Yan Q.; Cockerham, Sandra L.; Zimmerman, Karen M.; Karathanasis, Sotirios K.; Cannady, Ellen A.; Fields, Todd; Mantlo, Nathan B.
Cholesteryl ester transfer protein (CETP) catalyses the exchange of cholesteryl ester and triglyceride between HDL and apoB containing lipoprotein particles. The role of CETP in modulating plasma HDL cholesterol levels in humans is well established and there have been significant efforts to develop CETP inhibitors to increase HDL cholesterol for the treatment of coronary artery disease. These efforts, however, have been hampered by the fact that most CETP inhibitors either have low potency or have undesirable side effects. In this study, we describe a novel benzazepine compound evacetrapib (LY2484595), which is a potent and selective inhibitor of CETP both in vitro and in vivo. Evacetrapib inhibited human recombinant CETP protein (5.5 nM IC50) and CETP activity in human plasma (36 nM IC50) in vitro. In double transgenic mice expressing human CETP and apoAI, evacetrapib exhibited an ex vivo CETP inhibition ED50 of less than 5 mg/kg at 8 h post oral dose and significantly elevated HDL cholesterol. Importantly, no blood pressure elevation was observed in rats dosed with evacetrapib at high exposure multiples compared with the positive control, torcetrapib. In addition, in a human adrenal cortical carcinoma cell line (H295R cells), evacetrapib did not induce aldosterone or cortisol biosynthesis whereas torcetrapib dramatically induced aldosterone and cortisol biosynthesis. Our data indicate that evacetrapib is a potent and selective CETP inhibitor without torcetrapib-like off-target liabilities. Evacetrapib is currently in phase II clinical development. PMID:21957197
Gil, V F; Buhígues, F; Pedrera, V; Medina, E; Tevar, A; Quirce, F; Orozco, D; Merino, J
To validate to what extent the isolated determination of total Cholesterol (TC) is effective when seeking to predict coronary risk. An observational crossover study of the analytic determinations of the clinics which systematically request TC and HDL-Cholesterol (HDL)--case-finding method. Health Centre. 631 analytic determinations, with samples from people who attended a Health Centre between May and November 1992, were studied. As proof of certainty the Atherogenic Index (AI) was used for the relative risks (RR) of suffering a coronary event in line with the Framingham study. The confidence limits (CL) were calculated to 95% in order to quantify random error and permit comparison. On varying the cut-off points of TC the indicators changed, being more sensitive (S) and less specific (E) with the lower figures: 180 mg/dl, RR > 1, S = 97.5% (CL: 100-94.7) and E = 30.5% (36.8-24.2); RR > 2, S = 100%, E = 22.1% (26.9-17.3) and RR > 3, S = 100%, E = 20.8% (25.3-16.3). As values of TC increase, S diminishes and E increases: 250 mg/dl, RR > 1, S = 48.3% (57.2-39.4), E = 87.2% (91.8-82.6); RR > 2, S = 58.6% (76.5-40.7), E = 77.2% (82-72.4) and RR > 3, S = 63.6% (92-35.2), E = 75.3% (80.1-70.5). HDL must be determined if TC is -200 mg/dl. If everyone with RR > 2 is to be detected, HDL-cholesterol from TC > or = 180 mg/dl must be measured.
Alphonse, Peter A S; Ramprasath, Vanu; Jones, Peter J H
Dietary cholesterol and plant sterols differentially modulate cholesterol kinetics and circulating cholesterol. Understanding how healthy individuals with their inherent variabilities in cholesterol trafficking respond to such dietary sterols will aid in improving strategies for effective cholesterol lowering and alleviation of CVD risk. The objectives of this study were to assess plasma lipid responsiveness to dietary cholesterol v. plant sterol consumption, and to determine the response in rates of cholesterol absorption and synthesis to each sterol using stable isotope approaches in healthy individuals. A randomised, double-blinded, crossover, placebo-controlled clinical trial (n 49) with three treatment phases of 4-week duration were conducted in a Manitoba Hutterite population. During each phase, participants consumed one of the three treatments as a milkshake containing 600 mg/d dietary cholesterol, 2 g/d plant sterols or a control after breakfast meal. Plasma lipid profile was determined and cholesterol absorption and synthesis were measured by oral administration of [3, 4-13C] cholesterol and 2H-labelled water, respectively. Dietary cholesterol consumption increased total (0·16 (sem 0·06) mmol/l, P=0·0179) and HDL-cholesterol (0·08 (sem 0·03) mmol/l, P=0·0216) concentrations with no changes in cholesterol absorption or synthesis. Plant sterol consumption failed to reduce LDL-cholesterol concentrations despite showing a reduction (6 %, P=0·0004) in cholesterol absorption. An over-compensatory reciprocal increase in cholesterol synthesis (36 %, P=0·0026) corresponding to a small reduction in absorption was observed with plant sterol consumption, possibly resulting in reduced LDL-cholesterol lowering efficacy of plant sterols. These data suggest that inter-individual variability in cholesterol trafficking mechanisms may profoundly impact plasma lipid responses to dietary sterols in healthy individuals.
de Aguiar Vallim, Thomas Q.; Tarling, Elizabeth J.; Kim, Tammy; Civelek, Mete; Baldán, Ángel; Esau, Christine; Edwards, Peter A.
Rationale The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3′ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL-cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL-cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusion We have identified a novel pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. PMID:23519696
Khalil, H; Murrin, C; O'Reilly, M; Viljoen, K; Segurado, R; O'Brien, J; Somerville, R; McGillicuddy, F; Kelleher, C C
High-density lipoprotein (HDL) cholesterol efflux capacity in adults may be a measure of the atheroprotective property of HDL. Little however, is known about HDL cholesterol efflux capacity in childhood. We aimed to investigate the relationship between HDL cholesterol efflux capacity and childhood anthropometrics in a longitudinal study. Seventy-five children (mean age = 9.4 ± 0.4 years) were followed from birth until the age of 9 years. HDL cholesterol efflux capacity was determined at age 9 by incubating serum-derived HDL-supernatants with (3)H-cholesterol labeled J774 macrophages and percentage efflux determined. Mothers provided dietary information by completing food frequency questionnaires in early pregnancy and then 5 years later on behalf of themselves and their children. Pearson's correlations and multiple regression analyses were conducted to confirm independent associations with HDL efflux. There was a negative correlation between HDL cholesterol efflux capacity and waist circumference at age 5 (r = -0.3, p = 0.01) and age 9 (r = -0.24, p = 0.04) and BMI at age 5 (r = -0.45, p = 0.01) and age 9 (r = -0.19, p = 0.1). Multiple regression analysis showed that BMI at age 5 remained significantly associated with reduced HDL cholesterol efflux capacity (r = -0.45, p < 0.001). HDL-C was negatively correlated with energy-adjusted fat intake (r = -0.24, p = 0.04) and positively correlated with energy-adjusted protein (r = 0.24, p = 0.04) and starch (r = 0.29, p = 0.01) intakes during pregnancy. HDL-C was not significantly correlated with children dietary intake at age 5. There were no significant correlations between maternal or children dietary intake and HDL cholesterol efflux capacity. This novel analysis shows that efflux capacity is negatively associated with adiposity in early childhood independent of HDL-C. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the
Jové, Mariona; Naudí, Alba; Portero-Otin, Manuel; Cabré, Rosanna; Rovira-Llopis, Susana; Bañuls, Celia; Rocha, Milagros; Hernández-Mijares, Antonio; Victor, Victor M; Pamplona, Reinald
Lipidomics reveals a remarkable diversity of lipids in human plasma. In this study, we have performed an in-depth lipidomic analysis of human plasma from healthy individuals and subjects with metabolic syndrome (MetS) in order to determine the lipidomic profile that allows prognosis of a pathological subpopulation with altered high-density lipoprotein (HDL) metabolism. The MetS population was categorized as having pathological or nonpathological HDL. Anthropometric parameters, cardiovascular risk markers, and lipoprotein subclasses of HDL and low-density lipoproteins were also evaluated. Lipidomic analysis revealed 357 differential molecules that were clustered (k means) in the two groups. The molecules identified in the whole lipidome showed that MetS subjects presented lower levels of glycerolipids and higher levels of glycerophospholipids with respect to control subjects. In contrast, when only statistically differential lipids were taken into account, differences were found between the two groups in almost cases. Furthermore, levels of saturated fatty acids were higher in patients with pathological HDL levels than in controls, whereas levels of unsaturated fatty acids were lower. These results highlight the potential of lipidomics as a clinical tool for risk assessment and monitoring of disease.
Boden, William E; Probstfield, Jeffrey L; Anderson, Todd; Chaitman, Bernard R; Desvignes-Nickens, Patrice; Koprowicz, Kent; McBride, Ruth; Teo, Koon; Weintraub, William
In patients with established cardiovascular disease, residual cardiovascular risk persists despite the achievement of target low-density lipoprotein (LDL) cholesterol levels with statin therapy. It is unclear whether extended-release niacin added to simvastatin to raise low levels of high-density lipoprotein (HDL) cholesterol is superior to simvastatin alone in reducing such residual risk. We randomly assigned eligible patients to receive extended-release niacin, 1500 to 2000 mg per day, or matching placebo. All patients received simvastatin, 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL cholesterol level of 40 to 80 mg per deciliter (1.03 to 2.07 mmol per liter). The primary end point was the first event of the composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. A total of 3414 patients were randomly assigned to receive niacin (1718) or placebo (1696). The trial was stopped after a mean follow-up period of 3 years owing to a lack of efficacy. At 2 years, niacin therapy had significantly increased the median HDL cholesterol level from 35 mg per deciliter (0.91 mmol per liter) to 42 mg per deciliter (1.08 mmol per liter), lowered the triglyceride level from 164 mg per deciliter (1.85 mmol per liter) to 122 mg per deciliter (1.38 mmol per liter), and lowered the LDL cholesterol level from 74 mg per deciliter (1.91 mmol per liter) to 62 mg per deciliter (1.60 mmol per liter). The primary end point occurred in 282 patients in the niacin group (16.4%) and in 274 patients in the placebo group (16.2%) (hazard ratio, 1.02; 95% confidence interval, 0.87 to 1.21; P=0.79 by the log-rank test). Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of less than 70 mg per deciliter (1.81 mmol per liter), there was no incremental clinical benefit from the addition
Baruch, Lawrence; Chiong, Valerie J; Agarwal, Sanjay; Gupta, Bhanu
Objective. To determine if non-HDL cholesterol (N-HDL) and directly measured LDL cholesterol (D-LDL) are clinically equivalent measurements. Patients and Methods. Eighty-one subjects recruited for 2 cholesterol treatment studies had at least 1 complete fasting lipid panel and D-LDL performed simultaneously; 64 had a second assessment after 4 to 6 weeks, resulting in 145 triads of C-LDL, D-LDL, and N-HDL. To directly compare N-HDL to D-LDL and C-LDL, we normalized the N-HDL by subtracting 30 from the N-HDL (N-HDLA). Results. There was significant correlation between N-HDLA, D-LDL, and C-LDL. Correlation was significantly greater between N-HDLA and C-LDL than between N-HDLA and D-LDL. A greater than 20 mg/dL difference between measures was observed more commonly between N-HDLA and D-LDL, 29%, than between C-LDL and N-HDLA, 11% (P < 0.001), and C-LDL and D-LDL, 17% (P = 0.028). Clinical discordance was most common, and concordance was least common between N-HDL and D-LDL. Conclusions. Our findings suggest that N-HDL cholesterol and D-LDL cholesterol are not clinically equivalent and frequently discordant. As N-HDL may be superior to even C-LDL for predicting events in statin-treated patients, utilizing N-HDL to guide therapy would appear to be preferable to D-LDL when C-LDL is inaccurate.
Chiong, Valerie J.
Objective. To determine if non-HDL cholesterol (N-HDL) and directly measured LDL cholesterol (D-LDL) are clinically equivalent measurements. Patients and Methods. Eighty-one subjects recruited for 2 cholesterol treatment studies had at least 1 complete fasting lipid panel and D-LDL performed simultaneously; 64 had a second assessment after 4 to 6 weeks, resulting in 145 triads of C-LDL, D-LDL, and N-HDL. To directly compare N-HDL to D-LDL and C-LDL, we normalized the N-HDL by subtracting 30 from the N-HDL (N-HDLA). Results. There was significant correlation between N-HDLA, D-LDL, and C-LDL. Correlation was significantly greater between N-HDLA and C-LDL than between N-HDLA and D-LDL. A greater than 20 mg/dL difference between measures was observed more commonly between N-HDLA and D-LDL, 29%, than between C-LDL and N-HDLA, 11% (P < 0.001), and C-LDL and D-LDL, 17% (P = 0.028). Clinical discordance was most common, and concordance was least common between N-HDL and D-LDL. Conclusions. Our findings suggest that N-HDL cholesterol and D-LDL cholesterol are not clinically equivalent and frequently discordant. As N-HDL may be superior to even C-LDL for predicting events in statin-treated patients, utilizing N-HDL to guide therapy would appear to be preferable to D-LDL when C-LDL is inaccurate. PMID:23710352
Gillard, Baiba K.; Rosales, Corina; Pillai, Biju K.; Lin, Hu Yu; Courtney, Harry S.; Pownall, Henry J.
Serum opacity factor (SOF), a virulence determinant of Streptococcus pyogenes, converts plasma high density lipoproteins (HDL) to three distinct species: lipid-free apolipoprotein (apo) A-I, neo HDL, a small discoidal HDL-like particle, and a large cholesteryl ester-rich microemulsion (CERM), that contains the cholesterol esters (CE) of up to ~400,000 HDL particles and apo E as its major protein. Similar SOF reaction products are obtained with HDL, total plasma lipoproteins and whole plasma. We hypothesized that hepatic uptake of CERM-CE via multiple apo E dependent receptors would be faster than that of HDL-CE. We tested our hypothesis using human hepatoma cells and lipoprotein receptor-specific Chinese hamster ovary (CHO) cells. [3H]CE uptake by HepG2 and Huh7 cells from HDL after SOF treatment, which transfers >90% of HDL-CE to CERM, was respectively 2.4 and 4.5 times faster than from control HDL. CERM-[3H]CE uptake was inhibited by LDL and HDL, suggestive of uptake by both the LDL receptor (LDL-R) and scavenger receptor class B type I (SR-BI). Studies in CHO cells specifically expressing LDL-R and SR-BI confirmed CERM-[3H]CE uptake by both receptors. RAP and heparin inhibit CERM-[3H]CE but not HDL-[3H]CE uptake thereby implicating LRP-1 and cell surface proteoglycans in this process. These data demonstrate that SOF treatment of HDL increases CE uptake via multiple hepatic apo E receptors. In so doing, SOF might increase hepatic disposal of plasma cholesterol in a way that is therapeutically useful. PMID:20879789
Early work suggested that dietary cholesterol increased plasma total cholesterol concentrations in humans. Given the relationship between elevated plasma cholesterol concentrations and cardiovascular disease risk, dietary guidelines have consistently recommended limiting food sources of cholesterol....
Lai, Cheng-Tsung; Sun, Wangqiang; Palekar, Rohun U; Thaxton, C Shad; Schatz, George C
High-density lipoprotein (HDL) plays an important role in the transport and metabolism of cholesterol. Mimics of HDL are being explored as potentially powerful therapeutic agents for removing excess cholesterol from arterial plaques. Gold nanoparticles (AuNPs) functionalized with apolipoprotein A-I and with the lipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate] have been demonstrated to be robust acceptors of cellular cholesterol. However, detailed structural information about this functionalized HDL AuNP is still lacking. In this study, we have used X-ray photoelectron spectroscopy and lecithin/cholesterol acyltransferase activation experiments together with coarse-grained and all-atom molecular dynamics simulations to model the structure and cholesterol uptake properties of the HDL AuNP construct. By simulating different apolipoprotein-loaded AuNPs, we find that lipids are oriented differently in regions with and without apoA-I. We also show that in this functionalized HDL AuNP, the distribution of cholesteryl ester maintains a reverse concentration gradient that is similar to the gradient found in native HDL.
Heemskerk, Mattijs M.; Pieterman, Elsbet J.; van Klinken, Jan B.; van den Berg, Sjoerd A. A.; Smit, Johannes W. A.; Havekes, Louis M.; Rensen, Patrick C. N.; van der Hoorn, José W. A.; Princen, Hans M. G.; Jukema, J. Wouter
Objective Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD). Approach and Results Mice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by −50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (−30%; −55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (−36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (−46%; −47%, P<0.01; −53%, P<0.001), atherosclerotic lesion area (−78%; −49%, P<0.01; −87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (−71%, P<0.01; −81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R2 = 0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R2 = 0.20, P<0.001). Conclusion Niacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol
Laverdy, O G; Hueb, W A; Sprandel, M C O; Kalil-Filho, R; Maranhão, R C
Investigate the relations of glycemic levels with plasma lipids and in vitro lipid transfers to HDL in patients with type 2 diabetes mellitus. 143 patients with type 2 diabetes not taking anti-lipidemic drugs were separated into 2 groups: group A included 62 patients with glycated hemoglobin (HbA₁c)≤6.5% (48 mmol/mol) and group B 81 patients with HbA₁c>6.5%. In vitro transfer of lipids was determined by 1 h incubation of a donor nanoemulsion containing radioactively labeled unesterified and esterified cholesterol, phospholipids and triglycerides with whole plasma followed by chemical precipitation and radioactive counting in the supernatant (HDL). LDL and HDL cholesterol were similar in Group A and B, but group B had higher triglycerides (2.31±1.30 vs. 1.58±0.61 mmol/l, P<0.0001) and total and non-HDL unesterified cholesterol (36.3±7.8 vs. 33.9±5.9 mmol/l, P<0,05; 30.6±7.9 vs. 27.6±6.2 mmol/l, P<0,05; respectively) than group A and a non-significant trend to increased apolipoprotein B (103±20 vs. 97±20 mg/dl, P=0.08). 36 patients with the highest, ≥8.0% (64 mmol/mol), HbA₁c also showed non-significant trend of elevated non-esterified fatty acids (NEFA) compared to 37 with lowest, ≤6.0% (42 mmol/mol), HbA₁c (P=0.08). Patients with higher NEFA had higher triglycerides than those with lower NEFA levels (P<0.01).Transfers of all lipids from nanoemulsion to HDL and lipid composition of HDL were equal in both groups. For the first time it was shown that in addition to triglycerides, unesterified cholesterol is also a marker of poor glycemic control. In vitro HDL lipid transfers, an important aspect of HDL metabolism, were not related with the glycemic control. © Georg Thieme Verlag KG Stuttgart · New York.
Lee-Rueckert, Miriam; Escola-Gil, Joan Carles; Kovanen, Petri T
Whereas LDL-derived cholesterol accumulates in atherosclerotic lesions, HDL particles are thought to facilitate removal of cholesterol from the lesions back to the liver thereby promoting its fecal excretion from the body. Because generation of cholesterol-loaded macrophages is inherent to atherogenesis, studies on the mechanisms stimulating the release of cholesterol from these cells and its ultimate excretion into feces are crucial to learn how to prevent lesion development or even induce lesion regression. Modulation of this key anti-atherogenic pathway, known as the macrophage-specific reverse cholesterol transport, has been extensively studied in several mouse models with the ultimate aim of applying the emerging knowledge to humans. The present review provides a detailed comparison and critical analysis of the various steps of reverse cholesterol transport in mouse and man. We attempt to translate this in vivo complex scenario into practical concepts, which could serve as valuable tools when developing novel HDL-targeted therapies.
Bridges, Kristie Grove; Jarrett, Traci; Thorpe, Anthony; Baus, Adam; Cochran, Jill
Studies have suggested that triglyceride to HDL-cholesterol ratio (TRG/HDL) is a surrogate marker of insulin resistance (IR), but information regarding its use in pediatric patients is limited. This study investigated the ability of TRG/HDL ratio to assess IR in obese and overweight children. The sample consisted of de-identified electronic medical records of patients aged 10-17 years (n=223). Logistic regression was performed using TRG/HDL ratio as a predictor of hyperinsulinemia or IR defined using homeostasis model assessment score. TRG/HDL ratio had limited ability to predict hyperinsulinemia (AUROC 0.71) or IR (AUROC 0.72). Although females had higher insulin levels, male patients were significantly more likely to have hypertriglyceridemia and impaired fasting glucose. TRG/HDL ratio was not adequate for predicting IR in this population. Gender differences in the development of obesity-related metabolic abnormalities may impact the choice of screening studies in pediatric patients.
Fadini, Gian Paolo; Bonora, Benedetta Maria; Zatti, Giancarlo; Vitturi, Nicola; Iori, Elisabetta; Marescotti, Maria Cristina; Albiero, Mattia; Avogaro, Angelo
Sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce glucose levels, body weight, and blood pressure, possibly resulting in cardiovascular protection. In phase III trials, SGLT2i were shown to increase HDL cholesterol. We aimed to evaluate whether the SGLT2i dapagliflozin affects HDL function in a randomized placebo-controlled trial. Thirty-three type 2 diabetic patients were randomized to receive dapagliflozin 10 mg or placebo for 12 weeks on top of their glucose lowering medications. The primary end-point was the change in cholesterol efflux capacity (CEC) from macrophages at study end versus baseline. Secondary endpoints were changes in: distribution of HDL subfractions, lipid profile, activity of enzymes that mediate HDL antioxidant properties (PON1 and ARE) and cholesterol metabolism (CETP), HbA1c, body weight and composition. Thirty-one patients completed the study, n = 16 in the placebo group and n = 15 in the dapagliflozin group. Patients randomized to dapagliflozin were older and had lower adiposity indexes, although these differences disappeared after correction for multiple testing. Therapy with dapagliflozin reduced HbA1c by 0.9% and body weight by 3.1 kg, mainly attributable to reduction of body water and lean mass. As compared to placebo, dapagliflozin reduced CEC (-6.7 ± 2.4 versus 0.3 ± 1.8%; p = 0.043), but this effect was no longer significant after adjusting for age and BMI. No change was detected in HDL cholesterol, HDL subfractions, activity of PON1, ARE, and CETP. Despite improvements in glucose control and reduction in body weight, therapy with dapagliflozin exerted no significant effect on HDL cholesterol levels and HDL functionality. Trial registration EudraCT 2014-004270-42; NCT02327039.
Brown, Michael S.; Kovanen, Petri T.; Goldstein, Joseph L.
The lipoprotein transport system holds the key to understanding the mechanisms by which genes, diet, and hormones interact to regulate the plasma cholesterol level in man. Crucial components of this system are lipoprotein receptors in the liver and extrahepatic tissues that mediate the uptake and degradation of cholesterol-carrying lipoproteins. The number of lipoprotein receptors, and hence the efficiency of disposal of plasma cholesterol, can be increased by cholesterol-lowering drugs. Regulation of lipoprotein receptors can be exploited pharmacologically in the therapy of hypercholesterolemia and atherosclerosis in man.
Kowalski, Jan; Jędrzejczyk, Jacek Tadeusz; Barylski, Marcin; Ciećwierz, Julita; Sienkiewicz, Monika; Kowalczyk, Edward
Pulmonary embolism (PE) usually is a clinical manifestation of venous thromboembolism. The lack of simple and safe laboratory test to confirm or exclude PE is a problem that slows down the diagnosis. The aim of the study was the assessment the usefulness of D-dimer and HDL cholesterol concentration in predicting the occurrence of acute pulmonary embolism. The study group comprised 86 patients. High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured by catalase HDL-C and LDLC assay. The D-dimer level was assessed using immunoenzymatic method with high sensitivity test (VIDAS D-Dimer Exclusion). Pulmonary embolism was diagnosed using contrast-enhanced multidetector computer tomography (16-row GE Light Speed Pro and 64-row Toshiba Aquilion Systems). In all patients with PE, higher D-dimer concentration was found. Odds ratio (OR) calculated for the D-dimer indicates that the concentration of D-dimer ≥859,5 ng/ml increases the risk of PE 612 times, compared with those with levels below 859,5 ng/ml. HDL cholesterol level in patients with PE was significantly lower compared with the control group (p < 0,05). Odds ratio (OR) calculated for the HDL cholesterol indicates that the risk of PE in subjects with the concentration of HDL-C ≤44 mg/dl is 26,89 times higher, compared with individuals with HDL-C >44 mg/dl. According the studies, increase D-dimer and decrease HDL levels are an independent risk factors for occurrence of acute pulmonary embolism. © 2016 MEDPRESS.
Rizzo, Manfredi; Corrado, Egle; Coppola, Giuseppe; Muratori, Ida; Novo, Giuseppina; Novo, Salvatore
Low HDL-cholesterol concentrations are associated with increased cardiovascular risk and recent evidences suggest that HDL may aggravate the atherosclerotic process promoting inflammation: HDL are anti-inflammatory in the absence of inflammation but can become proinflammatory in the presence of atherosclerosis. Yet, no data is available on the cardiovascular outcome in subjects with low HDL-cholesterol and early stages of atherosclerosis. Therefore, we included in a prospective 5-year follow-up study 150 subjects with low HDL-cholesterol concentrations and subclinical carotid atherosclerosis, as assessed by carotid colour doppler, evaluating at baseline all the established traditional cardiovascular risk factors (e.g. male gender, older age, obesity, hypertension, diabetes, smoking, family history of coronary artery disease, hypercholesterolemia), as well as levels of two markers of inflammation (C-reactive protein and fibrinogen). At the end of the follow-up we registered vascular events in the 21% of patients and we found that lower HDL-cholesterol concentrations were associated with ischemic stroke (p=.0164), peripheral arterial disease (p=.0248) and the presence of any clinical event (p=.0105). By multivariate analysis we searched, among all baseline parameters, for independent variables associated with the events and we found a predictive role for elevated fibrinogen concentrations (OR 6.3, 95% CI 2.0-19.6, p=.0016), family history of coronary artery disease (OR 4.5, 95% CI 1.7-12.8, p=.0045) and lower HDL-cholesterol levels (OR 1.4, 95% CI 1.1-1.9, p=.0278). These findings further suggest a synergistic role of low-HDL and inflammation on the atherosclerotic disease progression from subclinical lesions to clinical events. Yet, their therapeutical implications remain to be established in future studies.
Carvalho, R. Piccolotto; Lemos, J.R. Gonzaga; de Aquino Sales, R. Souza; Martins, M. Gassen; Nascimento, C.H.; Bayona, M.; Marcon, J.L.; Monteiro, J. Barros
Introduction The lactating and post-lactating periods are marked by large metabolic change. Production of milk is 60% lipid dependent. We reported in a recent scientific meeting that Red pupunha palm tree fruit increases HDL cholesterol in lactating rats. This study evaluated if consumption of Red Pupunha by adult female rats has a beneficial impact on the lipid metabolism of lacting and post-lacting adult rats. Objective Evaluate if consumption of red pupunha has a beneficial effect in the lipid metabolism of lacting and post-lacting adult Wistar rats. Research Methods Four groups including two for control; (1) control adult lactating rats, (2) control adults post-lactating rats; and two experimental groups; (3) pupunha adults lactating rats and (4) pupunha adult post-lactating rats were evaluated and compared regarding: weight gain, food consumption, plasma total protein, glucose, total lipid, triglycerides, total cholesterol and HDL-cholesterol levels. The mean difference and its 95% confidence intervals were used for group comparisons. Group comparisons were evaluated by using analysis of variance (one-way ANOVA). The statistical significance of the pairwise differences among groups was assessed by using the two-sided Tukey test. Results There were no important differences in food consumption, plasma glucose, total lipids and triglycerides among groups. The red pupunha lactating group gain less weight showing lower body mass index (BMI) than controls (p < 0.05). Total cholesterol was lower in red pupunha lactating than in controls but not in the red pupunha post-lactating group as compared to controls. Triglycerides were lower in the post-lactating red pupunha group as compared to the control group (p = 0.039) but not for the lactating groups. Red pupunha lactating and post-lactating groups had higher HDL-cholesterol than their corresponding control groups (p ≤ 0.01). Conclusion Original findings include the beneficial effect of red pupunha in post
Perségol, Laurence; Duvillard, Laurence; Monier, Serge; Brindisi, Marie-Claude; Bouillet, Benjamin; Petit, Jean-Michel; Vergès, Bruno
High-density lipoproteins (HDLs) from type 2 diabetic patients are unable to counteract the inhibitory effect of oxidized low-density lipoproteins (ox-LDLs) on vasorelaxation. We hypothesized that glitazones, which improve glycemic control and dyslipidemia, could correct this abnormality. We compared the ability of HDL from controls (n = 12) and from type 2 diabetic patients before and after 6 months of treatment with either rosiglitazone (n = 11) or pioglitazone (n = 8) to counteract the inhibitory effect of ox-LDL on vasodilatation of rabbit aorta rings. Rosiglitazone induced a decrease in hemoglobin A1c (7.7% ± 1.1% vs 9.8% ± 1.0%, P = .003) and an increase in HDL cholesterol (1.14 ± 0.32 vs 0.98 ± 0.24 mmol/L, P = .033). Pioglitazone induced a decrease in hemoglobin A1c (8.3% ± 2.5% vs 9.5% ± 3.2%, P = .068) and serum triglycerides (1.58 ± 0.89 vs 2.03 ± 0.70 mmol/L, P = .069) and an increase in HDL cholesterol (1.39 ± 0.22 vs 1.14 ± 0.22 mmol/L, P = .018). The triglyceride content of HDL was unchanged by rosiglitazone and was decreased by 25% (P = .068) by pioglitazone. HDL from controls counteracted the inhibitory effect of ox-LDL on vasodilatation (maximal relaxation [Emax] = 74.4% ± 3.5% vs 51.9% ± 3.3%, P = .0029), whereas HDL from type 2 diabetic patients did not (Emax = 51.7% ± 5.8% vs 52.3% ± 4.6% [P = .66] and 52.7% ± 5.5% vs 51.9% ± 4.5% [P = .78] for the rosiglitazone and pioglitazone group, respectively). Rosiglitazone or pioglitazone did not improve Emax (58.6% ± 5.9% vs 52.3% ± 4.6% [P = .15] and 49.3% ± 6.5% vs 51.9% ± 4.5% [P = .48], respectively). Glitazones increased the concentration of HDL cholesterol without restoring the ability of HDL particles to protect the endothelium from oxidative stress-induced dysfunction, meaning that HDL remained dysfunctional with impaired antiatherogenic properties.
Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women.
Lamon-Fava, Stefania; Asztalos, Bela F; Howard, Timothy D; Reboussin, David M; Horvath, Katalin V; Schaefer, Ernst J; Herrington, David M
A high degree of inter-individual variability in plasma lipid level response to hormone therapy (HT) has been reported. Variations in the oestrogen receptor alpha gene (ESR1) and in genes involved in lipid metabolism may explain some of the variability in response to HT. Subjects Postmenopausal Caucasian women (n = 208) participating in a placebo-controlled randomized trial of 3.2 years of hormone therapy (HT). Plasma triglyceride (TG), remnant lipoprotein cholesterol (RLP-C), and high-density lipoprotein cholesterol (HDL-C) levels and HDL subpopulations were assessed at baseline and at follow up. Single nucleotide polymorphisms (SNPs) in ESR1 and in the ATP binding cassette A1 (ABCA1), cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), and scavenger receptor class B type I (SRB1) genes were assessed for their association with baseline plasma levels and HT-related changes in levels of RLP-C and HDL subpopulations. Carriers of the ESR1 PvuII or IVS1-1505 variants had lower plasma TG concentrations and higher plasma HDL-C and alpha-1 and prealpha-1 HDL particle levels at baseline and showed greater increases in HDL-C, apo A-I and alpha-1 particle levels after HT than wild-type carriers. Carriers of the N291S and D9N variants in the LPL gene had significantly higher remnant lipoproteins and lower alpha-2 HDL particle levels at baseline. The CETP TaqIB SNP was a significant determinant of baseline plasma HDL-C and HDL subpopulation profile. Single nucleotide polymorphisms in ESR1, CETP and LPL had significant effects on baseline plasma levels of TG-rich and HDL subpopulations. With the exception of ESR1 SNPs, variation in genes involved in lipid metabolism has a very modest effect on lipoprotein response to HT.
Pirillo, Angela; Catapano, Alberico L
Low high density lipoprotein cholesterol (HDL-C) levels represent an independent risk factor for cardiovascular disease; in addition to the reduced HDL-C levels commonly observed in patients at cardiovascular risk, the presence of dysfunctional HDL, i.e. HDL with reduced atheroprotective properties, has been reported. Despite the established inverse correlation between HDL-C levels and cardiovascular risk, several clinical trials with HDL-C-increasing drugs (such as niacin, CETP inhibitors or fibrate) failed to demonstrate that a significant rise in HDL-C levels translate into a cardiovascular benefit. Statins, that are the most used lipid-lowering drugs, can also increase HDL-C levels, although this effect is highly variable among studies and statins; the most recent developed statin, pitavastatin, beside its role as LDL-C-lowering agent, increases HDL-C levels at a significantly higher extent and progressively upon treatment; such increase was observed also when patients where shifted from another statin to pitavastatin. The stratification by baseline HDL-C levels revealed that only pitavastatin significantly increased HDL-C levels in patients with baseline HDL-C ≤45 mg/dl, while no changes were observed in patients with higher baseline HDL-C levels. In the last years the hypothesis that functional properties of HDL may be more relevant than HDL-C levels has risen from several observations. The treatment with pitavastatin not only increased HDL-C levels, but also increased the phospholipid content of HDL, increased the HDL efflux capacity and their anti-oxidant properties. These observations suggest that, besides its high LDL-C-lowering effect, pitavastatin also exhibits a significantly higher ability to increase HDL-C levels and may also positively affect the quality and functionality of HDL particles. Copyright © 2017 Elsevier B.V. All rights reserved.
Garg, Manohar L; Blake, Robert J; Wills, Ron B H
This study was conducted to assess the cholesterol-lowering potential of macadamia nuts. Seventeen hypercholesterolemic men (mean age 54 y) were given macadamia nuts (40-90 g/d), equivalent to 15% energy intake, for 4 wk. Plasma total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and homocysteine concentrations and the fatty acid composition of plasma lipids were determined before and after treatment. Plasma MUFA 16:1(n-7), 18:1(n-7) and 20:1(n-9) were elevated after intervention with macadamia nuts. Plasma (n-6) and (n-3) PUFA concentrations were unaffected by macadamia nut consumption. Plasma total cholesterol and LDL cholesterol concentrations decreased by 3.0 and 5.3%, respectively, and HDL cholesterol levels increased by 7.9% in hypercholesterolemic men after macadamia nut consumption. Plasma triglyceride and homocysteine concentrations were not affected by treatment. Macadamia nut consumption was associated with a significant increase in the relative intake of MUFA and a reduced relative intake of saturated fatty acids and PUFA. This study demonstrates that macadamia nut consumption as part of a healthy diet favorably modifies the plasma lipid profile in hypercholesterolemic men despite their diet being high in fat.
Cea-Calvo, L; Lozano, J V; Fernández-Pérez, C; Llisterri, J L; Martí-Canales, J C; Aznar, J; Gil-Guillén, V; Redón, J
To assess the prevalence of low serum high-density lipoprotein cholesterol (HDL-C) concentration and the relationship between HDL-C and established cardiovascular disease (CVD) in an elderly Mediterranean population. Analysis of Prevención del Riesgo de Ictus, a population-based study on Spanish subjects aged > or = 60 years. Low HDL-C was defined following the European guidelines for cardiovascular prevention [men: < 40 mg/dl (< 1.0 mmol/l); women: < 46 mg/dl (< 1.2 mmol/l)]. The relationship between low HDL-C or HDL-C concentration (in quintiles) and CVD was assessed through multivariate models that included cardiovascular risk factors, statins and subclinical organ damage. On 6010 subjects (71.7 years, 53.5% women), low HDL-C was present in 17.5% [95% confidence interval (CI): 16.5-18.5] and was more frequent in women [20.4% (19.0-21.8) vs. 14.1% (12.8-15.4) in men p < 0.001] and in patients with diabetes, CVD or statin therapy. Low HDL-C was independently associated with CVD [adjusted odds ratio (OR): 1.46, 95% CI: 1.22-1.74, p < 0.001]. The prevalence of CVD was higher as HDL-C concentration was lower (chi-square trend < 0.001). Compared with the highest quintile [> 65 mg/dl (> 1.67 mmol/l)], adjusted OR for CVD were 1.39 (1.10-1.76), 1.41 (1.11-1.80), 1.49 (1.18-1.89) and 1.91 (1.52-2.39), respectively for those in the fourth [57-65 mg/dl (1.46-1.67 mmol/l)], third [51-56 mg/dl (1.31-1.45 mmol/l)], second [46-50 mg/dl (1.18-1.30 mmol/l)] and first [< 46 mg/dl (< 1.18 mmol/l)] quintiles of HDL-C. This association was seen in males and females. A total of 17.5% of this Spanish population aged > or = 60 years had low HDL-C. We found a strong, independent and inverse association between HDL-C concentrations and established CVD, even at ranges of HDL-C considered as normal.
Okumura, Kenji; Tsukamoto, Hideto; Tsuboi, Hideyuki; Hirayama, Haruo; Kamiya, Haruo; Watarai, Masato; Ishiki, Ryoji; Murohara, Toyoaki
This study is a prospective multicenter study designed to investigate the effects of lipid-lowering therapy with pitavastatin on atherosclerotic plaque in patients with coronary heart disease, and to determine which factor is more closely associated with plaque regression. Participants (n = 63) were treated with pitavastatin for 12 months, and the carotid intima-media thickness (IMT) was measured by ultrasound before and after treatment. Mean IMT slightly but significantly decreased (from 0.99 ± 0.33 to 0.94 ± 0.28 mm for overall, P = 0.01) regardless of the presence of pretreatment with other statins. There were no significant relations with hs-CRP, malondialdehyde-LDL, LDL cholesterol, and smaller LDL cholesterol levels despite their decrease by pitavastatin. Decreases in mean IMT were observed significantly more frequently in subjects with high on-treatment HDL cholesterol levels than with low HDL cholesterol levels (P = 0.017). The change in mean IMT tended to be inversely correlated with increments in HDL cholesterol and apolipoprotein A-I. The IMT regression was more often observed in the absence of diabetes and metabolic syndrome. In conclusion, we demonstrated that treatment with pitavastatin attenuated atherosclerotic plaque. This effect was associated with the level of HDL cholesterol, and was stronger in the absence of diabetes and metabolic syndrome in our ischemic heart disease patients.
Kostara, Christina E; Tsimihodimos, Vasilis; Elisaf, Moses S; Bairaktari, Eleni T
Recent studies suggest that the cholesterol content of HDL (high density lipoproteins) may provide limited information on their antiatherogenic properties and that the composition and particles' structure provide more information on their functionality. We used NMR-based (nuclear magnetic resonance-based) lipidomics to study the relationships of serum HDL-C (HDL-cholesterol) levels with the lipid composition of HDL particles in three groups of subjects selected on the basis of their HDL-C levels. Subjects with low and high HDL-C levels exhibited differences in HDL lipidome compared to those with normal HDL-C levels. In pattern recognition analysis, the discrimination power among all groups was of high significance. The low HDL-C group presented enrichment of the core in triglycerides and depletion in cholesterol esters, whereas the high HDL-C group showed a decrease in triglycerides content. Additionally, as HDL-C increases, all lipid classes are esterified with higher percentage of unsaturated than saturated fatty acids. In addition to the aforementioned differences, the surface layer is enriched in sphingomyelin and free cholesterol in the high HDL-C level group. NMR-based lipidomic analysis of HDL can be particularly useful since it provides insights into molecular features and helps in the characterization of the atheroprotective function of HDL lipoproteins and in the identification of novel biomarkers of cardiovascular risk.
Hayes, K C; Pronczuk, A; Perlman, D
When free phytosterols are adequately heated and then cooled in fat, they recrystallize and are rendered bioavailable for blocking cholesterol absorption. To extend the application of phytosterols to fried foods, the activity of these modified crystals was assessed in 2 experiments with 26 male gerbils fed purified diets containing 0.15 g/100 g cholesterol with or without 0.75 g/100 g free phytosterols. The heat-modified soybean sterols were added directly to the diet (Expt. 1) or as phytosterol-enriched potato chips (Expt. 2). In the gerbil experiments, only the diet containing phytosterols significantly reduced plasma cholesterol (35-48%) and the total cholesterol/HDL cholesterol (HDL-C) ratio (40%), as well as hepatic cholesterol esters (80%). In a subsequent human study, subjects (n = 7) consumed two 28-g servings of tortilla chips fried in oil with or without phytosterols that provided 0 or 1.5 g/d for 4-wk periods in a crossover design (Expt. 3). During consumption of the phytosterol-enriched chips, significant reductions in plasma cholesterol (10%) and LDL cholesterol (15%) were achieved without affecting HDL-C. This novel means of delivering free phytosterols proved to be both functionally efficient and effective.
Zhang, Zili; Wang, Jian; Chen, Sifan; Wei, Zhaoyu; Li, Zhengtu; Zhao, Siwen; Lu, Wenju
Low plasma level of high density lipoprotein cholesterol (HDL-c) was an independent risk factor for cardio vascular disorder, and associated with poor outcomes in pulmonary arterial hypertension. To compare the effects of vegetarian diets and omnivorous diets on HDL-c in plasma, we identified cross-sectional and cohort studies related to HDL-c listed on PubMed and ISI Web of Knowledge as well as the corresponding references (until Nov, 2013). Twelve studies with a total of 4177 individuals were selected for meta-analysis. This meta-analysis indicates that vegetarian diets did not alter plasma HDL-c concentrations, as it wasn't initially expected by the authors [Standardized Mean Difference (SMD) = 0.02 mmol/l; 95% confidence interval (CI): -0.19 to 0.22 mmol/l]. In Asia and Latin America countries, no significant differences in HDL-c levels between vegetarians and omnivores were found (SMD = -0.09 mmol/l; 95% CI: -0.43 to 0.25 mmol/l). In Europe and North America countries, the plasma level of HDL-c was also not different between the two diets (SMD = 0.09 mmol/l; 95% CI: -0.19 to 0.36 mmol/l). In light of this meta-analysis, we conclude that there is no evidence that plasma HDL-c levels differs in vegetarians and omnivores, even after adjusting for cultural circumstances.
Chen, Sifan; Wei, Zhaoyu; Li, Zhengtu; Zhao, Siwen; Lu, Wenju
Low plasma level of high density lipoprotein cholesterol (HDL-c) was an independent risk factor for cardio vascular disorder, and associated with poor outcomes in pulmonary arterial hypertension. To compare the effects of vegetarian diets and omnivorous diets on HDL-c in plasma, we identified cross-sectional and cohort studies related to HDL-c listed on PubMed and ISI Web of Knowledge as well as the corresponding references (until Nov, 2013). Twelve studies with a total of 4177 individuals were selected for meta-analysis. This meta-analysis indicates that vegetarian diets did not alter plasma HDL-c concentrations, as it wasn’t initially expected by the authors [Standardized Mean Difference (SMD) = 0.02 mmol/l; 95% confidence interval (CI): −0.19 to 0.22 mmol/l]. In Asia and Latin America countries, no significant differences in HDL-c levels between vegetarians and omnivores were found (SMD = −0.09 mmol/l; 95% CI: −0.43 to 0.25 mmol/l). In Europe and North America countries, the plasma level of HDL-c was also not different between the two diets (SMD = 0.09 mmol/l; 95% CI: −0.19 to 0.36 mmol/l). In light of this meta-analysis, we conclude that there is no evidence that plasma HDL-c levels differs in vegetarians and omnivores, even after adjusting for cultural circumstances. PMID:24671216
Wesnigk, Jenny; De Guchtenaere, Ann; Fischer, Tina; Schuler, Gerhard; Vrints, Christiaan J.
Background. Endothelial dysfunction occurs in obese children and adolescent and is regarded as a key step in the development of atherosclerosis. Important components for the development of endothelial dysfunction are reduced activity of endothelial nitric oxide synthase (eNOS) and an increase in cholesterol deposition in the vessel wall, due to reduced reverse cholesterol transport (RCT) activity. High density lipoprotein (HDL) exhibits antiatherosclerotic properties including modulation of eNOS activity and cholesterol efflux capacity. Lifestyle intervention programs can modify endothelial dysfunction in obese adolescents, but their impact on HDL-mediated eNOS activation and RCT is unknown so far. Methods. Obese adolescents (15 ± 1 years, BMI > 35 kg/m2) where randomized either to an intervention group (IG, n = 8; restricted diet and exercise) or to a usual care group (UC, n = 8). At the beginning and after 10 months of treatment HDL-mediated eNOS phosphorylation and cholesterol efflux capacity were evaluated. Results. Ten months of treatment resulted in a substantial weight loss (−31%), an improvement of endothelial function, and an increase in HDL-mediated eNOS-Ser1177 phosphorylation and RCT. A correlation between change in eNOS-Ser1177 phosphorylation or RCT and change in endothelial function was noted. Conclusion. A structured lifestyle intervention program improves antiatherosclerotic HDL functions, thereby positively influencing endothelial function. PMID:27965912
Zhao, Shui-ping; Yang, Jun; Li, Jing; Dong, Shao-zhuang; Wu, Zhi-hong
Adipose tissue contains a large amount of cholesterol and performs a buffer function for circulating cholesterol. Liver X receptors (LXR) alpha and peroxisome proliferator-activated receptor gamma (PPARgamma) might play a significant role in adipocyte cholesterol metabolism through mediation of cholesterol efflux. The aim of this study was to evaluate the effect of niacin on LXRalpha and PPARgamma expression and HDL-induced cholesterol efflux in adipocytes from hypercholesterolemic rabbits. Twelve rabbits fed with high-cholesterol diet for 8 weeks were randomly divided into two groups: (1) high cholesterol group (n=6): maintained high cholesterol diet for 6 weeks; (2) niacin group (n=6): the same cholesterol diet plus niacin (200 mg/kg/d) for 6 weeks. Control group (n=6) was fed with normal diet for 14 weeks. Subcutaneous adipose was collected for adipocyte culture. Reverse transcription polymerase chain reaction (RT-PCR) was used to evaluate adipocytes LXRalpha mRNA expressions. Cholesterol efflux rate was determined through measuring release of radioactivity from (3)H-cholesterol prelabeled cells into medium containing high-density lipoprotein (HDL). The direct effect of niacin on LXRalpha and PPARgamma mRNA expression in primary rabbit adipocytes was assayed. High cholesterol diet resulted in decreased LXRalpha mRNA expressions and reduced HDL-induced cholesterol efflux rate in adipocytes. Six weeks of niacin treatment significantly enhanced the cholesterol efflux from adipocytes, which was related to the increased mRNA expressions of LXRalpha (r=0.71, P<0.05). In in vitro study, niacin dose-dependently stimulated LXRalpha and PPARgamma mRNA expression in cultured adipocytes. And various doses of niacin-induced cholesterol efflux was positive correlation with LXRalpha and PPARgamma mRNA expression (r=0.83 P<0.01; r=0.76 P<0.05; respectively). Niacin can up-regulate LXRalpha and PPARgamma mRNA expression and promote the HDL-induced cholesterol efflux in
Badimon, J J; Badimon, L; Galvez, A; Dische, R; Fuster, V
The effects of in vivo administration of high density lipoprotein-very high density lipoprotein (HDL-VHDL) on the development of aortic fatty streaks were studied in cholesterol-fed rabbits. The rabbits received a 0.5% cholesterol-rich diet for 8 weeks. During this period, the HDL-VHDL group was intravenously administered with 50 mg/week of homologous HDL-VHDL protein; the control group received normal saline (0.9% NaCl). HDL-VHDL fraction was obtained at density range 1.063 to 1.25 gm/ml by ultracentrifugation of normal rabbit plasma. Along the study, plasma lipid levels followed a similar profile in both groups. At the completion of the study, atherosclerotic-like lipid-rich lesions covered 37.9 +/- 6% (X +/- SEM) of the intimal aortic surface in the control group, and 14.9 +/- 2.1% in the treated group (p less than 0.001). The values of total and free cholesterol, esterified cholesterol, and phospholipids deposited within vessel wall were significantly lower in the aortas of the HDL-VHDL treated group than those in the control group. Cholesterol accumulation in the livers was also significantly lower (p less than 0.01) in the treated group than in the control. We concluded that administration of homologous HDL-VHDL lipoprotein fraction to cholesterol-fed rabbits, dramatically inhibited the extent of aortic fatty streaks and lowered lipid deposition in the arterial wall and liver without modification of the plasma lipid levels.
Triglycerides-to-high-density-lipoprotein (HDL)-cholesterol ratio (TG/HDL-C ratio) has been proposed to be a useful predictor of cardiovascular disease. Habitual alcohol drinking causes elevation of triglycerides and HDL cholesterol levels. The purpose of this study was to determine how the TG/HDL-C ratio is influenced by alcohol intake. Subjects were 21,572 Japanese men (age range: 35-60 years) who were divided into non-, light (<22 g ethanol/day), heavy (≥22 but <44 g ethanol/day), and very heavy (≥44 g ethanol/day) drinkers. The relationship between alcohol intake and TG/HDL-C ratio was investigated by using analysis of covariance and logistic regression analysis. Log-transformed TG/HDL-C ratio was significantly lower in light, heavy, and very heavy drinkers than in nondrinkers and was lowest in light drinkers. Odds ratios for high TG/HDL-C ratios in light and heavy drinkers versus nondrinkers were significantly lower than a reference level of 1.00 (light drinkers: 0.63, 95% CI [0.57, 0.71],p < .01); heavy drinkers: 0.75, 95% CI [0.69, 0.81],p < .01]). Odds ratios for high waist-to-height ratio of subjects with versus subjects without high TG/HDL-C ratios were significantly higher than the reference level in non-, light, heavy, and very heavy drinkers and were significantly lower in heavy and very heavy drinkers than in nondrinkers (nondrinkers: 3.84 [3.42,4.31]; light drinkers: 3.65 [2.97,4.48]; heavy drinkers: 3.17 [2.84, 3.54],p < .05 compared with nondrinkers; very heavy drinkers: 2.61 [2.29, 2.97],p < .01 compared with nondrinkers). Alcohol drinking is inversely associated with TG/ HDL-C ratio and confounds the relationship between TG/HDL-C ratio and obesity.
Soška, Vladimír; Jarkovský, Jiří; Ravčuková, Barbora; Tichý, Lukáš; Fajkusová, Lenka; Freiberger, Tomáš
The aim of this study was to determine whether the atherogenic index of plasma (AIP=log[triglycerides/HDL-cholesterol]) differs in heterozygous familial hypercholesterolemia (FH) patients with and without a history of cardiovascular disease (CVD). A total of 555 FH patients with known mutations in the LDL receptor or the apolipoprotein B gene, of whom 53 had a history of CVD (CVD+ group), were retrospectively analyzed. Compared to patients without CVD (CVD- group), CVD+ patients showed significantly higher fasting LDL-cholesterol, triglycerides and AIP as well as lower HDL-cholesterol. After both adjustment for age and diabetes and using analysis based on age and sex matched groups, only the increase in triglycerides and AIP in the CVD+ vs. the CVD- group remained significant. The results of the present study indicate that AIP, which reflects the presence of atherogenic small LDL and small HDL particles, may be connected to the risk of CVD in FH patients. Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
Calabresi, Laura; Gomaraschi, Monica; Simonelli, Sara; Bernini, Franco; Franceschini, Guido
Plasma high density lipoproteins (HDL) comprise a highly heterogeneous family of lipoprotein particles, differing in density, size, surface charge, and lipid and protein composition. Epidemiological studies have shown that plasma HDL level inversely correlates with atherosclerotic cardiovascular disease. The most relevant atheroprotective function of HDL is to promote the removal of cholesterol from macrophages within the arterial wall and deliver it to the liver for excretion in a process called reverse cholesterol transport. In addition, HDLs can contribute to the maintenance of endothelial cell homeostasis and have potent antioxidant properties. It has been long suggested that individual HDL subclasses may differ in terms of their functional properties, but which one is the good particle remains to be defined. Inherited HDL disorders are rare monogenic diseases due to mutations in genes encoding proteins involved in HDL metabolism. These disorders are not only characterized by extremely low or high plasma HDL levels but also by an abnormal HDL subclass distribution, and thus represent a unique tool to understand the relationship between plasma HDL concentration, HDL function, and HDL-mediated atheroprotection. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. Copyright © 2014 Elsevier B.V. All rights reserved.
Schwingel, Andiara; Nakata, Yoshio; Ito, Lucy S; Chodzko-Zajko, Wojtek J; Shigematsu, Ryosuke; Erb, Christopher T; Souza, Simone M; Oba-Shinjo, Sueli M; Matsuo, Tomoaki; Marie, Suely K N; Tanaka, Kiyoji
Blood lipid levels are determined by a combination of genetic and environmental factors. Higher than average values of high-density lipoprotein cholesterol (HDL-cholesterol) have been observed in people of Japanese ethnicity. The aim of this study was to investigate whether Japanese immigrants to Brazil and subsequent generations maintain the protective benefits associated with higher levels of HDL-cholesterol, and to examine the potential associations between HDL-cholesterol and a variety of other blood lipids, anthropometric and lifestyle factors. Healthy men and women aged 35 years and older who were Native Japanese (n = 198) or Japanese-Brazilians (JB) living in São Paulo, Brazil (n = 198) and in some Japanese cities (n = 246) were investigated. Anthropometric variables, blood lipids including HDL-cholesterol, and lifestyle factors were assessed. Serum HDL-cholesterol was observed to be lower for JB in São Paulo (both women and men) compared with Natives and JB in Japan. Among the groups, triglycerides, waist circumference, LDL-cholesterol, meat intake, stress, and smoking were observed to be independently negatively associated with HDL-cholesterol, whereas total cholesterol, fish intake, and physical activity were positively associated. Lower levels of HDL-cholesterol among both men and women of JB in São Paulo compared with both other groups were confirmed even after lifestyle adjustments. Our findings highlight the significantly lower levels of HDL-cholesterol among Japanese-Brazilians living in São Paulo city compared to Japanese-Brazilians and Native Japanese residing in Japan. Although several lifestyle factors were found to be significantly associated with HDL-cholesterol, they cannot adequately explain the role of the Brazilian cultural environment on HDL-cholesterol levels.
Dogan, Adnan; Oylumlu, Muhammed
Cardiac syndrome X (CSX) is typically identified with ischaemia in treadmill exercise test or stress myocardial perfusion scintigraphy as well as angina-like chest pain without stenosis in coronary angiography. The purpose of the present study is to investigate the association between cardiac syndrome X and monocyte-to-HDL cholesterol ratio (MHR) which is a new marker associated with inflammation. A total of 230 patients (105 patients with cardiac syndrome X and 125 normal controls) were included in the study. Peripheral venous blood samples were drawn from all study population before coronary angiography for measuring MHR and other haematological parameters. The patients with cardiac syndrome X were more likely to have higher platelet counts, plateletcrit (PCT), monocyte count and MHR values. Monocyte count and MHR of the CSX group were significantly higher than the control group [0.53 (0.35-1) vs. 0.49 (0.23-0.96); p = .002, .011 (0.006-0.038) vs. 0.010 (0.004-0.034); p < .001, respectively]. HDL-cholesterol levels of the CSX group were significantly lower than the control groups (46.3 ± 10.1 vs. 49.6 ± 11.6; p = .021). Higher MHR and PCT values were found to be associated with the presence of CSX by multivariate logistic regression analysis. Elevated MHR level independently was found in association with the presence of CSX. The value of MHR appears additive to conventional expensive methods commonly used in CSX prediction.
Glomset, John A.; Norum, Kaare R.; King, Weiling
Plasma lipoproteins from patients with familial lecithin:cholesterol acyltransferase (LCAT) deficiency have been fractioned by preparative ultra-centrifugation and gel filtration and their lipid content and reactivity studied. All of the lipoproteins are abnormal with respect to lipid concentration or relative lipid content. The low density lipoproteins (LDL) and high density lipoproteins (HDL) appear to react normally with partially purified LCAT from normal plasma. Also, the lipids of the very low density lipoproteins (VLDL) and LDL, like those of the corresponding lipoproteins of normal plasma, are indirectly altered by the action of LCAT on normal HDL. Thus, during incubation in vitro VLDL cholesteryl ester is increased and VLDL triglyceride is decreased, as described by others for VLDL from hyperlipemic plasma, and both the unesterified cholesterol and lecithin of the VLDL and LDL are decreased. The patients' VLDL and LDL are abnormal, however, in that they lose unesterified cholesterol and lecithin to normal HDL in the absence of LCAT. Also, the patients' HDL lose these lipids to erythrocyte membranes in the absence of the enzyme. Our results provide further evidence that the abnormal cholesterol and phospholipid composition of the patients' lipoproteins is caused by the LCAT deficiency. They support the postulate that an excess of unesterified cholesterol and lecithin develops as VLDL are converted to LDL and HDL and suggest that in the absence of LCAT this excess lipid distributes among plasma lipoproteins and plasma membranes. They further suggest that LCAT normally reduces this excess lipid through a combination of direct and indirect effects. PMID:5456796
Cui, Mingxuan; Li, Wei; Ma, Liangkun; Ping, Fan; Liu, Juntao; Wu, Xueyan; Mao, Jiangfeng; Wang, Xi; Nie, Min
To investigate whether HDL-C level in pregnant Chinese Han women of late second trimester correlated with loci in high-density lipoprotein-cholesterol (HDL-C)-related genes found in genome-wide association studies (GWAS). Seven single-nucleotide polymorphisms (rs3764261 in CETP, rs1532085 in LIPC, rs7241918 in LIPG, rs1883025 in ABCA1, rs4225 in APOC3, rs1059611 in LPL, and rs16851339 in GALNT2) were genotyped using the Sequenom MassArray system for 1,884 pregnant women. The following polymorphisms were statistically associated with HDL-C level after adjusting for age, gestational week, pre-pregnancy BMI and state of GDM or HOMAIR: (i) rs3764261 (b = -0.055 mmol/L, 95% CI -0.101 to -0.008, p = 0.021), (ii) rs1883025 (b = -0.054 mmol/L, 95% CI -0.097 to -0.012, p = 0.013), (iii) rs4225 (b = -0.071 mmol/L, 95% CI -0.116 to -0.027, p = 1.79E-3) and (iv) rs16851339 (b = -0.064 mmol/L, 95% CI -0.120 to -0.008, p = 0.025). The more risk alleles the pregnant women have, the lower the plasma HDL-C levels of the subjects are. Several risk alleles found to be related to HDL-C in GWAS are also associated with HDL-C levels in pregnant Chinese Han women and these risk loci contribute additively to low HDL-C levels.
Aizawa, Koichi; Inakuma, Takahiro
The effects of dietary capsanthin, the main carotenoid in paprika (Capsicum annuum), on lipid metabolism were examined. Young male Wistar rats were fed diets containing paprika powder, paprika organic solvent extract, residue of paprika extract, and purified capsanthin. Administration of purified capsanthin for 2 weeks resulted in a significant increase in plasma HDL-cholesterol (P < 0.05) without detectable differences in plasma total cholesterol and TAG concentrations. A statistically significant correlation (r 0.567; P < 0.001) was found between dietary capsanthin concentrations and plasma HDL-cholesterol concentrations. Animals receiving diets containing two different capsanthin concentrations exhibited dose-dependent increases in plasma HDL-cholesterol (r 0.597; P < 0.005). While capsanthin was absent in the liver of animals fed the basal diet, it increased markedly in capsanthin-fed animals (P < 0.001). Quantitative analyses of hepatic mRNA levels revealed that capsanthin administration resulted in up-regulation of mRNA for apoA5 and lecithin cholesterol acyltransferase (LCAT), without significant differences in other mRNA levels related to HDL-cholesterol metabolism. These results suggest that capsanthin had an HDL-cholesterol-raising effect on plasma, and the potential to increase cholesterol efflux to HDL particles by increasing apoA5 levels and/or enhancement of LCAT activity.
El Khoury, Petra; Ghislain, Mathilde; Villard, Elise F.; Le Goff, Wilfried; Lascoux-Combe, Caroline; Yeni, Patrick; Meyer, Laurence; Vigouroux, Corinne; Goujard, Cécile; Guerin, Maryse
The capacity of HDL to remove cholesterol from macrophages is inversely associated with the severity of angiographic coronary artery disease. The effect of human immunodeficiency virus (HIV) infection or its treatment on the ability of HDL particles to stimulate cholesterol efflux from human macrophages has never been studied. We evaluated the capacity of whole plasma and isolated HDL particles from HIV-infected subjects (n = 231) and uninfected controls (n = 200), as well as in a subset of 41 HIV subjects receiving highly active antiretroviral therapy (HAART) to mediate cholesterol efflux from human macrophages. Plasma cholesterol efflux capacity was reduced (−12%; P = 0.001) in HIV patients as compared with controls. HIV infection reduced by 27% (P < 0.05) the capacity of HDL subfractions to promote cholesterol efflux from macrophages. We observed a reduced ABCA1-dependent efflux capacity of plasma (−27%; P < 0.0001) from HIV-infected subjects as a result of a reduction in the efflux capacity of HDL3 particles. HAART administration restored the capacity of plasma from HIV patients to stimulate cholesterol efflux from human macrophages (9.4%; P = 0.04). During HIV infection, the capacity of whole plasma to remove cholesterol from macrophages is reduced, thus potentially contributing to the increased coronary heart disease in the HIV population. HAART administration restored the removal of cholesterol from macrophages by increasing HDL functionality. PMID:25573889
Tischler, U.; Rueckert, D.S.; Schubert, R.; Jaroni, H.W.; Schmidt, K.H.
Interaction of large unilamellar phosphatidylcholine vesicles (LUV, 75nm) and plasma high density lipoproteins (HDL) resulted in a non-leaky vesiculation of LUV. This vesiculation was detected by a HPLC-system consisting of a combination of three TSK-gel columns (6000PW, 5000PW, 3000SW). With increasing incubation time liposomal (/sup 14/C)PC, entrapped (/sup 3/H)inulin, and apoprotein of HDL origin decreased. The decrease was accompanied by a formation of new particles, consisting of liposomal PC and apoprotein. These particles also enclosed (3H)inulin, reflecting a hydrophilic inner space. The formation of the particles reached a maximum after one day of incubation. Retention time was 21 minutes for LUV, 28 minutes for the new particles, and 36 minutes for HDL. In vesicles with membranes consisting of phosphatidylcholine and 30% cholesterol no interactions were observed.
Nanjee, M N; Miller, N E
When plasma from rabbits, which several weeks earlier had been infused with [3H]cholesterol, was subjected to equilibrium density gradient ultracentrifugation, the specific radioactivity of cholesterol in the very-high-density lipoprotein (VHDL) fraction (d 1.22-1.32 g/ml) was three to 8-fold greater (mean, 5.5-fold; P less than 0.001) than that in high-density lipoproteins (HDL; d 1.06-1.21 g/ml). On size exclusion chromatography of plasma, no increase in specific radioactivity was seen in particles smaller than HDL. These findings suggest that those apolipoprotein-lipid complexes that dissociate from HDL during ultracentrifugation to form the VHDL fraction contain proportionately more tissue-derived cholesterol than do those that are more tightly bound to HDL.
Rosa-Bray, M; Wisdom, C; Wada, S; Johnson, BR; Grifols-Roura, V; Grifols-Lucas, V
Background and Objectives LDL apheresis is used to treat patients with familial hypercholesterolaemia, and low-volume plasmapheresis for plasma donation may similarly lower cholesterol levels in some donors. This study was designed to assess the effect of plasmapheresis on total, LDL and HDL cholesterol levels in a plasma donor population. Materials and Methods This was a prospective, unblinded longitudinal cohort study in which a blood sample was obtained for analysis before each donation. Data from 663 donors were analysed using a multivariable repeated measures regression model with a general estimating equations approach with changes in cholesterol as the primary outcome measure. Results The model predicted a significant decrease in total and LDL cholesterol for both genders and all baseline cholesterol levels (P < 0·01). The greatest total cholesterol decreases (women, −46·8 mg/dL; men, −32·2 mg/dL) were associated with high baseline levels and 2–4 days between donations. Small but statistically significant increases (P ≤ 0·01) in HDL cholesterol were predicted for donors with low baseline levels. Conclusions These results suggest that, in donors with elevated baseline cholesterol levels, total and LDL cholesterol levels may decrease during routine voluntary plasmapheresis. PMID:23517282
Lee, I-Te; Huang, Chien-Ning; Lee, Wen-Jane; Lee, Hong-Shen; Sheu, Wayne Huey-Herng
We conducted a prospective study to determine the risk factors for decrease in ABI in Chinese subjects with type 2 diabetes during a 3-year period. Type 2 diabetic subjects with normal ABI were enrolled in this study. The risk factors for PVD and ABI were examined before and after the follow-up period. A total of 107 type 2 diabetic subjects completed the assessment. Based on the change of ABI, the study subjects were divided into two groups. Forty subjects, in Group 1, had a decrease in ABI; 67 subjects, in Group 2, had no decrease in ABI after the 3-year follow-up. The baseline total-to-HDL cholesterol ratio (4.5+/-1.2 vs. 3.9+/-1.0, P=0.018) and serum creatinine (99.0+/-18.0micromol/L vs. 88.8+/-15.7micromol/L, P=0.004) were significantly higher, and the HDL cholesterol concentration was significantly lower (1.11+/-0.26mmol/L vs. 1.27+/-0.39mmol/L, P=0.011) in Group 1 than in Group 2. Furthermore, total-to-HDL cholesterol ratio was the variable showed an inverse correlation and independent predictor for the change in ABI after the 3-year follow-up. Total-to-HDL cholesterol ratio is a major risk factor for PVD and showed an inverse trend to change in ABI in Asian type 2 diabetic subjects.
Garcia-Rios, Antonio; Nikolic, Dragana; Perez-Martinez, Pablo; Lopez-Miranda, Jose; Rizzo, Manfredi; Hoogeveen, Ron C
Low-density lipoproteins (LDL) are considered as important risk factors for cardiovascular diseases (CVD), while highdensity lipoproteins (HDL) are well recognized for their putative role in reverse cholesterol transport and other atheroprotective functions. Both LDL and HDL are heterogeneous in nature, including various subfractions depending on the method of isolation (≥ 7 LDL and 10 HDL subspecies, respectively). While it is established that small, dense LDL (sdLDL) have atherogenic potential, the role of different HDL subfractions is still largely unclear. The majority of clinical studies suggest an atheroprotective role of larger HDL particles, although recent work has highlighted the role of dysfunctional HDL within different subfractions. Several therapeutic approaches are able to primarily target cholesterol concentration in LDL or HDL. Certain drugs, such as niacin, statins and fibrates target multiple lipid traits (i.e. pleiotropic drug effects), while cholesterol ester transfer protein (CETP) inhibitors are able to increase plasma HDL cholesterol levels. Statins represent the most used lipid-lowering drugs, but there is a continued interest in the development of novel therapeutic approaches, including those that might affect dysfunctional HDL. Targeting distinct LDL and HDL subfractions may potentially reduce the residual risk seen in clinical endpoint trials.
Navab, Mohamad; Anantharamaiah, G. M.; Reddy, Srinivasa T.; Van Lenten, Brian J.; Buga, Georgette M.; Fogelman, Alan M.
Over the past decade evidence has accumulated that suggests that the anti-inflammatory properties of HDL may be at least as important as the levels of HDL-cholesterol. The recent failure of the torcetrapib clinical trails has highlighted the potential differences between HDL-cholesterol levels and HDL function. Agents to improve HDL function including HDL anti-inflammatory properties provide a new therapeutic strategy for ameliorating atherosclerosis and other chronic inflammatory conditions related to dyslipidemia. Seeking guidance from the structure of the apolipoproteins of the plasma lipoproteins has allowed the creation of a series of polypeptides that have interesting functionality with therapeutic implications. In animal models of atherosclerosis, peptide mimetics of apolipoproteins have been shown to improve the anti-inflammatory properties of HDL, significantly reduce lesions and improve vascular inflammation and function without necessarily altering HDL-cholesterol levels. Some of these are now entering the clinical arena as interventions in pharmacologic and pharmacodynamic studies. PMID:18449337
Cordova, C; Alessandri, C; Basili, S; Peverini, F; Ferro, D; Barsi, R; Paradiso, M
A case of a 45 years old man with an atherosclerotic stenosis of right internal carotid and TIA event is reported. The patient showed an increase of total cholesterol and LDL-cholesterol serum levels and, in particular, a very low familiar HDL2-cholesterol serum value. The possibility that this last condition could represent an important co-factor of the extracranial cerebrovascular disease is discussed. The usefulness of a long-term follow-up of all family members, showing the same lipids pattern, is also suggested.
Hafiane, Anouar; Bielicki, John K.; Johansson, Jan O.; Genest, Jacques; Zhu, Xuewei
Apolipoprotein (apo) mimetic peptides replicate some aspects of HDL function. We have previously reported the effects of compound ATI-5261 on its ability to replicate many functions of native apo A-I in the process of HDL biogenesis. ATI-5261 induced muscle toxicity in wild type C57Bl/6 mice, increased CPK, ALT and AST and increase in triglyceride (Tg) levels. Aromatic phenylalanine residues on the non-polar face of ATI-5261, together with positively charged arginine residues at the lipid-water interface were responsible for these effects. This information was used to create a novel analog (CS-6253) that was non-toxic. We evaluated this peptide designed from the carboxyl terminus of apo E, in its ability to mimic apo A-I functionality. Our data shows that the lipidated particles generated by incubating cells overexpressing ABCA1 with lipid free CS-6253 enhances the rate of ABCA1 lipid efflux with high affinity interactions with native ABCA1 oligomeric forms and plasma membrane micro-domains. Interaction between ABCA1 and lipid free CS-6253 resulted in formation of nascent HDL-CS-6253 particles that are actively remodeled in plasma. Mature HDL-CS-6253 particles deliver cholesterol to liver cells via SR-BI in-vitro. CS-6253 significantly increases cholesterol efflux in murine macrophages and in human THP-1 macrophage-derived foam cells expressing ABCA1. Addition of CS-6253 to plasma dose-dependently displaced apo A-I from α-HDL particles and led to de novo formation of preβ-1 HDL that stimulates ABCA1 dependent cholesterol efflux efficiently. When incubated with human plasma CS-6253 was also found to bind with HDL and LDL and promoted the transfer of cholesterol from HDL to LDL predominantly. Our data shows that CS-6253 mimics apo A-I in its ability to promote ABCA1-mediated formation of nascent HDL particles, and enhances formation of preβ-1 HDL with increase in the cycling of apo A-I between the preβ and α-HDL particles in-vitro. These
Memon, R A; Kifayet, A; Shahid, F; Lateef, A; Chiang, J; Hussain, R
The concentrations of serum lipids and tumor necrosis factor (TNF) were measured in leprosy patients across the spectrum of the disease and in erythema nodosum leprosum (ENL) patients at the onset of the reaction and after the reaction had clinically subsided. Lepromatous/borderline lepromatous (LL/BL) patients had significantly higher serum triglyceride and lower HDL-cholesterol levels; there was no such change in the tuberculoid/borderline tuberculoid (TT/BT) patients. The household contacts (HC) of the LL/BL patients also had significantly lower serum HDL levels. ENL patients during the acute phase of the reaction had significantly lower total, LDL-, HDL-cholesterol levels compared to the stable LL/BL patients, and these changes were reversible to pre-ENL levels after the reaction had subsided. Serum TNF levels were significantly higher in household contacts and in LL/BL patients but were not statistically different in TT/BT patients. Serum TNF levels were also significantly higher during the acute phase of ENL, and declined after the clinical remission of the reaction to levels comparable with those of LL/BL patients. There was a significant negative correlation between serum TNF and HDL-cholesterol levels during and after ENL reaction. However, there was no such correlation between TNF and total or LDL-cholesterol levels in ENL patients. Our results suggest that the changes in HDL-cholesterol metabolism are a specific part of the host response to lepromatous leprosy and to the ENL reaction and may be mediated by increased TNF production.
Bielinski, Suzette J; Tang, Weihong; Pankow, James S; Miller, Michael B; Mosley, Thomas H; Boerwinkle, Eric; Olshen, Richard A; Curb, J David; Jaquish, Cashell E; Rao, D C; Weder, Alan; Arnett, Donna K
Atherosclerosis accounts for 75% of all deaths from cardiovascular disease and includes coronary heart disease (CHD), stroke, and other diseases of the arteries. More than half of all CHD is attributable to abnormalities in levels and metabolism of lipids. To locate genes that affect total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides, genome-wide linkage scans for quantitative trait loci were performed using variance components methods as implemented in SOLAR on a large diverse sample recruited as part of the Family Blood Pressure Program. Phenotype and genetic marker data were available for 9,299 subjects in 2,953 families for total cholesterol, 8,668 subjects in 2,736 families for HDL, and 7,760 subjects in 2,499 families for triglycerides. Mean lipid levels were adjusted for the effects of sex, age, age2, age-by-sex interaction, body mass index, smoking status, and field center. HDL-C and triglycerides were further adjusted for average total alcoholic drinks per week and estrogen use. Significant linkage was found for total cholesterol on chromosome 2 (LOD=3.1 at 43 cM) in Hispanics and for HDL-C on chromosome 3 (LOD=3.0 at 182 cM) and 12 (LOD=3.5 at 124 cM) in Asians. In addition, there were 13 regions that showed suggestive linkage (LOD >or= 2.0); 7 for total cholesterol, 4 for HDL, and 2 for triglycerides. The identification of these loci affecting lipid phenotypes and the apparent congruence with previous linkage results provides increased support that these regions contain genes influencing lipid levels.
Comparison of non-HDL-cholesterol versus triglycerides-to-HDL-cholesterol ratio in relation to cardiometabolic risk factors and preclinical organ damage in overweight/obese children: the CARITALY study.
Di Bonito, P; Valerio, G; Grugni, G; Licenziati, M R; Maffeis, C; Manco, M; Miraglia del Giudice, E; Pacifico, L; Pellegrin, M C; Tomat, M; Baroni, M G
Lipid ratios to estimate atherosclerotic disease risk in overweight/obese children are receiving great attention. We aimed to compare the performance of non-high-density lipoprotein-cholesterol (HDL-C) versus triglycerides-to-HDL-C ratio (Tg/HDL-C) in identifying cardiometabolic risk factors (CMRFs) or preclinical signs of organ damage in outpatient Italian overweight/obese children. In this retrospective, cross-sectional study, 5505 children (age 5-18 years) were recruited from 10 Italian centers for the care of obesity, of which 4417 (78%) showed obesity or morbid obesity. Anthropometric, biochemical, and blood pressure variables were analyzed in all children. Liver ultrasound scan, carotid artery ultrasound, and echocardiography were performed in 1257, 601, and 252 children, respectively. The entire cohort was divided based on the 75th percentile of non-HDL-C (≥130 mg/dl) or Tg/HDL-C ratio (≥2.2). The odds ratio for insulin resistance, high blood pressure, metabolic syndrome, presence of liver steatosis, increased levels of carotid intima-media thickness (cIMT) and concentric left ventricular hypertrophy (cLVH) was higher in children with high levels of Tg/HDL-C with respect to children with high levels of non-HDL-C. In an outpatient setting of overweight/obese children, Tg/HDL-C ratio discriminated better than non-HDL-C children with CMRFs or preclinical signs of liver steatosis, and increased cIMT and cLVH. Copyright © 2015 Elsevier B.V. All rights reserved.
Wood, W. Gibson; Igbavboa, Urule; Müller, Walter E.; Eckert, Gunter P.
Lipids are essential for the structural and functional integrity of membranes. Membrane lipids are not randomly distributed but are localized in different domains. A common characteristic of these membrane domains is their association with cholesterol. Lipid rafts and caveolae are examples of cholesterol enriched domains, which have attracted keen interest. However, two other important cholesterol domains are the exofacial and cytofacial leaflets of the plasma membrane. The two leaflets that make up the bilayer differ in their fluidity, electrical charge, lipid distribution, and active sites of certain proteins. The synaptic plasma membrane (SPM) cytofacial leaflet contains over 85% of the total SPM cholesterol as compared with the exofacial leaflet. This asymmetric distribution of cholesterol is not fixed or immobile but can be modified by different conditions in vivo: 1) chronic ethanol consumption; 2) statins; 3) aging; and 4) apoE isoform. Several potential candidates have been proposed as mechanisms involved in regulation of SPM cholesterol asymmetry: apoE, low-density-lipoprotein receptor, sterol carrier protein-2, fatty acid binding proteins, polyunsaturated fatty acids, p-glycoprotein and caveolin-1. This review examines cholesterol asymmetry in SPM, potential mechanisms of regulation and impact on membrane structure and function. PMID:21214553
Lee, Ji-Hye; Park, Jung-Heun; Lee, Sang-Hak; Kim, Jae-Ryong; Cho, Kyung-Hyun
A female patient (64 years of age; body mass index, 26) had a markedly and relatively low low-density lipoprotein-cholesterol (LDL-C) level (97 mg/dl) despite high serum total cholesterol (TC) (331 mg/dl) and triacylglyceride levels (307 mg/dl). Since the expected LDL-C was 222 mg/dl, there was a significant difference between the calculation and measurement based on direct enzyme assay. Only 30% of serum cholesterol was associated with LDL-C in this patient. To determine the basis for the markedly low LDL-C/TC ratio, we isolated and analyzed lipoproteins from the patient as well as age- and gender-matched controls. The patient had lowered serum CETP activity and elevated paraoxonase activity with GOT and GPT values in the normal range. The very low-density lipoprotein particles from the patient were larger than those of the controls and enriched with lipid and protein, while the LDL from the patient (LDL-P) had a lower particle number and protein content than the controls. The LDL-P was more resistant to cupric ion-mediated oxidation. HDL2 from the patient (HDL2-P) had highly enhanced paraoxonase activity and antioxidant ability. The patient had a 1.5-fold higher level of apolipoprotein (apo) A-I expression in HDL2. ApoA-I in HDL2 and HDL3 from the patient showed no fragmentation, while the control had fragmented bands (17 and 21 kDa) in the HDL. The HDL2-P also had a larger particle size and greater protein content with less lipid content. HDL3-associated cholesteryl ester transfer protein was reduced in the patient, although the particle size was similar to the controls. In conclusion, a patient who had a markedly lower LDL-C/TC ratio despite hyperlipidemia associated with higher paraoxonase activity, higher apoA-I level and lower CETP activity without fragmentation of apoA-I in the HDL fraction is presented. The enhanced antioxidant and anti-inflammatory activity of HDL might contribute to the low LDL-C/TC ratio in this patient.
Slowing, K; Ganado, P; Sanz, M; Ruiz, E; Tejerina, T
Garlic is known for its pharmacologic and nutritional properties. In previous studies, garlic elicited a reduction in plasma levels of lipids by inhibiting hepatic cholesterol synthesis. The aim of this study was to investigate in an in vivo model the effects of garlic extract and some fractions on cholesterol levels and vascular reactivity in cholesterol-fed rats. Rats were fed a cholesterol-enriched diet for 16 wk and were divided into 10 groups as follows: control and hypercholesterolemic diet groups, 4 groups fed frozen garlic fractions and 4 groups fed raw garlic fractions with different doses. Blood samples were obtained to analyze HDL and LDL cholesterol levels. After treatment, rats were killed. The heart, liver and kidneys were weighed; the aorta was isolated, mounted in organ chambers and vascular reactivity was tested. Plasma concentration of cholesterol was 58 mg/dL (100%) at the beginning of the study and increased to 102 mg/dL (153%; hypercholesterolemic group) at the end of the treatment. Plasma total cholesterol decreased in all groups treated with garlic; moreover, this effect was higher in rats fed raw garlic fractions and extracts. LDL decreased significantly with respect to the hypercholesterolemic group in all groups treated with garlic fractions and extracts (P: < 0.01); however, an increase in HDL was found in those treated with frozen fractions and extracts. The liver:body weight ratio decreased in all treated groups. The relaxing effect of acetylcholine (ACh) was enhanced in arteries contracted with noradrenaline (NE). These data suggest that garlic fractions could prevent diet-induced hypercholesterolemia and vascular alterations in the endothelium-dependent relaxation associated with atherosclerosis.
Nikolić, Milan; Stanić, Dragana; Baricević, Ivona; Jones, David R; Nedić, Olgica; Niketić, Vesna
The interior of red blood cells (RBCs) contains a variable amount of cholesterol and phospholipids bound to haemoglobin (Hb). This current study was devised to determine if this pool of lipids (termed Hb-Ch) was available for exchange with plasma lipoproteins. We studied the in vitro efflux of lipids from human RBCs into fasting plasma in men with either low (control group) or high Hb-Ch (study group). When plasma was incubated with a two-fold excess of autologous RBCs the plasma cholesterol level increased due to a decrease in the level of cholesterol from the RBC membrane (in the control group) and due to a decrease in the level of cholesterol both from the RBC membrane and the Hb-Ch fraction (in the study group). The loss of Hb-Ch-derived phospholipids during lipid efflux was roughly equal to that of Hb-Ch-derived cholesterol. The loss of RBC cholesterol into plasma high-density lipoproteins (HDL) was more pronounced in our study group and correlated with the loss of cholesterol from Hb-Ch. The Hb-Ch adduct significantly contributes to the lipid efflux from RBCs into plasma. The majority of cholesterol released from Hb-Ch appears in the plasma HDL fraction suggesting that Hb-Ch may play a role in reverse cholesterol transport in vivo.
Lim, Hwee Ying; Thiam, Chung Hwee; Yeo, Kim Pin; Bisoendial, Radjesh; Hii, Chung Shii; McGrath, Kristine C Y; Tan, Kar Wai; Heather, Alison; Alexander, J Steven Jonathan; Angeli, Veronique
Removal of cholesterol from peripheral tissues to the bloodstream via reverse cholesterol transport (RCT) is a process of major biological importance. Here we demonstrate that lymphatic drainage is required for RCT. We have previously shown that hypercholesterolemia in mice is associated with impaired lymphatic drainage and increased lipid accumulation in peripheral tissues. We now show that restoration of lymphatic drainage in these mice significantly improves cholesterol clearance. Conversely, obstruction of lymphatic vessels in wild-type mice significantly impairs RCT. Finally, we demonstrate using silencing RNA interference, neutralizing antibody, and transgenic mice that removal of cholesterol by lymphatic vessels is dependent on the uptake and transcytosis of HDL by scavenger receptor class B type I expressed on lymphatic endothelium. Collectively, this study challenges the current view that lymphatic endothelium is a passive exchange barrier for cholesterol transport and provides further evidence for its interplay with lipid biology in health and disease. Copyright © 2013 Elsevier Inc. All rights reserved.
Myant, N B
This review includes a brief account of the routes of entry of cholesterol into the plasma by (a) secretion of lipoproteins and (b) uptake of tissue free cholesterol by lipoproteins in the interstitial fluid, the metabolic transformation undergone by cholesterol within the plasma, with particular reference to the esterification of plasma free cholesterol by lecithin:cholesteryl acyltransferase and the redistribution of esterified cholesterol from high-density to low-density and very-low-density lipoprotein, and the routes by which cholesterol is removed from the plasma by bulk transport. The review end with a balance sheet showing the approximate amounts of cholesterol entering and leaving the plasma by different routes.
Wongcharoen, Wanwarang; Sutthiwutthichai, Satjatham; Gunaparn, Siriluck; Phrommintikul, Arintaya
It has recently been shown that non-high density lipoprotein cholesterol (non-HDL-C) may be a better predictor of cardiovascular risk than low density lipoprotein cholesterol (LDL-C). Based on known ethic differences in lipid parameters and cardiovascular risk prediction, we sought to study the predictability of attaining non-HDL-C target and long-term major adverse cardiovascular event (MACE) in Thai patients after acute myocardial infarction (AMI) compared to attaining LDL-C target. We retrospectively obtained the data of all patients who were admitted at Maharaj Nakorn Chiang Mai hospital due to AMI during 2006-2013. The mean non-HDL-C and LDL-C during long-term follow-up were used to predict MACE at each time point. The patients were classified as target attainment if non-HDL-C <100 mg/dl and/or LDL-C <70 mg/dl. The MACE was defined as combination of all-cause death, nonfatal coronary event and nonfatal stroke. During mean follow-up of 2.6 ± 1.6 years among 868 patients after AMI, 34.4% achieved non-HDL-C target, 23.7% achieved LDL-C target and 21.2% experienced MACEs. LDL-C and non-HDL-C were directly compared in Cox regression model. Compared with non-HDL-C <100 mg/dl, patients with non-HDL-C of >130 mg/dl had higher incidence of MACEs (HR 3.15, 95% CI 1.46-6.80, P = 0.003). Surprisingly, LDL-C >100 mg/dl was associated with reduced risk of MACE as compared to LDL <70 mg/dl (HR 0.42, 95% CI 0.18-0.98, p = 0.046) after direct pairwise comparison with non-HDL-C level. Non-attaining non-HDL-C goal predicted MACE at long-term follow-up after AMI whereas non-attaining LDL-C goal was not associated with the higher risk. Therefore, non-HDL-C may be a more suitable target of dyslipidemia treatment than LDL-C in patients after AMI.
Singh, Surendra Pratap; Mehla, Ram Kumar; Singh, Mahendra
Ten dry and pregnant Murrah buffaloes were selected to investigate the effect of Asparagus racemosus feeding on hormones, metabolites, milk yield, and plasma cholesterol levels. The treatment groups of buffaloes were fed with A. racemosus (shatavari) @ 150 g/day/animal during prepartum and @ 300 g/day/animal during the postpartum period. Blood samples collected on -6, -4, -2-week, day of parturition (0), and +2, +4, and +6-week postpartum were analyzed for plasma total cholesterol, triglycerides, HDL, low-density lipoproteins (LDL), prolactin, cortisol, and blood metabolites. Milk samples collected at weekly intervals (+1, +3, +5, and 7 weeks) were analyzed for total milk fat cholesterol. Prepartum plasma cholesterol concentrations were significantly higher in treatment group over the control (P < 0.05). Mean plasma triglycerides, LDL cholesterol, HDL cholesterol, glucose, and nonesterified fatty acid (NEFA) levels varied nonsignificantly between groups. Plasma prolactin and cortisol concentrations were significantly (P < 0.01) more in treatment group than in control group. On day of parturition, plasma prolactin, cortisol, LDL, and plasma total cholesterol were higher (P < 0.01) in treatment group buffaloes in comparison to control group. A. racemosus feeding significantly (P < 0.01) increased plasma prolactin, cortisol (P < 0.01), and milk fat cholesterol (P < 0.05) without affecting total cholesterol, HDL, LDL, glucose, and NEFA concentrations. The buffaloes of treatment group produced more milk (@ 0.526 kg/animal/day) suggesting thereby that A. racemosus is galactopoietic. It was concluded that feeding of A. racemosus increases plasma prolactin and cortisol and decreased plasma total cholesterol and LDL concentration.
Høstmark, Arne Torbjørn; Lunde, Marianne Sylvana Haug; Haug, Anna
Previous data suggested that intake of sodas and other acid beverages might be associated with increased levels of serum triglycerides, lowered HDL cholesterol, and increased formation of mono unsaturated fatty acids, which are the preferred ones for triglyceride synthesis. The present work is an extension of these studies. Thirty male rats were divided into 3 groups. All groups were given the same food, but various beverages: water (W), ammonium chloride, 200 mmol/L (AC), or sodium bicarbonate, 200 mmol/L (SB). Serum triglycerides, HDL cholesterol, and the fatty acid distribution in total serum lipids were determined. Delta9-desaturase in serum lipids was estimated by the ratio of palmitoleic to palmitic acid, and by the oleic/stearic acid ratio. Correlation and ANOVA were used to study associations and group differences. After 3 weeks, the AC group had higher triglyceride concentration and higher Delta9 desaturase indexes, but lower serum HDL and body weight as compared with the SB and W groups. In each of the groups, the oleic acid/stearic acid ratio correlated positively with serum triglycerides; in the pooled group the correlation coefficient was r = 0.963, p<0.01. Rats ingesting ammonium chloride as compared with sodium bicarbonate responded with increased desaturase indexes, increased serum triglycerides, and lowered HDL cholesterol concentration, thereby possibly contributing to explain the increased triglyceride concentration previously observed in subjects with a frequent intake of acid beverages, such as sodas containing carbonic acid, citric acid, and phosphoric acid.
Alkhouri, Naim; Eng, Katharien; Lopez, Rocio; Nobili, Valerio
Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular disease (CVD) risk in children. Non-high density lipoprotein-cholesterol (non-HDL-C) has been shown to be a good predictor of cardiovascular events. Recent data in adults found non-alcoholic steatohepatitis (NASH) to be associated with significantly higher levels of non-HDL-C than simple steatosis, suggestive it might be used as a non-invasive tool to diagnose NASH. The goal of our study was to assess non-HDL-C levels in children with NAFLD. Our cohort consisted of pediatric patients with biopsy-proven NAFLD. Anthropometric, laboratory, and histologic data were obtained on all patients. Univariable analysis was performed to assess differences in clinical characteristics between groups. Spearman rank correlation coefficients were calculated to assess the correlation between non-HDL-C levels and clinical variables. ANCOVA was used to adjust for possible confounders. 302 subjects with NAFLD were included in our study; 203 with NASH and 99 without NASH. Subjects with NASH had significantly higher non-HDL-C levels than those without (p = 0.004). Histologic features of NASH, including ballooning, inflammation, and fibrosis were found to be weakly correlated with non-HDL-C levels, (p < 0.05 for all). After adjusting for the presence of metabolic syndrome (MetS), ALT, and GGT, the association between non-HDL-C and NASH was not significant (p = 0.66). In Conclusion, non-HDL-C levels are higher in children with NASH than those with simple steatosis, suggesting increased CVD risk. This may be a reflection of the higher prevalence of MetS. Non-HDL-C had a positive association with histologic features of NASH.
Brites, Fernando Daniel; Verona, Julián; Schreier, Laura Ester; Fruchart, Jean-Charles; Castro, Graciela Rosa; Wikinski, Regina Luisa
Previous studies have shown that high density lipoprotein (HDL)-deficient states are associated with reduced paraoxonase 1 (PON1) activity. However, HDL reduction caused by primary hypertriglyceridemia has not been fully explored. The aim of the present study was to evaluate whether PON1 and platelet-activating factor acetylhydrolase (PAF-AH), two antioxidant enzymes, were altered in patients with low HDL-cholesterol levels with or without primary hypertriglyceridemia in comparison with control normolipemic subjects. We studied 24 patients with low HDL-cholesterol levels with (n=12) or without (n=12) primary hypertriglyceridemia in comparison with 12 control subjects who presented normal HDL-cholesterol and triglyceride levels. Paraoxon and phenylacetate were used as substrate for measuring PON1 activities and 1-hexadecyl-2-[3H]acetyl-glycero-3-phosphocholine for platelet-activating factor acetylhydrolase (PAF-AH) activity. Double substrate method was used to assign phenotypes. Lipid, lipoprotein, apolipoprotein, and lipoprotein particles were determined by standardized methods. Both PON1 activities were significantly reduced in patients with low HDL-cholesterol levels. This reduction could be selectively attributed to the hypertriglyceridemic subgroup. PAF-AH activity was not different between hypoalphalipoproteinemic patients and controls. PON1 activities correlated positively and significantly with HDL-cholesterol, HDL2-cholesterol, HDL3-cholesterol, HDL-phospholipids, apo A-I, apo A-II, and LpA-I:A-II. PAF-AH correlated positively and significantly with total and low density lipoprotein-cholesterol. Data from this study would suggest that in hypoalphalipoproteinemic syndrome, particularly when associated with hypertriglyceridemia, there is impairment in enzymatic antioxidant activity exclusively related with HDL.
Wilson, T A; DeSimone, A P; Romano, C A; Nicolosi, R J
The aims of this study were to compare the cholesterol-lowering properties of corn fiber oil (CFO) to corn oil (CO), whether the addition of soy stanols or soy sterols to CO at similar levels in CFO would increase CO's cholesterol-lowering properties, and the mechanism(s) of action of these dietary ingredients. Fifty male Golden Syrian hamsters were divided into 5 groups of 10 hamsters each, based on similar plasma total cholesterol (TC) levels. The first group of hamsters was fed a chow-based hypercholesterolemic diet containing either 5% coconut oil + 0.24% cholesterol (coconut oil), 5% CO, 5% CFO, 5% CO + 0.6% soy sterols (sterol), or 5% CO + 0.6% soy stanols (stanol) in place of the coconut oil for 4 weeks. The stanol diet significantly inhibited the elevation of plasma TC compared to all other dietary treatments. Also, the CFO and sterol diets significantly inhibited the elevation of plasma TC compared to the CO and coconut oil diets. The CFO, sterol, and stanol diets significantly inhibited the elevation of plasma non-high density lipoprotein cholesterol compared to the CO and coconut oil diets. The stanol diet significantly inhibited the elevation of plasma high density lipoprotein cholesterol (HDL-C) compared to all other dietary treatments. The sterol diet significantly inhibited the elevation of plasma HDL-C compared to the CO and coconut oil diets, whereas the CFO diet significantly inhibited the elevation of plasma HDL-C compared to the coconut oil diet only. No differences were observed between the CFO and CO for plasma HDL-C. There were no differences observed between groups for plasma triglycerides. The CO and CFO diets had significantly less hepatic TC compared to the coconut oil, sterol, and stanol diets. The CO and CFO diets had significantly less hepatic free cholesterol compared to the sterol and stanol diets but not compared to the coconut oil diet; whereas the coconut oil and sterol diets had significantly less hepatic free cholesterol
Thacker, Seth G; Rousset, Xavier; Esmail, Safiya; Zarzour, Abdalrahman; Jin, Xueting; Collins, Heidi L; Sampson, Maureen; Stonik, John; Demosky, Stephen; Malide, Daniela A; Freeman, Lita; Vaisman, Boris L; Kruth, Howard S; Adelman, Steven J; Remaley, Alan T
LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol (FC) in atherosclerosis, we examined the effect of LCAT over- and underexpression in diet-induced atherosclerosis in scavenger receptor class B member I-deficient [Scarab(-/-)] mice, which have a secondary defect in cholesterol esterification. Scarab(-/-)×LCAT-null [Lcat(-/-)] mice had a decrease in HDL-cholesterol and a high plasma ratio of FC/total cholesterol (TC) (0.88 ± 0.033) and a marked increase in VLDL-cholesterol (VLDL-C) on a high-fat diet. Scarab(-/-)×LCAT-transgenic (Tg) mice had lower levels of VLDL-C and a normal plasma FC/TC ratio (0.28 ± 0.005). Plasma from Scarab(-/-)×LCAT-Tg mice also showed an increase in cholesterol esterification during in vitro cholesterol efflux, but increased esterification did not appear to affect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. Scarab(-/-)×LCAT-Tg mice also displayed a 51% decrease in aortic sinus atherosclerosis compared with Scarab(-/-) mice (P < 0.05). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective, most likely through its ability to increase HDL levels and decrease pro-atherogenic apoB-containing lipoprotein particles.
Gillard, Baiba K; Rosales, Corina; Pillai, Biju K; Lin, Hu Yu; Courtney, Harry S; Pownall, Henry J
Serum opacity factor (SOF), a virulence determinant of Streptococcus pyogenes, converts plasma high-density lipoproteins (HDL) to three distinct species: lipid-free apolipoprotein (apo) A-I, neo HDL, a small discoidal HDL-like particle, and a large cholesteryl ester-rich microemulsion (CERM) that contains the cholesterol esters (CE) of up to ∼400000 HDL particles and apo E as its major protein. Similar SOF reaction products are obtained with HDL, total plasma lipoproteins, and whole plasma. We hypothesized that hepatic uptake of CERM-CE via multiple apo E-dependent receptors would be faster than that of HDL-CE. We tested our hypothesis using human hepatoma cells and lipoprotein receptor-specific Chinese hamster ovary (CHO) cells. The uptake of [(3)H]CE by HepG2 and Huh7 cells from HDL after SOF treatment, which transfers >90% of HDL-CE to CERM, was 2.4 and 4.5 times faster, respectively, than from control HDL. CERM-[(3)H]CE uptake was inhibited by LDL and HDL, suggestive of uptake by both the LDL receptor (LDL-R) and scavenger receptor class B type I (SR-BI). Studies in CHO cells specifically expressing LDL-R and SR-BI confirmed CERM-[(3)H]CE uptake by both receptors. RAP and heparin inhibit CERM-[(3)H]CE but not HDL-[(3)H]CE uptake, thereby implicating LRP-1 and cell surface proteoglycans in this process. These data demonstrate that SOF treatment of HDL increases the rate of CE uptake via multiple hepatic apo E receptors. In so doing, SOF might increase the level of hepatic disposal of plasma cholesterol in a way that is therapeutically useful.
Bruckert, E; Baccara-Dinet, M; Eschwege, E
To measure the prevalence of low high-density lipoprotein (HDL)-cholesterol (men < 1.03 mmol/l; women < 1.29 mmol/l) in European Type 2 diabetic patients receiving treatment for dyslipidaemia. The pan-European Survey of HDL-cholesterol measured lipids and other cardiovascular risk factors in 3866 patients with Type 2 diabetes and 4436 non-diabetic patients undergoing treatment for dyslipidaemia in 11 European countries. Diabetic patients were more likely to be obese or hypertensive than non-diabetic patients. Most patients received lifestyle interventions (87%) and/or a statin (89%); treatment patterns were similar between groups. Diabetic patients had [means (SD)] lower HDL-cholesterol [1.22 (0.37) vs. 1.35 mmol/l (0.44) vs. non-diabetic patients, P < 0.001] and higher triglycerides [2.32 (2.10) vs. 1.85 mmol/l (1.60), P < 0.001]. More diabetic vs. non-diabetic patients had low HDL-cholesterol (45% vs. 30%), high triglycerides (> or = 1.7 mmol/l; 57% vs. 42%) or both (32% vs. 19%). HDL-cholesterol < 0.9 mmol/l was observed in 18% of diabetic and 12% of non-diabetic subjects. Differences between diabetic and non-diabetic groups were slightly greater for women. LDL- and total cholesterol were lower in the diabetic group [3.02 (1.05) vs. 3.30 mmol/l (1.14) and 5.12 (1.32) vs. 5.38 mmol/l (1.34), respectively, P < 0.001 for each]. Low HDL-cholesterol is common in diabetes: one in two diabetic women has low HDL-cholesterol and one diabetic man in four has very low HDL-cholesterol. Management strategies should include correction of low HDL-cholesterol to optimize cardiovascular risk in diabetes.
Ucar, Fatih Mehmet
Oxidation and inflammation play significant roles in the pathogenesis of coronary artery diseases. Monocyte count to high-density lipoprotein (HDL) cholesterol ratio (MHR) is a new marker and has revealed as an indicator of inflammation in the literature. The present study aimed to search the effect of MHR on in-stent restenosis (ISR) in patients with stable or unstable angina pectoris undergoing bare-metal stent (BMS) implantation. A total of 468 consecutive stable or unstable angina pectoris patients (mean age 60.3 ± 10.1 and 70 % men) who had undergone successful BMS implantation were included the study. Serum samples were obtained before the procedure. The mean period between two coronary angiography procedures was 14 ± 7.9 months. The baseline MHR levels were significantly higher in patients that had ISR (odds ratio, 3.64; 95 % confidence interval, 2.45- 4.84; P < 0.001). Stent diameter, the time between the two coronary angiographic studies, uric acid and MHR levels emerged as independent predictors of ISR. Our results indicate that elevated MHR is an independent and powerful predictor of ISR in patients with stable or unstable angina pectoris who underwent successful BMS implantation.
Bridges, Kristie Grove; Jarrett, Traci; Thorpe, Anthony; Baus, Adam; Cochran, Jill
Background Studies have suggested that triglyceride to HDL-cholesterol ratio (TRG/HDL) is a surrogate marker of insulin resistance (IR), but information regarding its use in pediatric patients is limited. Objective This study investigated the ability of TRG/HDL ratio to assess IR in obese and overweight children. Subjects The sample consisted of de-identified electronic medical records of patients aged 10–17 years (n = 223). Materials and methods Logistic regression was performed using TRG/HDL ratio as a predictor of hyperinsulinemia or IR defined using homeostasis model assessment score. Results TRG/HDL ratio had limited ability to predict hyperinsulinemia (AUROC 0.71) or IR (AUROC 0.72). Although females had higher insulin levels, male patients were significantly more likely to have hypertriglyceridemia and impaired fasting glucose. Conclusions TRG/HDL ratio was not adequate for predicting IR in this population. Gender differences in the development of obesity-related metabolic abnormalities may impact the choice of screening studies in pediatric patients. PMID:26352085
Weerarathna, Thilak Priyantha; Herath, Herath Mudiyanselage Meththananda; Liyanage, Gayani
We aimed to study the prevalence and associations of suboptimal high density lipoproteins level, a characteristic feature in diabetic dyslipidemia among patients under statin therapy. From a database of 2416 patients, data on age, gender, duration of diabetes, body mass index (BMI) and waist circumference (WC), low density lipoproteins (LDL), triglyceride, high density lipoproteins (HDL) were obtained. Prevalence of suboptimal HDL (<40mg/dL in males and <50mg/dL in females) and its association with gender, age, duration of diabetes, BMI and WC were studied. The mean (SD) age of the sample (n=2416) was 53 (10) years and 64.2% of them (n=1550) were males. Prevalence of suboptimal HDL was 17.6%. Regression analysis revealed female gender, (OR 7.73, 95% CI 5.99-9.97) younger age (OR 0.98, 95% CI 0.97-0.99), higher BMI (OR1.05. 95% CI 1.00-1.2) and LDL level over 100mg/dL (OR 1.004, 95% CI 1.00-1.007) had significant associations with suboptimal HDL. Every sixth diabetic patient on statins has suboptimal HDL level. Females, younger and obese diabetic individuals should be more focused on achieving optimal HDL cholesterol levels. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.
Wilson, Thomas A; Nicolosi, Robert J; Kotyla, Timothy; Sundram, Kalyana; Kritchevsky, David
Several studies have reported on the effect of refined, bleached and deodorized palm oil (RBD-PO) incorporation into the diet on blood cholesterol concentrations and on the development of atherosclerosis. However, very little work has been reported on the influence of red palm oil (RPO), which is higher in carotenoid and tocopherol content than RBD-PO. Thus, we studied the influence of RPO, RBD-PO and a RBD-PO plus red palm oil extract (reconstituted RBD-PO) on plasma cholesterol concentrations and aortic accumulation vs. hamsters fed coconut oil. Forty-eight F1B Golden Syrian hamsters (Mesocricetus auratus) (BioBreeders, Watertown, MA) were group housed (three/cage) in hanging polystyrene cages with bedding in an air-conditioned facility maintained on a 12-h light/dark cycle. The hamsters were fed a chow-based hypercholesterolemic diet (HCD) containing 10% coconut oil and 0.1% cholesterol for 2 weeks at which time they were bled after an overnight fast and segregated into four groups of 12 with similar plasma cholesterol concentrations. Group 1 continued on the HCD, Group 2 was fed the HCD containing 10% RPO in place of coconut oil, Group 3 was fed the HCD containing 10% RBD-PO in place of coconut oil and Group 4 was fed the HCD with 10% reconstituted RBD-PO for an additional 10 weeks. Plasma total cholesterol (TC) and non-high-density lipoprotein-cholesterol (HDL-C) (very low- and low-density lipoprotein) concentrations were significantly lower in the hamsters fed the RPO (-42% and -48%), RBD-PO (-32% and -36%) and the reconstituted RBD-PO (-37% and -41%) compared to the coconut oil-fed hamsters. Plasma HDL-C concentrations were significantly higher by 14% and 31% in hamsters fed the RBD-PO and RPO compared to the coconut oil-fed hamsters. Plasma triglyceride (TG) concentrations were significantly lower in hamsters fed RBD-PO (-32%) and the reconstituted RBD-PO (-31%) compared to the coconut oil-fed hamsters. The plasma gamma-tocopherol concentrations were higher
Hashimoto, Naoto; Shinomiya, Noriyuki; Saito, Katsuichi; Noda, Takahiro; Han, Kyu-Ho; Fukushima, Michihiro
We investigated the cholesterol-lowering effect of a potato ethanol residue (PER). The plasma cholesterol levels excluding high-density lipoprotein cholesterol were lower in the rats given a PER-containing diet for 6 weeks than in the control group, whereas the fecal cholesterol levels were higher. These results suggest that PER partially reduced plasma cholesterol levels via excretion of cholesterol into the feces.
Badimon, J J; Badimon, L; Fuster, V
The effects of homologous plasma HDL and VHDL fractions on established atherosclerotic lesions were studied in cholesterol-fed rabbits. Atherosclerosis was induced by feeding the animals a 0.5% cholesterol-rich diet for 60 d (group 1). Another group of animals were maintained on the same diet for 90 d (group 2). A third group was also fed the same diet for 90 d but received 50 mg HDL-VHDL protein per wk (isolated from normolipemic rabbit plasma) during the last 30 d (group 3). Aortic atherosclerotic involvement at the completion of the study was 34 +/- 4% in group 1, 38.8 +/- 5% in group 2, and 17.8 +/- 4% in group 3 (P less than 0.005). Aortic lipid deposition was also significantly reduced in group 3 compared with group 1 (studied at only 60 d) and group 2. This is the first in vivo, prospective evidence of the antiatherogenic effect of HDL-VHDL against preexisting atherosclerosis. Our results showed that HDL plasma fractions were able to induce regression of established aortic fatty streaks and lipid deposits. Our results suggest that it may be possible not only to inhibit progression but even to reduce established atherosclerotic lesions by HDL administration.
Shimizu, Yuji; Nakazato, Mio; Sekita, Takaharu; Kadota, Koichiro; Yamasaki, Hironori; Takamura, Noboru; Aoyagi, Kiyoshi; Maeda, Takahiro
Although many studies have reported that elevated serum triglycerides to high-density lipoprotein cholesterol (TG-HDL) ratios constitute a risk for insulin resistance and increased arterial stiffness, no study has clarified as yet the association, in terms of the TG-HDL ratio, between diabetes and increased arterial stiffness evaluated by means of carotid intima-media thickness (CIMT) and cardio-ankle vascular index (CAVI). To investigate this association, we conducted a cross-sectional study of 1344 Japanese men aged 36-79 years undergoing a general health check. We investigated the associations between atherosclerosis/arterial stiffness, evaluated by means of CIMT and CAVI, and diabetes for all subjects, who were divided into tertiles according to TG-HDL levels. Diabetes was defined as HbA1c (NGSP) ≥6.5%, and/or initiation of glucose-lowering medication or insulin therapy. Of the 130 diabetes patients identified in the cohort, 56 patients had high TG-HDL (high TG-HDL diabetes) and 43 had low TG-HDL (low TG-HDL diabetes). We found that only diabetic patients with high TG-HDL were at a significant risk for atherosclerosis (diagnosed as CIMT ≥ 1.1 mm) and increased arterial stiffness (diagnosed as CAVI ≥ 8.0). The multivariable-adjusted odds ratios and 95% confidence intervals of atherosclerosis and increased arterial stiffness for diabetes were 2.67 (95%CI: 1.35-5.28) and 2.36 (95%CI: 1.01-5.50), for total TG-HDL diabetes 2.57 (95%CI: 1.32-5.02) and 3.56 (95%CI: 1.50-8.46) for high TG-HDL diabetes, and 1.17 (95%CI: 0.52-2.63) and 0.80 (95%CI: 0.33-1.90) for low TG-HDL diabetes, respectively. Diabetes, especially high TG-HDL diabetes, constitutes a significant risk for increased arterial stiffness and atherosclerosis. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Tuvdendorj, Demidmaa; Munoz, Alejandro O.; Ruiz-Barros, Viviana; Schwarz, Jean-Marc; Montalto, Giuseppe; Chandalia, Manisha; Sowers, Lawrence C.; Rizzo, Manfredi; Murphy, Elizabeth J; Abate, Nicola
Backgrounds and aims Low concentrations of plasma HDL-C are associated with the development of atherosclerotic cardiovascular diseases and type 2 diabetes. Here we aimed to explore the relationship between the in vivo fractional synthesis of triglycerides (fTG) in subcutaneous (s.q.) abdominal adipose tissue (AT), HDL-C concentrations and HDL particle size composition in non-diabetic humans. Methods The fTG in s.q. abdominal AT was measured in 16 non-diabetic volunteers (7 women, 9 men; Age: 49±20 years; BMI: 31±5 kg/m; Fasting Plasma Glucose: 90±10 mg/dl) after 2H2O labeling. HDL-C concentration and subclasses, large (L-HDL), intermediate (I-HDL) and small (S-HDL) were measured. Results Linear regression analyses demonstrated significant associations of fTG with plasma concentration of HDL-C (r=0.625,p=0.009) and percent contribution of L-HDL (r=0.798,p<0.001), I-HDL (r=−0.765,p<0.001) and S-HDL (r=−0.629, p=0.009). When analyses were performed by gender, the associations remained significant in women (HDL-C: r=0.822,p=0.023; L-HDL: r=0.892,p=0.007; I-HDL: r=−0.927,p=0.003) but not men. Conclusions Our study demonstrated an in vivo association between subcutaneous abdominal adipose tissue lipid dynamics and HDL parameters in humans, but this was true for women not men. Positive association with L-HDL and negative with I-HDL suggest that subcutaneous abdominal adipose tissue lipid dynamics may play an important role in production of mature functional HDL particles. Further studies evaluating the mechanism responsible for these associations and the observed gender differences are important and warranted to identify potential novel targets of intervention to increase the production of atheroprotective subclasses of HDL-Cs and thus decreasing the risks of development of atherosclerotic conditions. PMID:27323227
Cold, Frederik; Winther, Kristian H; Pastor-Barriuso, Roberto; Rayman, Margaret P; Guallar, Eliseo; Nybo, Mads; Griffin, Bruce A; Stranges, Saverio; Cold, Søren
Although cross-sectional studies have shown a positive association between Se and cholesterol concentrations, a recent randomised controlled trial in 501 elderly UK individuals of relatively low-Se status found that Se supplementation for 6 months lowered total plasma cholesterol. The Danish PRECISE (PREvention of Cancer by Intervention with Selenium) pilot study (ClinicalTrials.gov ID: NCT01819649) was a 5-year randomised, double-blinded, placebo-controlled trial with four groups (allocation ratio 1:1:1:1). Men and women aged 60-74 years (n 491) were randomised to 100 (n 124), 200 (n 122) or 300 (n 119) μg Se-enriched yeast or matching placebo-yeast tablets (n 126) daily for 5 years. A total of 468 participants continued the study for 6 months and 361 participants, equally distributed across treatment groups, continued for 5 years. Plasma samples were analysed for total and HDL-cholesterol and for total Se concentrations at baseline, 6 months and 5 years. The effect of different doses of Se supplementation on plasma lipid and Se concentrations was estimated by using linear mixed models. Plasma Se concentration increased significantly and dose-dependently in the intervention groups after 6 months and 5 years. Total cholesterol decreased significantly both in the intervention groups and in the placebo group after 6 months and 5 years, with small and nonsignificant differences in changes in plasma concentration of total cholesterol, HDL-cholesterol, non-HDL-cholesterol and total:HDL-cholesterol ratio between intervention and placebo groups. The effect of long-term supplementation with Se on plasma cholesterol concentrations or its sub-fractions did not differ significantly from placebo in this elderly population.
Vinagre, Juliana C; Vinagre, Carmen C G; Pozzi, Fernanda S; Zácari, Cristiane Z; Maranhão, Raul C
Previously, it was showed that vegan diet improves the metabolism of triglyceride-rich lipoproteins by increasing the plasma clearance of atherogenic remnants. The aim of the current study was to investigate this metabolism in lacto-ovo vegetarians whose diet is less strict, allowing the ingestion of eggs and milk. Transfer of lipids to HDL, an important step in HDL metabolism, was tested in vitro. Eighteen lacto-ovo vegetarians and 29 omnivorous subjects, all eutrophic and normolipidemic, were intravenously injected with triglyceride-rich emulsions labeled with ¹⁴C-cholesterol oleate and ³H-triolein. Fractional clearance rates (FCR, in min⁻¹) were calculated from samples collected during 60 min. Lipid transfer to HDL was assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids. LDL cholesterol was lower in vegetarians than in omnivores (2.1 ± 0.8 and 2.7 ± 0.7 mmol/L, respectively, p < 0.05), but HDL cholesterol and triglycerides were equal. Cholesteryl ester FCR was greater in vegetarians than in omnivores (0.016 ± 0.012, 0.003 ± 0.003, p < 0.01), whereas triglyceride FCR was equal. Cholesteryl ester transfer to HDL was lower in vegetarians than in omnivores (2.7 ± 0.6, 3.5 ± 1.5 %, p < 0.05), but free cholesterol, triglyceride and phospholipid transfers and HDL size were equal. Similarly to vegans, lacto-ovo vegetarian diet increases remnant removal, as indicated by cholesteryl oleate FCR, which may favor atherosclerosis prevention, and has the ability to change lipid transfer to HDL.
Gong, Shaoqing; Xu, Chun; Wang, Liang; Liu, Ying; Owusu, Daniel; Bailey, Beth A; Li, Yujing; Wang, Kesheng
The pleckstrin and Sec7 domain-containing 3 (PSD3) gene has been linked to immune diseases. We examined whether the genetic variants within the PSD3 gene are associated with obesity, type 2 diabetes (T2D), and high-density lipoprotein (HDL) cholesterol level. Multiple logistic regression model and linear regression model were used to examine the associations of 259 single nucleotide polymorphisms (SNPs) within the PSD3 gene with obesity and T2D as binary traits, and HDL level as a continuous trait using the Marshfield data, respectively. A replication study of obesity was conducted using the Health Aging and Body Composition (Health ABC) sample. 23SNPs were associated with obesity (p<0.05) in the Marshfield sample and rs4921966 revealed the strongest association (p=3.97×10(-6)). Of the 23SNPs, 20 were significantly associated with obesity in the meta-analysis of two samples (p<0.05). Furthermore, 6SNPs revealed associations with T2D in the Marshfield data (top SNP rs12156368 with p=3.05×10(-3)); while two SNPs (rs6983992 and rs7843239) were associated with both obesity and T2D (p=0.0188 and 0.023 for obesity and p=8.47×10(-3) and 0.0128 for T2D, respectively). Furthermore, 11SNPs revealed associations with HDL level (top SNP rs13254772 with p=2.79×10(-3)) in the Marshfield data; meanwhile rs7009615 was associated with both T2D (p=0.038) and HDL level (p=4.44×10(-3)). In addition, haplotype analyses further supported the results of single SNP analysis. Common variants in PSD3 were associated with obesity, T2D and HDL level. These findings add important new insights into the pathogenesis of obesity, T2D and HDL cholesterol. Published by Elsevier B.V.
Zhao, Qin; Li, Jianfei; Yang, Jin; Li, Rongshan
The aim of the study was to evaluate associations of total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) levels with prognosis in coronary heart disease (CHD) patients with heart failure (HF).Patients who were angiographical-diagnosis of CHD and echocardiographical-diagnosis of left ventricular ejection fraction (LVEF) < 45% were enrolled. Baseline characteristics were collected and association of TC and HDL-C levels with rehospitalization for HF and all-cause mortality was assessed.A total of 118 patients were recruited. Mean age was 58.6 ± 10.9 years and male accounted for 65%. Mean LVEF was 39.5 ± 4.0%. Twenty-eight patients were rehospitalized for HF and 6 patients were dead. In patients with poor prognosis, lower body mass index (BMI), TC, HDL-C and albumin while higher high sensitivity C-reactive protein (Hs-CRP) was observed. TC was positively correlated with BMI and albumin, and HDL-C was inversely correlated with Hs-CRP. The associations of TC level and rehospitalization for HF and all-cause mortality were attenuated but consistently significant through model 1 to 4, with odds ratio (OR) of 0.97 (95% confidence interval [CI]: 0.92-0.99). Associations of HDL-C level and rehospitalization for HF and all-cause mortality were also consistently significant through model 1 to 4, with OR of 0.95 (95% CI: 0.90-0.98). Strength of association was attenuated prominently in model 3 after adjusted for Hs-CRP, and no change was observed after further adjusted for BMI and albumin.Higher baseline TC and HDL-C levels are associated with better outcome in CHD patients with HF.
Zhao, Qin; Li, Jianfei; Yang, Jin; Li, Rongshan
Abstract The aim of the study was to evaluate associations of total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) levels with prognosis in coronary heart disease (CHD) patients with heart failure (HF). Patients who were angiographical-diagnosis of CHD and echocardiographical-diagnosis of left ventricular ejection fraction (LVEF) < 45% were enrolled. Baseline characteristics were collected and association of TC and HDL-C levels with rehospitalization for HF and all-cause mortality was assessed. A total of 118 patients were recruited. Mean age was 58.6 ± 10.9 years and male accounted for 65%. Mean LVEF was 39.5 ± 4.0%. Twenty-eight patients were rehospitalized for HF and 6 patients were dead. In patients with poor prognosis, lower body mass index (BMI), TC, HDL-C and albumin while higher high sensitivity C-reactive protein (Hs-CRP) was observed. TC was positively correlated with BMI and albumin, and HDL-C was inversely correlated with Hs-CRP. The associations of TC level and rehospitalization for HF and all-cause mortality were attenuated but consistently significant through model 1 to 4, with odds ratio (OR) of 0.97 (95% confidence interval [CI]: 0.92–0.99). Associations of HDL-C level and rehospitalization for HF and all-cause mortality were also consistently significant through model 1 to 4, with OR of 0.95 (95% CI: 0.90–0.98). Strength of association was attenuated prominently in model 3 after adjusted for Hs-CRP, and no change was observed after further adjusted for BMI and albumin. Higher baseline TC and HDL-C levels are associated with better outcome in CHD patients with HF. PMID:28248864
Laurinavicius, Antonio G; Santos, Itamar S; Santos, Raul D; Bensenor, Isabela M; Conceição, Raquel D; Lotufo, Paulo A
There is evidence that extremely elevated high-density lipoprotein cholesterol (HDL-c), that is, hyperalphalipoproteinemia (HALP) may indicate dysfunctional HDL, conferring increased cardiovascular risk. We studied carotid intima-media thickness (cIMT) a marker of subclinical vascular disease according to HDL-c distribution. cIMT was studied in subjects with "normal" HDL-c levels (HDL-c 40-50 mg/dL for men; 50-60 mg/dL for women, mean 49.6 ± 5.7 mg/dL, n = 3226); in those with HALP (HDL-c ≥90 mg/dL for both sexes, mean 101.2 ± 10 mg/dL, n = 264) and according to HDL-c quintile distribution (n = 9779). Multiple linear regression was used to test the association of HDL-c and cIMT. Subjects with HALP were older (54.5 ± 9.6 vs 51.1 ± 8.8 years, P < .001); more frequently females (86.4% vs 49%, P < .001); and presented a lower burden of risk factors: hypertension (24.6% vs 32.7%, P = .009), diabetes (10.2% vs 20.4%, P < .001), and obesity (18.6% vs 37.6%, P < .001). A similar profile was seen with higher HDL-c quintiles in the whole study population. When compared to normal HDL-c values, HALP was associated with lower maximal cIMT (0.779 ± 0.189 mm vs 0.818 ± 0.200 mm, P = .002), and there was a lower prevalence of individuals with cIMT ≥ 75(th) percentile for age and gender or high cIMT (17.5% vs 26.2%, P = .003). After multivariate analysis, no association was seen between HALP and increasing cIMT values, indeed the 5(th) HDL-c quintile was associated with lower risk of high cIMT (OR = 0.80; 95% CI = 0.68-0.95). HALP is associated with lower cIMT and does not indicate a pro-atherogenic phenotype. Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.
Odden, Michelle C.; Tager, Ira B.; Gansevoort, Ron T.; Bakker, Stephan J.L.; Fried, Linda F.; Newman, Anne B.; Katz, Ronit; Satterfield, Suzanne; Harris, Tamara; Sarnak, Mark J.; Siscovick, David; Shlipak, Michael G.
Purpose To determine if the associations among established risk factors and reduced kidney function vary by age. Methods We pooled cross-sectional data from 14,788 non-diabetics aged 40–100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort. Results Hypertension and low HDL-cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95% CI 0.1, 4.4), 5.1 (4.1, 6.1), and 6.9 (3.0, 10.4) mL/min/1.73 m2 lower eGFR in participants 40–59, 60–79, and 80+ years, respectively (p-value for interaction <0.001). The association of low HDL-cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (3.5, 6.3), 7.1 (CI 6.0, 8.3), 8.9 (CI 5.4, 11.9) mL/min/1.73 m2 (p-value for interaction <0.001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest. Conclusions Hypertension, obesity, smoking, and low HDL-cholesterol are modestly associated with reduced kidney function in non-diabetics. The associations of hypertension and HDL-cholesterol with reduced kidney function appear stronger in older adults. PMID:23313266
Boes, Eva; Coassin, Stefan; Kollerits, Barbara; Heid, Iris M; Kronenberg, Florian
High-density lipoprotein (HDL) particles exhibit multiple antiatherogenic effects. They are key players in the reverse cholesterol transport which shuttles cholesterol from peripheral cells (e.g. macrophages) to the liver or other tissues. This complex process is thought to represent the basis for the antiatherogenic properties of HDL particles. The amount of cholesterol transported in HDL particles is measured as HDL cholesterol (HDLC) and is inversely correlated with the risk for coronary artery disease: an increase of 1mg/dL of HDLC levels is associated with a 2% and 3% decrease of the risk for coronary artery disease in men and women, respectively. Genetically determined conditions with high HDLC levels (e.g. familial hyperalphalipoproteinemia) often coexist with longevity, and higher HDLC levels were found among healthy elderly individuals. HDLC levels are under considerable genetic control with heritability estimates of up to 80%. The identification and characterization of genetic variants associated with HDLC concentrations can provide new insights into the background of longevity. This review provides an extended overview on the current genetic-epidemiological evidence from association studies on genes involved in HDLC metabolism. It provides a path through the jungle of association studies which are sometimes confusing due to the varying and sometimes erroneous names of genetic variants, positions and directions of associations. Furthermore, it reviews the recent findings from genome-wide association studies which have identified new genes influencing HDLC levels. The yet identified genes together explain only a small amount of less than 10% of the HDLC variance, which leaves an enormous room for further yet to be identified genetic variants. This might be accomplished by large population-based genome-wide meta-analyses and by deep-sequencing approaches on the identified genes. The resulting findings will probably result in a re-drawing and extension of
Hanai, Ko; Babazono, Tetsuya; Yoshida, Naoshi; Nyumura, Izumi; Toya, Kiwako; Hayashi, Toshihide; Bouchi, Ryotaro; Tanaka, Nobue; Ishii, Akiko; Iwamoto, Yasuhiko
The impact of serum lipid abnormalities on the progression of diabetic kidney disease (DKD) remains conflicting. Furthermore, gender differences in the association between dyslipidaemia and outcome of DKD are largely unknown. We therefore conducted this single-centre observational cohort study to clarify gender differences in the association between serum lipid profiles and the progression of DKD. Seven hundred and twenty-three Japanese type 2 diabetes mellitus (T2DM) patients with normoalbuminuria or microalbuminuria, 280 women and 443 men, with a mean (± SD) age of 63 ± 11 years were studied. The endpoint was the progression to a more advanced stage of albuminuria. For statistical analyses, Cox proportional hazard model analyses were conducted. During the mean follow-up period of 4.3 years, 62 of 477 patients with normoalbuminuria and 69 of 246 patients with microalbuminuria reached the endpoint. A significant interaction between high-density lipoprotein (HDL) cholesterol and gender was detected (P(interaction) = 0.04); therefore, separate analyses were conducted for men and women. Overall, in men, the univariate Cox proportional hazard model revealed that higher triglycerides and lower HDL cholesterol levels were significantly associated with higher risk of reaching the endpoint. In the multivariate Cox proportional hazard model, only HDL cholesterol levels remained as an independent predictor of the endpoint (hazard ratio 0.391, P = 0.01). In women, no serum lipid parameters were associated with the endpoint. Lower HDL cholesterol levels seem to be associated with the progression of DKD in men but not in women.
Boes, Eva; Coassin, Stefan; Kollerits, Barbara; Heid, Iris M.; Kronenberg, Florian
High-density lipoprotein (HDL) particles exhibit multiple antiatherogenic effects. They are key players in the reverse cholesterol transport which shuttles cholesterol from peripheral cells (e.g. macrophages) to the liver or other tissues. This complex process is thought to represent the basis for the antiatherogenic properties of HDL particles. The amount of cholesterol transported in HDL particles is measured as HDL cholesterol (HDLC) and is inversely correlated with the risk for coronary artery disease: an increase of 1 mg/dL of HDLC levels is associated with a 2% and 3% decrease of the risk for coronary artery disease in men and women, respectively. Genetically determined conditions with high HDLC levels (e.g. familial hyperalphalipoproteinemia) often coexist with longevity, and higher HDLC levels were found among healthy elderly individuals. HDLC levels are under considerable genetic control with heritability estimates of up to 80%. The identification and characterization of genetic variants associated with HDLC concentrations can provide new insights into the background of longevity. This review provides an extended overview on the current genetic-epidemiological evidence from association studies on genes involved in HDLC metabolism. It provides a path through the jungle of association studies which are sometimes confusing due to the varying and sometimes erroneous names of genetic variants, positions and directions of associations. Furthermore, it reviews the recent findings from genome-wide association studies which have identified new genes influencing HDLC levels. The yet identified genes together explain only a small amount of less than 10% of the HDLC variance, which leaves an enormous room for further yet to be identified genetic variants. This might be accomplished by large population-based genome-wide meta-analyses and by deep-sequencing approaches on the identified genes. The resulting findings will probably result in a re-drawing and extension of
Bostan, Mehmet; Uydu, Hüseyin Avni; Yildirmis, Sermet; Malkoç, Meltem; Atak, Mehtap; Demir, Adem; Yilmaz, Adnan; Uğurlu, Yavuz; Karadağ, Zakir; Duman, Hakan; Satiroğlu, Omer
High-density lipoprotein cholesterol (HDL-C) levels are inversely related to the risk of coronary artery disease (CAD). Alterations in HDL-C subclass distribution and HDL-associated enzyme activities may be more important than total HDL levels for the progression of CAD. We intended to investigate the relationship of HDL-C subclass distribution and HDL-associated enzyme activities with CAD. Our study included 101 patients with stable coronary artery disease, and 64 healthy subjects. Serum levels of HDL lipoprotein-associated-phospholipase A2 (HDL-LpPLA2), paraoxonase 1 (PON1), and HDL subfraction distribution were measured. We found increased small HDL (sHDL) subfractions in patients with one-vessel disease (P < 0.001). We also found a reverse correlation between total HDL-C levels and affected vessel number (P < 0.05). Plasma HDL-Lp PLA2 enzyme level was higher in each vessel disease category compared to the control group (P < 0.001). However, PON1 enzyme activity in patients with CAD was not statically significant. Plasma sHDL, HDL-Lp PLA2 enzyme and Lp(a) were significantly different between subjects with CAD and control participants. We demonstrated decreased sHDL particles and a lower cardioprotective HDL-LpPLA, enzyme activity in all patient subgroups compared to controls. Measurement of total HDL-C level only may not be sufficient to predict CAD risk.
Verma, Nitin; Figueredo, Vincent M
Lowering low-density lipoprotein cholesterol (LDL) has been definitely shown to reduce cardiovascular events and improve clinical outcomes in the literature. As a result, LDL lowering has become the cornerstone of therapeutic approaches to cardiovascular disease prevention. Recently, there has been a focus on targeting other lipid fractions to improve the clinical risk profile of patients. Raising high-density lipoprotein (HDL) has received considerable attention. Low HDL levels are often seen in combination with elevated triglyceride levels. New therapeutic modalities are being developed to increase HDL levels. Recent failure of agents such as cholesteryl ester transferase protein inhibitor torcetrapib has highlighted the importance of measuring functionality of HDL particles and not just focus quantitatively on HDL-C levels. The heterogeneity of HDL within the systemic circulation results from constant remodeling of particles in response to several factors. Established dyslipidemia therapies such as stains, fibrates, and niacin have already been well known in the literature to have a substantial benefit. Lifestyle changes such as smoking cessation and moderate alcohol consumption have also shown to have some benefit. Several novel HDL therapies are currently being developed, but only the cholesteryl ester transferase protein inhibitors have received considerable attention. Although torcetrapib has received some negative attention due to adverse effects, this overall class of therapeutic agents still holds a lot of promise. Newer agents without the concerned toxicities are currently being developed. ApoA-1-related peptides, peroxisome proliferator-activated receptor agonists, endothelial lipase inhibitors, and liver X receptor agonists are some of the other novel agents currently in various stages of development.
Rondanelli, Mariangela; Giacosa, Attilio; Opizzi, Annalisa; Faliva, Milena Anna; Sala, Patrizio; Perna, Simone; Riva, Antonella; Morazzoni, Paolo; Bombardelli, Ezio
The aim of this study was to evaluate the effects of artichoke leaf extract (ALE) supplementation (250 mg, 2 b.i.d.) on the lipid pattern. A randomized, double-blind, placebo-controlled clinical trial was performed on 92 overweight subjects with primary mild hypercholesterolaemia for 8 weeks. Forty-six subjects were randomized to supplementation (age: 54.2 ± 6.6 years, body mass index (BMI): 25.8 ± 3.9 kg/m(2), male/female: 20/26) and 46 subjects to placebo (age: 53.8 ± 9.0 years, BMI: 24.8 ± 1.6 kg/m(2), male/female: 21/25). Verum supplementation was associated with a significant increase in mean high-density lipoprotein (HDL)-cholesterol (p < 0.001) and in mean change in HDL-cholesterol (HDL-C) (p = 0.004). A significantly decreased difference was also found for the mean change in total cholesterol (p = 0.033), low-density lipoprotein (LDL)-cholesterol (p < 0.001), total cholesterol/HDL ratio (p < 0.001) and LDL/HDL ratio (p < 0.001), when verum and placebo treatment were compared. These results indicate that ALE could play a relevant role in the management of mild hypercholesterolaemia, favouring in particular the increase in HDL-C, besides decreasing total cholesterol and LDL-cholesterol.
Background Previous data suggested that intake of sodas and other acid beverages might be associated with increased levels of serum triglycerides, lowered HDL cholesterol, and increased formation of mono unsaturated fatty acids, which are the preferred ones for triglyceride synthesis. The present work is an extension of these studies. Methods Thirty male rats were divided into 3 groups. All groups were given the same food, but various beverages: water (W), ammonium chloride, 200 mmol/L (AC), or sodium bicarbonate, 200 mmol/L (SB). Serum triglycerides, HDL cholesterol, and the fatty acid distribution in total serum lipids were determined. Delta9-desaturase in serum lipids was estimated by the ratio of palmitoleic to palmitic acid, and by the oleic/stearic acid ratio. Correlation and ANOVA were used to study associations and group differences. Results After 3 weeks, the AC group had higher triglyceride concentration and higher Delta9 desaturase indexes, but lower serum HDL and body weight as compared with the SB and W groups. In each of the groups, the oleic acid/stearic acid ratio correlated positively with serum triglycerides; in the pooled group the correlation coefficient was r = 0.963, p<0.01. Conclusions Rats ingesting ammonium chloride as compared with sodium bicarbonate responded with increased desaturase indexes, increased serum triglycerides, and lowered HDL cholesterol concentration, thereby possibly contributing to explain the increased triglyceride concentration previously observed in subjects with a frequent intake of acid beverages, such as sodas containing carbonic acid, citric acid, and phosphoric acid. PMID:23800210
Salazar, Martin R; Carbajal, Horacio A; Espeche, Walter G; Leiva Sisnieguez, Carlos E; Balbín, Eduardo; Dulbecco, Carlos A; Aizpurúa, Marcelo; Marillet, Alberto G; Reaven, Gerald M
Results of recent studies using the ratio of plasma triglyceride (TG) to high-density lipoprotein (HDL) cholesterol concentration to identify insulin-resistant patients at increased cardiometabolic risk have emphasized that the cut point used for this purpose will vary with race. Because TG and HDL cholesterol concentrations vary with gender, this analysis was initiated to define gender-specific plasma TG/HDL cholesterol concentration ratios that best identified high-risk subjects among women (n = 1,102) and men (n = 464) of primarily European ancestry. Insulin resistance was defined as the 25% of the population with the highest values for fasting plasma insulin concentration and homeostasis model assessment of insulin resistance. Using TG/HDL concentration ratios >2.5 in women and >3.5 in men identified subgroups of men and women that were comparable in terms of insulin resistance and associated cardiometabolic risk, with significantly higher values for fasting plasma insulin, homeostasis model assessment of insulin resistance, blood pressure, body mass index, waist circumference, and glucose and TG concentrations and lower HDL cholesterol concentrations than in women and men below these cut points. The sensitivity and specificity of these gender-specific cut points to identify insulin-resistant subjects were about 40% and about 80%, respectively. In conclusion, the plasma TG/HDL cholesterol concentration ratio that identifies patients who are insulin resistant and at significantly greater cardiometabolic risk varies between men and women.
Gan, Chaoye; Wang, Zhexuan; Chen, Yong
The major apolipoproteins of plasma lipoproteins play vital roles in the structural integrity and physiological functions of lipoproteins. More than ten structural models of apolipoprotein A-I (apoA-I), the major apolipoprotein of high-density lipoprotein (HDL), have been developed successively. In these models, apoA-I was supposed to organize in a ring-shaped form. To date, however, there is no direct evidence under physiological condition. Here, atomic force microscopy (AFM) was used to in situ visualize the organization of apoA-I, which was exposed via depletion of the lipid component of plasma HDL pre-immobilized on functionalized mica sheets. For the first time, the ring-shaped coarse structure and three detailed structures (crescent-shaped, gapped "O"-shaped, and parentheses-shaped structures, respectively) of apoA-I in plasma HDL, which have the ability of binding scavenger receptors, were directly observed and quantitatively measured by AFM. The three detailed structures probably represent the different extents to which the lipid component of HDL was depleted. Data on lipid depletion of HDL may provide clues to understand lipid insertion of HDL. These data provide important information for the understanding of the structure/maturation of plasma HDL. Moreover, they suggest a powerful method for directly visualizing the major apolipoproteins of plasma lipoproteins or the protein component of lipoprotein-like lipid-protein complexes. Copyright © 2017 Elsevier B.V. All rights reserved.
Kido, Toshimi; Kurata, Hideaki; Kondo, Kazuo; Itakura, Hiroshige; Okazaki, Mitsuyo; Urata, Takeyoshi; Yokoyama, Shinji
Plasma concentration of apoA-I, apoA-II and apoA-II-unassociated apoA-I was analyzed in 314 Japanese subjects (177 males and 137 females), including one (male) homozygote and 37 (20 males and 17 females) heterozygotes of genetic CETP deficiency. ApoA-I unassociated with apoA-II markedly and linearly increased with HDL-cholesterol, while apoA-II increased only very slightly and the ratio of apoA-II-associated apoA-I to apoA-II stayed constant at 2 in molar ratio throughout the increase of HDL-cholesterol, among the wild type and heterozygous CETP deficiency. Thus, overall HDL concentration almost exclusively depends on HDL with apoA-I without apoA-II (LpAI) while concentration of HDL containing apoA-I and apoA-II (LpAI:AII) is constant having a fixed molar ratio of 2 : 1 regardless of total HDL and apoA-I concentration. Distribution of apoA-I between LpAI and LpAI:AII is consistent with a model of statistical partitioning regardless of sex and CETP genotype. The analysis also indicated that LpA-I accommodates on average 4 apoA-I molecules and has a clearance rate indistinguishable from LpAI:AII. Independent evidence indicated LpAI:A-II has a diameter 20% smaller than LpAI, consistent with a model having two apoA-I and one apoA-II. The functional contribution of these particles is to be investigated. PMID:27526664
Watanabe, Hiroshi; Söderlund, Sanni; Soro-Paavonen, Aino; Hiukka, Anne; Leinonen, Eeva; Alagona, Corradina; Salonen, Riitta; Tuomainen, Tomi-Pekka; Ehnholm, Christian; Jauhiainen, Matti; Taskinen, Marja-Riitta
High-density lipoprotein (HDL) cholesterol correlates inversely with the risk of coronary heart disease (CHD). The precise antiatherogenic mechanisms of HDL subspecies are not thoroughly elucidated. We studied the relationship between carotid intima-media thickness (IMT) and HDL subspecies distribution in Finnish families with low HDL cholesterol and premature CHD. Altogether, 148 members of Finnish low-HDL families and 133 healthy control subjects participated in our study. HDL particle size was significantly smaller in affected family members (HDL < or =10th Finnish age-sex specific percentile) compared with unaffected family members and control subjects (9.1+/-0.04 nm versus 9.5+/-0.05 nm, P<0.0001, versus 9.8+/-0.03 nm, P<0.0001 [mean+/-SE]). Large HDL2b particles as well as prebeta-HDL concentration were significantly decreased among the affected family members. Mean IMT was significantly higher in the affected family members than in the control subjects (0.85+/-0.01 mm versus 0.79+/-0.01 mm; P<0.0001). Age, HDL2b, systolic blood pressure, and prebeta-HDL were significant independent determinants of mean IMT. The decreased levels of HDL2b and prebeta-HDL reflect the potentially efflux-deficient HDL subspecies profile in the affected low-HDL family members. Decreased HDL particle size caused by the decrease of plasma concentration of HDL2b and decreased prebeta-HDL levels correlate with increased IMT.
Jauhiainen, M.; Stevenson, K.J.; Dolphin, P.J.
Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme which catalyzes the transacylation of the fatty acid at the sn-2 position of lecithin to cholesterol forming lysolecithin and cholesteryl ester. The substrates for and products of this reaction are present within the plasma lipoproteins upon which the enzyme acts to form the majority of cholesteryl ester in human plasma. The authors proposed a covalent catalytic mechanism of action for LCAT in which serine and histidine residues mediate lecithin cleavage and two cysteine residues cholesterol esterification. With the aid of sulfhydryl reactive trivalent organoarsenical compounds which are specific for vicinal thiols they have probed the geometry of the catalytic site. They conclude that the two catalytic cysteine residues of LCAT (Cys/sup 31/ and Cys /sup 184/) are vicinal with a calculated distance between their sulfur atoms of 3.50-3.62 A. The additional residue alkylated by teh bifunctional reagent is within the catalytic site and may represent a previously identified catalytic serine or histidine residue.
Oaks, Brietta M; Stewart, Christine P; Laugero, Kevin D; Adu-Afarwuah, Seth; Lartey, Anna; Vosti, Stephen A; Ashorn, Per; Dewey, Kathryn G
Low plasma cholesterol may be associated with preterm birth; however, results are mixed and limited primarily to high-income countries. Our objective was to determine whether maternal plasma lipid concentrations are associated with pregnancy duration. We performed a nested cohort (n = 320) study of pregnant Ghanaian women enrolled in a randomized controlled trial. Total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, and triglyceride concentrations were analyzed in plasma at ≤20and 36 weeks gestation as continuous variables and also categorized into low, referent, or high (<10th, 10th-90th, >90th percentile). At ≤20 weeks, plasma lipid concentrations were not associated with pregnancy duration. At 36 weeks, total cholesterol and triglyceride concentrations were not associated with pregnancy duration. Higher HDL-C at 36 weeks was associated with a longer pregnancy duration (adjusted β-coefficient ± standard error: 0.05 ± 0.02 days mg(-1) /dL, p = .02); pregnancy duration was 5.9 ± 2.0 (mean ± standard error) days shorter among women with low HDL-C compared with the referent group (10th-90th percentile) (p = .02) and 8.6 ± 2.6 days shorter when compared with the high HDL-C group (p = .003). Pregnancy duration was 4.9 ± 2.1 days longer among women with low low-density lipoprotein cholesterol at 36 weeks gestation when compared with the referent group (p = .051). Our data suggest that low HDL-C in the third trimester of pregnancy is associated with a shorter duration of pregnancy in this study population but do not support the hypothesis that low total cholesterol is associated with a shorter pregnancy duration. © 2016 John Wiley & Sons Ltd.
DiMarco, Diana M; Norris, Gregory H; Millar, Courtney L; Blesso, Christopher N; Fernandez, Maria Luz
Background: HDL function may be more important than HDL concentration in determining risk for cardiovascular disease. In addition, HDL is a carrier of carotenoids and antioxidant enzymes, which protect HDL and LDL particles against oxidation.Objective: The goal of this study was to determine the impact of consuming 0-3 eggs/d on LDL and HDL particle size, HDL function, and plasma antioxidants in a young, healthy population.Methods: Thirty-eight healthy men and women [age 18-30 y, body mass index (in kg/m(2)) 18.5-29.9] participated in this 14-wk crossover intervention. Subjects underwent a 2-wk washout (0 eggs/d) followed by sequentially increasing intake of 1, 2, and 3 eggs/d for 4 wk each. After each period, fasting blood was collected for analysis of lipoprotein subfractions, plasma apolipoprotein (apo) concentration, lutein and zeaxanthin concentration, and activities of lecithin-cholesterol acyltransferase, cholesteryl ester transfer protein, and paraoxonase-1.Results: Compared with intake of 0 eggs/d, consuming 1-3 eggs/d resulted in increased large-LDL (21-37%) and large-HDL (6-13%) particle concentrations, plasma apoAI (9-15%), and lecithin-cholesterol acyltransferase activity (5-15%) (P < 0.05 for all biomarkers). Intake of 2-3 eggs/d also promoted an 11% increase in apoAII (P < 0.05) and a 20-31% increase in plasma lutein and zeaxanthin (P < 0.05), whereas intake of 3 eggs/d resulted in a 9-16% increase in serum paraoxonase-1 activity compared with intake of 1-2 eggs/d (P < 0.05). Egg intake did not affect cholesteryl ester transfer protein activity.Conclusions: Intake of 1 egg/d was sufficient to increase HDL function and large-LDL particle concentration; however, intake of 2-3 eggs/d supported greater improvements in HDL function as well as increased plasma carotenoids. Overall, intake of ≤3 eggs/d favored a less atherogenic LDL particle profile, improved HDL function, and increased plasma antioxidants in young, healthy adults. This trial was
Ji, Xiang; Xu, Hao; Zhang, Hao; Hillery, Cheryl A.; Gao, Hai-qing; Pritchard, Kirkwood A.
Proinflammatory high-density lipoprotein (p-HDL) is a biomarker of cardiovascular disease. Sickle cell disease (SCD) is characterized by chronic states of oxidative stress that many consider to play a role in forming p-HDL. To measure p-HDL, apolipoprotein (apo) B containing lipoproteins are precipitated. Supernatant HDL is incubated with an oxidant/LDL or an oxidant alone and rates of HDL oxidation monitored with dichlorofluorescein (DCFH). Although apoB precipitation is convenient for isolating HDL, the resulting supernatant matrix likely influences HDL oxidation. To determine effects of supernatants on p-HDL measurements we purified HDL from plasma from SCD subjects by anion exchange (AE) chromatography, determined its rate of oxidation relative to supernatant HDL. SCD decreased total cholesterol but not triglycerides or HDL and increased cell-free (cf) hemoglobin (Hb) and xanthine oxidase (XO). HDL isolated by AE-HPLC had lower p-HDL levels than HDL in supernatants after apoB precipitation. XO+xanthine (X) and cf Hb accelerated purified HDL oxidation. Although the plate and AE-HPLC assays both showed p-HDL directly correlated with cf-Hb in SCD plasma, the plate assay yielded p-HDL data that was influenced more by cf-Hb than AE-HPLC generated p-HDL data. The AE-HPLC p-HDL assay reduces the influence of the supernatants and shows that SCD increases p-HDL. PMID:24609013
Shiu, S W; Wong, Y; Tan, K C
Pre-β1 HDL, being a major acceptor of free cholesterol from cells, plays an important role in reverse cholesterol transport. This study was performed to determine whether abnormalities in pre-β1 HDL concentration were present in type 2 diabetes irrespective of their HDL-cholesterol levels, and the impact on cholesterol efflux. 640 type 2 diabetic patients with or without cardiovascular disease (CVD) and 360 non-diabetic controls matched for serum HDL-cholesterol levels were recruited. Plasma pre-β1 HDL was measured by ELISA, and cholesterol efflux to serum, mediated by ATP-binding cassette transporter A1 (ABCA1), was determined by measuring the transfer of [3H]cholesterol from cultured cells expressing ABCA1 to the medium containing the tested serum. Despite the diabetic subjects having matched HDL-cholesterol and total apoA1 as controls, plasma pre-β1 HDL was significantly reduced in both male (p < 0.01) and female diabetic patients (p < 0.05), and patients with CVD had the lowest pre-β1 HDL level. Serum capacity to induce ABCA1-mediated cholesterol efflux was impaired in the diabetic group (p < 0.01) and cholesterol efflux correlated with pre-β1 HDL (Pearson's r = 0.38, p < 0.01), and this association remained significantly even after controlling for age, gender, body mass index, diabetes status, smoking, apoA1, triglyceride and LDL. Plasma pre-β1 HDL level was significantly decreased in type 2 diabetes and was associated with a reduction in cholesterol efflux mediated by ABCA1. Our data would suggest that low pre-β1 HDL might cause impairment in reverse cholesterol transport in type 2 diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.
Jacek, Rysz; Anna, Gluba; Danilo, Fliser; Timo, Speer; Andrzej, Wiecek
Chronic kidney disease (CKD) is an emerging health hazard, connected to very high cardiovascular mortality due to accelerated atherosclerosis. Increased cardiovascular risk cannot be explained only by traditional risk factors. Patients with renal dysfunction have significant disturbances in lipoprotein metabolism and HDL in these patients becomes dysfunctional. It has been documented that in patients with CKD lower plasma level of HDL cholesterol and reduced ability of HDL to bind to ABCA1 are seen, which result in slowing down the reverse cholesterol transport and disturbances in HDL maturation due to decreased lecithin cholesterol ester transfer protein. Studies demonstrated that HDL of CKD patients loses its vasoprotective, antioxidative and anti-inflammatory properties and turns into a noxious particle which promotes endothelial dysfunction via stimulating superoxide production and limiting NO bioavailability. Alterations of HDL at the 'molecular and functional level' are also seen in renal transplant recipients even in those with excellent graft function.
Moyad, Mark A; Merrick, Gregory S
Pfizer Inc. recently discontinued its billion-dollar investment and phase III clinical trial of their new high-density lipoprotein (HDL) or "good cholesterol" boosting drug torceptrapib because of unexpected life-threatening side effects. To provide an objective discussion with patients looking for the next miracle drug or even dietary supplement in medicine, it is important to provide an overview of the history of this drug. It should serve as an important lesson that traditional lifestyle factors and proven heart healthy medications have stood the test of time in terms of research. Despite the current interest in drug development, traditional HDL-boosting lifestyle initiatives such as exercise, weight loss, and smoking cessation can be incorporated now and are heart and urologic healthy.
Lin, Yuguang; Vermeer, Mario A; Trautwein, Elke A
Hawthorn (Crataegus pinnatifida) is an edible fruit used in traditional Chinese medicine to lower plasma lipids. This study explored lipid-lowering compounds and underlying mechanisms of action of hawthorn. Hawthorn powder extracts inhibited acylCoA:cholesterol acyltransferase (ACAT) activity in Caco-2 cells. The inhibitory activity was positively associated with triterpenic acid (i.e., oleanolic acid (OA) and ursolic acid (UA)) contents in the extracts. Cholesterol lowering effects of hawthorn and its potential additive effect in combination with plant sterol esters (PSE) were further studied in hamsters. Animals were fed a semi-synthetic diet containing 0.08% (w/w) cholesterol (control) or the same diet supplemented with (i) 0.37% hawthorn dichloromethane extract, (ii) 0.24% PSE, (iii) hawthorn dichloromethane extract (0.37%) plus PSE (0.24%) or (iv) OA/UA mixture (0.01%) for 4 weeks. Compared to the control diet, hawthorn, PSE, hawthorn plus PSE and OA/UA significantly lowered plasma non-HDL (VLDL + LDL) cholesterol concentrations by 8%, 9%, 21% and 6% and decreased hepatic cholesterol ester content by 9%, 23%, 46% and 22%, respectively. The cholesterol lowering effects of these ingredients were conversely associated with their capacities in increasing fecal neutral sterol excretion. In conclusion, OA and UA are responsible for the cholesterol lowering effect of hawthorn by inhibiting intestinal ACAT activity. In addition, hawthorn and particularly its bioactive compounds (OA and UA) enhanced the cholesterol lowering effect of plant sterols.
Beer-Ljubić, B; Aladrović, J; Marenjak, T S; Laskaj, R; Majić-Balić, I; Milinković-Tur, S
The aim of this study was to investigate the relationship between lipid composition of bovine serum and seminal plasma, seasonality, and semen quality. The experiment was carried out in two groups of Simmental breeding bulls: Group I (ages 2 to 4 yr) and Group II (ages 5 to 10 yr). Blood samples were collected from jugular vein, and bovine semen was sampled with an artificial vagina once per season. Serum concentrations of total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triacylglycerols, nonesterified fatty acids (NEFAs), and lipoprotein electrophoretic patterns were determined. Seminal plasma concentrations of total cholesterol, HDL-C, and LDL-C were assayed. Serum concentration of triacylglycerols in young bulls was significantly higher in winter compared with that in autumn, whereas serum NEFA concentration was significantly higher in autumn compared with that in other seasons. Serum concentration of total cholesterol, LDL-C, and LDL lipoproteins in older bulls was significantly higher in winter than in spring. Seminal plasma concentration of total cholesterol in young bulls was significantly higher in spring compared with that in summer, whereas in older bulls it was significantly higher in winter compared with that in autumn samples. Sperm volume of both groups was significantly higher in summer compared with that in autumn and winter. Sperm motility in young bulls was lowest in summer and differed significantly from the values recorded in other seasons. The changes observed in seminal plasma cholesterol concentration were associated with extracellular lipid use and appeared to be applicable as a biochemical marker of sperm quality.
Khetarpal, Sumeet A; Edmondson, Andrew C; Raghavan, Avanthi; Neeli, Hemanth; Jin, Weijun; Badellino, Karen O; Demissie, Serkalem; Manning, Alisa K; DerOhannessian, Stephanie L; Wolfe, Megan L; Cupples, L Adrienne; Li, Mingyao; Kathiresan, Sekar; Rader, Daniel J
Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5' UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5' UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci.
Engel, Sara; Tholstrup, Tine
Butter is known to have a cholesterol-raising effect and, therefore, has often been included as a negative control in dietary studies, whereas the effect of moderate butter intake has not been elucidated to our knowledge. We compared the effects of moderate butter intake, moderate olive oil intake, and a habitual diet on blood lipids, high-sensitivity C-reactive protein (hsCRP), glucose, and insulin. The study was a controlled, double-blinded, randomized 2 × 5-wk crossover dietary intervention study with a 14-d run-in period during which subjects consumed their habitual diets. The study included 47 healthy men and women (mean ± SD total cholesterol: 5.22 ± 0.90 mmol/L) who substituted a part of their habitual diets with 4.5% of energy from butter or refined olive oil. Study subjects were 70% women with a mean age and body mass index (in kg/m²) of 40.4 y and 23.5, respectively. Butter intake increased total cholesterol and LDL cholesterol more than did olive oil intake (P < 0.05) and the run-in period (P < 0.005 and P < 0.05, respectively) and increased HDL cholesterol compared with the run-in period (P < 0.05). No difference in effects was observed for triacylglycerol, hsCRP, insulin, and glucose concentrations. The intake of saturated fatty acids was significantly higher in the butter period than in the olive oil and run-in periods (P < 0.0001). Moderate intake of butter resulted in increases in total cholesterol and LDL cholesterol compared with the effects of olive oil intake and a habitual diet (run-in period). Furthermore, moderate butter intake was also followed by an increase in HDL cholesterol compared with the habitual diet. We conclude that hypercholesterolemic people should keep their consumption of butter to a minimum, whereas moderate butter intake may be considered part of the diet in the normocholesterolemic population. © 2015 American Society for Nutrition.
Takahashi, Yuji; Ito, Yasuki; Wada, Norio; Nagasaka, Atsushi; Fujikawa, Masato; Sakurai, Toshihiro; Shrestha, Rojeet; Hui, Shu-Ping; Chiba, Hitoshi
Pathophysiological role for high-density lipoprotein (HDL) subclasses remains to be elucidated. Homogeneous assay for simultaneous measurements of apoE-deficient HDL-cholesterol (HDL-C), apoE-containing HDL-C, and total HDL-C is desired, because apoE plays important roles in lipid metabolism. The proposed assay consists of a primary reaction to remove non-HDL-C, a secondary reaction to measure apoE-deficient HDL-C, and a tertiary reaction to measure apoE-containing HDL-C. The assay is completed within 10 min. For control study, 13% polyethylene glycol precipitation assay and phosphotungstate-dextran sulfate-magnesium precipitation assay were carried out. Good correlations between the control assays and the proposed assay was obtained in serum samples from patients without liver disease (n=33): r=0.987, 0.957, and 0.991 for apoE-deficient, apoE-containing, and total HDL-C, respectively. ApoE-containing HDL-C by the proposed method in healthy individuals (n=12) and patients with hyper-HDL-cholesterolemia (n=5) were 0.11±0.03 and 0.26±0.05 mmol/l (4.1±1.3 and 10.1±2.0 mg/dl), respectively. ApoE-containing HDL-C increased rapidly at >2.59 mmol/l (100 mg/dl) of total HDL-C, suggesting a unique regulating mechanism of apoE-containing HDL-C. The established homogeneous assay might be useful for clinical and epidemiological studies on apoE-deficient and apoE-containing HDL subclasses. Copyright © 2016 Elsevier B.V. All rights reserved.
Vogt, A; Kassner, U; Hostalek, U; Steinhagen-Thiessen, E
Substantial residual cardiovascular risk persists despite effective LDL lowering treatment in populations at elevated risk for adverse cardiovascular outcomes. Low HDL cholesterol is an independent cardiovascular risk factor and occurs in about one-third of patients treated for dyslipidaemia in Europe. Moreover, randomised intervention studies have shown that increasing HDL cholesterol improves cardiovascular outcomes. Correcting low HDL cholesterol therefore presents a rational and proven strategy for intervention to produce further reductions in cardiovascular risk beyond those possible with a statin alone. Nicotinic acid (niacin in the USA) is the most effective agent currently available for increasing levels of HDL cholesterol. A once-daily, prolonged-release formulation of nicotinic acid (Niaspan) is as effective on HDL cholesterol as the immediate-release formulation, and is equally effective at increasing HDL cholesterol whether or not patients are already taking a statin. Niaspan also shares the antiatherogenic benefit of nicotinic acid, and induced regression of atherosclerosis in patients with cardiovascular disease during a period of treatment of up to 2 years. The incidence of flushing, the principal side effect of nicotinic acid, is lower with Niaspan than with immediate-release nicotinic acid. Simple practical measures are available to minimise the incidence and impact of flushing, including careful dose titration and avoiding hot or spicy foods near the time of ingestion of Niaspan. The potential for hepatotoxicity, muscle toxicity or marked exacerbation of hyperglycaemia in diabetes with Niaspan is very low, with or without concomitant statin treatment. Niaspan provides a practical means of delivering the cardioprotective benefits associated with correction of low HDL cholesterol.
Chang, Tae Ik; Streja, Elani; Soohoo, Melissa; Kim, Tae Woo; Rhee, Connie M; Kovesdy, Csaba P; Kashyap, Moti L; Vaziri, Nosratola D; Kalantar-Zadeh, Kamyar; Moradi, Hamid
Elevated serum triglyceride/HDL cholesterol (TG/HDL-C) ratio has been identified as a risk factor for cardiovascular (CV) disease and mortality in the general population. However, the association of this important clinical index with mortality has not been fully evaluated in patients with ESRD on maintenance hemodialysis (MHD). We hypothesized that the association of serum TG/HDL-C ratio with all-cause and CV mortality in patients with ESRD on MHD is different from the general population. We studied the association of serum TG/HDL-C ratio with all-cause and CV mortality in a nationally representative cohort of 50,673 patients on incident hemodialysis between January 1, 2007 and December 31, 2011. Association of baseline and time-varying TG/HDL-C ratios with mortality was assessed using Cox proportional hazard regression models, with adjustment for multiple variables, including statin therapy. During the median follow-up of 19 months (interquartile range, 11-32 months), 12,778 all-cause deaths and 4541 CV deaths occurred, respectively. We found that the 10th decile group (reference: sixth deciles of TG/HDL-C ratios) had significantly lower risk of all-cause mortality (hazard ratio, 0.91 [95% confidence interval, 0.83 to 0.99] in baseline and 0.86 [95% confidence interval, 0.79 to 0.94] in time-varying models) and CV mortality (hazard ratio, 0.83 [95% confidence interval, 0.72 to 0.96] in baseline and 0.77 [95% confidence interval, 0.66 to 0.90] in time-varying models). These associations remained consistent and significant across various subgroups. Contrary to the general population, elevated TG/HDL-C ratio was associated with better CV and overall survival in patients on hemodialysis. Our findings provide further support that the nature of CV disease and mortality in patients with ESRD is unique and distinct from other patient populations. Hence, it is vital that future studies focus on identifying risk factors unique to patients on MHD and decipher the underlying
Di Paola, R; Marucci, A; Trischitta, V
A wide range of studies both in humans and animal models point GALNT2 as a shaper of serum HDL-C and TG levels. Available data in humans indicate that, while under conditions of extreme GALNT2 loss-of-function HDL-C is the main target, a fine-tuning of GALNT2 changes is mostly associated with TG levels. Understanding whether different degrees of GALNT2 change do modulate different serum lipid fractions and, if so, addressing the mechanisms underlying such pleiotropic effects has the potential not only to improve our understanding of HDL-C and TG metabolism, but also to make GALNT2 becoming a target for treating atherogenic dyslipidemia and related clinical events. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
Proudfoot, Julie M.; Barden, Anne E.; Loke, Wai Mun; Croft, Kevin D.; Puddey, Ian B.; Mori, Trevor A.
Enhanced oxidative stress is implicated in the development of atherosclerosis in humans and animal models. F2-isoprostanes are formed in vivo via free radical peroxidation of arachidonic acid, and their quantification has allowed assessment of oxidative stress in vivo. F2-isoprostanes associate with lipids, although their distribution in human plasma lipoproteins is unknown. Our aim was to determine the distribution and levels of F2-isoprostanes in lipoproteins isolated from human plasma by ultracentrifugation and fast protein liquid chromatography (FPLC). F2-isoprostanes were significantly higher in HDL compared with LDL or VLDL after isolation by ultracentrifugation or FPLC. Furthermore, HDL3 particles contained elevated levels of F2-isoprostanes compared with HDL2. Platelet activating factor acetylhydrolase (PAF-AH), which hydrolyses esterified F2-isoprostanes from phospholipids, was predominantly associated with LDL. Reduced F2-isoprostanes in LDL may be related to higher PAF-AH activity in LDL. Paraoxonase 1 (PON-1) activity was associated with HDL2 and may be a contributing factor to the lower F2-isoprostanes in HDL2 compared with HDL3. Further studies are required to establish the implications of these findings on HDL function. PMID:19050315
Han, Chang Yeop; Tang, Chongren; Guevara, Myriam E.; Wei, Hao; Wietecha, Tomasz; Shao, Baohai; Subramanian, Savitha; Omer, Mohamed; Wang, Shari; O’Brien, Kevin D.; Marcovina, Santica M.; Wight, Thomas N.; Vaisar, Tomas; de Beer, Maria C.; de Beer, Frederick C.; Osborne, William R.; Elkon, Keith B.; Chait, Alan
HDL from healthy humans and lean mice inhibits palmitate-induced adipocyte inflammation; however, the effect of the inflammatory state on the functional properties of HDL on adipocytes is unknown. Here, we found that HDL from mice injected with AgNO3 fails to inhibit palmitate-induced inflammation and reduces cholesterol efflux from 3T3-L1 adipocytes. Moreover, HDL isolated from obese mice with moderate inflammation and humans with systemic lupus erythematosus had similar effects. Since serum amyloid A (SAA) concentrations in HDL increase with inflammation, we investigated whether elevated SAA is a causal factor in HDL dysfunction. HDL from AgNO3-injected mice lacking Saa1.1 and Saa2.1 exhibited a partial restoration of antiinflammatory and cholesterol efflux properties in adipocytes. Conversely, incorporation of SAA into HDL preparations reduced antiinflammatory properties but not to the same extent as HDL from AgNO3-injected mice. SAA-enriched HDL colocalized with cell surface–associated extracellular matrix (ECM) of adipocytes, suggesting impaired access to the plasma membrane. Enzymatic digestion of proteoglycans in the ECM restored the ability of SAA-containing HDL to inhibit palmitate-induced inflammation and cholesterol efflux. Collectively, these findings indicate that inflammation results in a loss of the antiinflammatory properties of HDL on adipocytes, which appears to partially result from the SAA component of HDL binding to cell-surface proteoglycans, thereby preventing access of HDL to the plasma membrane. PMID:26642365
Ho, Hoang V T; Sievenpiper, John L; Zurbau, Andreea; Blanco Mejia, Sonia; Jovanovski, Elena; Au-Yeung, Fei; Jenkins, Alexandra L; Vuksan, Vladimir
Oats are a rich source of β-glucan, a viscous, soluble fibre recognised for its cholesterol-lowering properties, and are associated with reduced risk of CVD. Our objective was to conduct a systematic review and meta-analysis of randomised-controlled trials (RCT) investigating the cholesterol-lowering potential of oat β-glucan on LDL-cholesterol, non-HDL-cholesterol and apoB for the risk reduction of CVD. MEDLINE, Embase, CINAHL and Cochrane CENTRAL were searched. We included RCT of ≥3 weeks of follow-up, assessing the effect of diets enriched with oat β-glucan compared with controlled diets on LDL-cholesterol, non-HDL-cholesterol or apoB. Two independent reviewers extracted data and assessed study quality and risk of bias. Data were pooled using the generic inverse-variance method with random effects models and expressed as mean differences with 95 % CI. Heterogeneity was assessed by the Cochran's Q statistic and quantified by the I 2-statistic. In total, fifty-eight trials (n 3974) were included. A median dose of 3·5 g/d of oat β-glucan significantly lowered LDL-cholesterol (-0·19; 95 % CI -0·23, -0·14 mmol/l, P<0·00001), non-HDL-cholesterol (-0·20; 95 % CI -0·26, -0·15 mmol/l, P<0·00001) and apoB (-0·03; 95 % CI -0·05, -0·02 g/l, P<0·0001) compared with control interventions. There was evidence for considerable unexplained heterogeneity in the analysis of LDL-cholesterol (I 2=79 %) and non-HDL-cholesterol (I 2=99 %). Pooled analyses showed that oat β-glucan has a lowering effect on LDL-cholesterol, non-HDL-cholesterol and apoB. Inclusion of oat-containing foods may be a strategy for achieving targets in CVD reduction.
Sutherland, Wayne H F; de Jong, Sylvia A; Walker, Robert J
Postprandial chylomicrons are potent ultimate acceptors of cell membrane cholesterol and are believed to accelerate reverse cholesterol transport (RCT). We compared the effects of meals rich in polyunsaturated fat (PUFA) and either high (605 mg) or low (151 mg) in cholesterol and a meal rich in dairy fat (DF) in the form of cream on net in vitro transport of red blood cell (RBC) membrane cholesterol to 4 and 6 h postprandial plasma in eight normotriglyceridemic (NTG-H) and eight hypertriglyceridemic (HTG-H) men with mild to moderate hypercholesterolemia. In HTG-H men, cell cholesterol accumulation in 6-h postprandial plasma was significantly (P = 0.02) less after the PUFA-HC meal compared with the other meals. The significant (P < 0.001) increase in cell plus endogenous cholesterol accumulation in the triglyceride-rich lipoprotein (TRL) fraction of 4 h postprandial plasma incubated with RBC was significantly (P = 0.007) higher after the PUFA-HC meal compared with DF meal in HTG-H men. In NTG-H men, cholesterol accumulation in plasma and plasma lipoproteins in the presence and absence of RBC was not significantly affected by the type of meal ingested. These data suggest that addition of large amounts of cholesterol to a PUFA meal may impair diffusion-mediated transport of cell membrane cholesterol to postprandial plasma and that replacing DF with PUFA in a meal increases postprandial lipemia and may potentially increase cholesterol accumulation in atherogenic postprandial TRL in HTG-H men.
de Oliveira Alvim, Rafael; Mourao, Carlos Alberto; Magalhães, Géssica Lopes; de Oliveira, Camila Maciel; Krieger, José Eduardo; Mill, José Geraldo; Pereira, Alexandre Costa
OBJECTIVES: Increased arterial stiffness is an important determinant of the risk of cardiovascular disease. Lipid profile impairment, especially hypercholesterolemia, is associated with stiffer blood vessels. Thus, the aim of this study was to determine which of the five circulating lipid components (high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL), total cholesterol (TC) and triglycerides) is the best predictor of increased arterial stiffness in an urban Brazilian population. METHODS: A random sample of 1,662 individuals from the general population of Vitoria, Brazil (25-64 years), was selected, and lipid components were measured using standard methods. Pulse wave velocity was measured using a non-invasive automatic device, and increased arterial stiffness was defined as a pulse wave velocity ≥10 m/s. RESULTS: In men, only total cholesterol (OR=1.59; CI=1.02 to 2.48, p=0.04) was associated with the risk of increased arterial stiffness. In women, HDL-C (OR=1.99; CI=1.18 to 3.35, p=0.01) and non-HDL-C (OR=1.61; CI=1.01 to 2.56, p=0.04) were good predictors of the risk of increased arterial stiffness. However, these associations were only found in postmenopausal women (OR=2.06; CI=1.00 to 4.26, p=0.05 for HDL-C and OR=1.83; CI=1.01 to 3.33, p=0.04 for non-HDL-C). CONCLUSION: Our findings indicate that both HDL-C and non-HDL-C are good predictors of the risk of increased arterial stiffness in postmenopausal women in an urban Brazilian population and may be useful tools for assessing the risk of arterial stiffness. PMID:28273234
Gossell-Williams, M; Hyde, C; Hunter, T; Simms-Stewart, D; Fletcher, H; McGrowder, D; Walters, C A
Pumpkin seed oil is rich in phytoestrogens and animal studies suggest that there is some benefit to supplementation in low estrogen conditions. This study is the first to evaluate the benefit of pumpkin seed oil in postmenopausal women. This pilot study was randomized, double-blinded and placebo-controlled. Study participants included 35 women who had undergone natural menopause or had iatrogenically entered the climacteric due to surgery for benign pathology. Wheat germ oil (placebo; n = 14) and pumpkin seed oil (n = 21) were administered to eligible participants over a 12-week period at a dose of 2 g per day. Serum lipids, fasting plasma glucose and blood pressure were measured and an 18-point questionnaire regarding menopausal symptoms was administered; the atherogenic index was also calculated. Differences between groups, as well as before and after the period of supplementation, were evaluated with Student's t-test, Wilcoxon matched-pair signed-ranked test and Mann-Whitney test, as appropriate (Stata version 10.1). Women receiving pumpkin seed oil showed a significant increase in high density lipoprotein cholesterol concentrations (0.92 ± 0.23 mmol/l vs. 1.07 ± 0.27 mmol/l; p = 0.029) and decrease in diastolic blood pressure (81.1 ± 7.94 mmHg vs. 75.67 ± 11.93 mmHg; p < 0.046). There was also a significant improvement in the menopausal symptom scores (18.1 ± 9.0 vs. 13.2 ± 6.7; p < 0.030), with a decrease in severity of hot flushes, less headaches and less joint pains being the main contributors. Women in the group receiving wheat germ oil reported being more depressed and having more unloved feeling. This pilot study showed pumpkin seed oil had some benefits for postmenopausal women and provided strong evidence to support further studies.
Choi, Eun-Young; Jang, Jin-Young
This study investigated the effect of coffee intake and exercise on the antioxidative activity and plasma cholesterol profile of physically trained rats while they were exercising. Forty eight rats were under either the control diet with water (C) or control diet with coffee (CF) and at the same time they were given physical training for 4 weeks. In terms of physical training, the rats were exercised on a treadmill for 30 minutes everyday. At the end of 4 weeks, animals in each dietary group were subdivided into 3 groups: before-exercise (BE); during-exercise (DE); after-exercise (AE). Animals in the DE group were exercised on a treadmill for one hour, immediately before being sacrificed. Animals in the AE group were allowed to take a rest for one hour after exercise. TG levels were significantly high in coffee intake group than in control group. Also TG level of AE group was significantly higher than that of BE group. Exercise and coffee-exercise interaction effects were significant in total cholesterol (P = 0.0004, 0.0170). The AE of coffee intake group showed highest total cholesterol levels. HDL-cholesterol was significantly lower in coffee intake group than in control group. Coffee, exercise, and coffee-exercise interaction effects were significant in SOD (P = 0.0001, 0.0001, and 0.0001). The AE and BE of coffee intake group showed higher SOD levels than the other four groups. Catalase activities were significantly higher in coffee intake group than control group. No significant main effect was found in GSH/GSSG. Coffee, exercise, and coffee-exercise interaction effects were significant in MDA levels (P = 0.0464, 0.0016, and 0.0353). The DE and AE of coffee intake group and the DE of control group showed higher MDA levels than the BE of control group. Therefore, coffee intake can promote activities of antioxidant enzyme but it also increases MDA and decreases HDL-cholesterol in physically trained rats. PMID:20827343
Chan, Jeannie; Kushwaha, Rampratap S.; VandeBerg, Jane F.; VandeBerg, John L.
Partially inbred lines of laboratory opossums differ in plasma LDL cholesterol concentration and cholesterol absorption on a high cholesterol diet. The aim of the present studies was to determine whether ezetimibe inhibits cholesterol absorption and eliminates the differences in plasma cholesterol and hepatic cholesterol metabolism between high and low responders on a high cholesterol diet. Initially, we determined that the optimum dose of ezetimibe was 5 mg/kg/day, and treated six high and six low responding opossums with this dose (with equal numbers of controls) for 3 weeks while opossums consumed a high cholesterol and low fat (HCLF) diet. Plasma and LDL cholesterol concentrations decreased significantly (P<0.05) in treated but not in untreated high responding opossums. Plasma cholesterol concentrations of untreated low responders increased slightly (P<0.05) but not in treated low responders. Percent cholesterol absorption was significantly higher in untreated high responders than in other groups. Livers from high responders with or without treatment were significantly (P <0.01) heavier than livers from low responders with or without treatment. Hepatic cholesterol concentrations in untreated high responders were significantly (P<0.05) higher than in low responders with or without treatment (P<0.001). The gall bladder bile cholesterol concentrations in untreated high responders were significantly (P<0.05) lower than in other groups. A decrease in biliary cholesterol in low responders treated with ezetimibe was associated with a decrease in hepatic expression of ABCG5 and ABCG8. These studies suggest that ezetimibe decreases plasma cholesterol levels in high responders mainly by decreasing cholesterol absorption and increasing biliary cholesterol concentrations. Since ezetimibe’s target is NPC1L1 and NPC1L1 is expressed in the intestine of opossums, its effect on cholesterol absorption may be mediated by inhibiting NPC1L1 function in the intestine. PMID
Chan, Jeannie; Kushwaha, Rampratap S; Vandeberg, Jane F; Vandeberg, John L
Partially inbred lines of laboratory opossums differ in plasma low-density lipoprotein cholesterol concentration and cholesterol absorption on a high-cholesterol diet. The aim of the present studies was to determine whether ezetimibe inhibits cholesterol absorption and eliminates the differences in plasma cholesterol and hepatic cholesterol metabolism between high and low responders on a high-cholesterol diet. Initially, we determined that the optimum dose of ezetimibe was 5 mg/(kg d) and treated 6 high- and 6 low-responding opossums with this dose (with equal numbers of controls) for 3 weeks while the opossums consumed a high-cholesterol and low-fat diet. Plasma and low-density lipoprotein cholesterol concentrations decreased significantly (P < .05) in treated but not in untreated high-responding opossums. Plasma cholesterol concentrations increased slightly (P < .05) in untreated low responders but not in treated low responders. The percentage of cholesterol absorption was significantly higher in untreated high responders than in other groups. Livers from high responders with or without treatment were significantly (P < .01) heavier than livers from low responders with or without treatment. Hepatic cholesterol concentrations in untreated high responders were significantly (P < .05) higher than those in low responders with or without treatment (P < .001). The gall bladder bile cholesterol concentrations in untreated high responders were significantly (P < .05) lower than those in other groups. A decrease in biliary cholesterol in low responders treated with ezetimibe was associated with a decrease in hepatic expression of ABCG5 and ABCG8. These studies suggest that ezetimibe decreases plasma cholesterol levels in high responders mainly by decreasing cholesterol absorption and increasing biliary cholesterol concentrations. Because ezetimibe's target is NPC1L1 and NPC1L1 is expressed in the intestine of opossums, its effect on cholesterol absorption may be mediated
Kirkland, R.T.; Keenan, B.S.; Probstfield, J.L.; Patsch, W.; Lin, T.L.; Clayton, G.W.; Insull, W. Jr.
A three-phase study tested the hypothesis that the decrease in the high-density lipoprotein cholesterol (HDL-C) level observed in boys at puberty is related to an increase in the plasma testosterone concentration. In phase I, 57 boys aged 10 to 17 years were categorized into four pubertal stages based on clinical parameters and plasma testosterone levels. These four groups showed increasing plasma testosterone values and decreasing HDL-C levels. In phase II, 14 boys with delayed adolescence were treated with testosterone enanthate. Plasma testosterone levels during therapy were in the adult male range. Levels of HDL-C decreased by a mean of 7.4 mg/dL (0.20 mmol/L) and 13.7 mg/dL (0.35 mmol/L), respectively, after the first two doses. In phase III, 13 boys with delayed adolescence demonstrated increasing plasma testosterone levels and decreasing HDL-C levels during spontaneous puberty. Levels of HDL-C and apolipoprotein A-1 were correlated during induced and spontaneous puberty. Testosterone should be considered a significant determinant of plasma HDL-C levels during pubertal development.
Lee, Jenny C; Weissglas-Volkov, Daphna; Kyttälä, Mira; Dastani, Zari; Cantor, Rita M; Sobel, Eric M; Plaisier, Christopher L; Engert, James C; van Greevenbroek, Marleen M J; Kane, John P; Malloy, Mary J; Pullinger, Clive R; Huertas-Vazquez, Adriana; Aguilar-Salinas, Carlos A; Tusie-Luna, Teresa; de Bruin, Tjerk W A; Aouizerat, Bradley E; van der Kallen, Carla C J; Croce, Carlo M; Aqeilan, Rami I; Marcil, Michel; Viikari, Jorma S A; Lehtimäki, Terho; Raitakari, Olli T; Kuusisto, Johanna; Laakso, Markku; Taskinen, Marja-Riitta; Genest, Jacques; Pajukanta, Päivi
Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 x 10(-7)). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 x 10(-4) to 2 x 10(-5). Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function.
Lee, Jenny C.; Weissglas-Volkov, Daphna; Kyttälä, Mira; Dastani, Zari; Cantor, Rita M.; Sobel, Eric M.; Plaisier, Christopher L.; Engert, James C.; van Greevenbroek, Marleen M.J.; Kane, John P.; Malloy, Mary J.; Pullinger, Clive R.; Huertas-Vazquez, Adriana; Aguilar-Salinas, Carlos A.; Tusie-Luna, Teresa; de Bruin, Tjerk W.A.; Aouizerat, Bradley E.; van der Kallen, Carla C.J.; Croce, Carlo M.; Aqeilan, Rami I.; Marcil, Michel; Viikari, Jorma S.A.; Lehtimäki, Terho; Raitakari, Olli T.; Kuusisto, Johanna; Laakso, Markku; Taskinen, Marja-Riitta; Genest, Jacques; Pajukanta, Päivi
Low serum HDL-cholesterol (HDL-C) is a major risk factor for coronary artery disease. We performed targeted genotyping of a 12.4 Mb linked region on 16q to test for association with low HDL-C by using a regional-tag SNP strategy. We identified one SNP, rs2548861, in the WW-domain-containing oxidoreductase (WWOX) gene with region-wide significance for low HDL-C in dyslipidemic families of Mexican and European descent and in low-HDL-C cases and controls of European descent (p = 6.9 × 10−7). We extended our investigation to the population level by using two independent unascertained population-based Finnish cohorts, the cross-sectional METSIM cohort of 4,463 males and the prospective Young Finns cohort of 2,265 subjects. The combined analysis provided p = 4 × 10−4 to 2 × 10−5. Importantly, in the prospective cohort, we observed a significant longitudinal association of rs2548861 with HDL-C levels obtained at four different time points over 21 years (p = 0.003), and the T risk allele explained 1.5% of the variance in HDL-C levels. The rs2548861 resides in a highly conserved region in intron 8 of WWOX. Results from our in vitro reporter assay and electrophoretic mobility-shift assay demonstrate that this region functions as a cis-regulatory element whose associated rs2548861 SNP has a specific allelic effect and that the region forms an allele-specific DNA-nuclear-factor complex. In conclusion, analyses of 9,798 subjects show significant association between HDL-C and a WWOX variant with an allele-specific cis-regulatory function. PMID:18674750
Rice bran oil and oryzanol reduce plasma lipid and lipoprotein cholesterol concentrations and aortic cholesterol ester accumulation to a greater extent than ferulic acid in hypercholesterolemic hamsters.
Wilson, Thomas A; Nicolosi, Robert J; Woolfrey, Benjamin; Kritchevsky, David
Our laboratory has reported that the hypolipidemic effect of rice bran oil (RBO) is not entirely explained by its fatty acid composition. Because RBO has a greater content of the unsaponifiables, which also lower cholesterol compared to most vegetable oils, we wanted to know whether oryzanol or ferulic acid, two major unsaponifiables in RBO, has a greater cholesterol-lowering activity. Forty-eight F(1)B Golden Syrian hamsters (Mesocricetus auratus) (BioBreeders, Watertown, MA) were group housed (three per cage) in cages with bedding in an air-conditioned facility maintained on a 12-h light/dark cycle. The hamsters were fed a chow-based hypercholesterolemic diet (HCD) containing 10% coconut oil and 0.1% cholesterol for 2 weeks, at which time they were bled after an overnight fast (16 h) and segregated into 4 groups of 12 with similar plasma cholesterol concentrations. Group 1 (control) continued on the HCD, group 2 was fed the HCD containing 10% RBO in place of coconut oil, group 3 was fed the HCD plus 0.5% ferulic acid and group 4 was fed the HCD plus 0.5% oryzanol for an additional 10 weeks. After 10 weeks on the diets, plasma total cholesterol (TC) and non-high-density lipoprotein cholesterol (HDL-C) (very low- and low-density lipoprotein) concentrations were significantly lower in the RBO (-64% and -70%, respectively), the ferulic acid (-22% and -24%, respectively) and the oryzanol (-70% and -77%, respectively) diets compared to control. Plasma TC and non-HDL-C concentrations were also significantly lower in the RBO (-53% and -61%, respectively) and oryzanol (-61% and -70%, respectively) diets compared to the ferulic acid. Compared to control and ferulic acid, plasma HDL-C concentrations were significantly higher in the RBO (10% and 20%, respectively) and oryzanol (13% and 24%, respectively) diets. The ferulic acid diet had significantly lower plasma HDL-C concentrations compared to the control (-9%). The RBO and oryzanol diets were significantly lower for
Maes, M; Smith, R; Christophe, A; Vandoolaeghe, E; Van Gastel, A; Neels, H; Demedts, P; Wauters, A; Meltzer, H Y
Recently, there have been some reports that changes in serum lipid composition may be related to suicide, major depression and immune-inflammatory responses. Findings from our laboratory suggest that major depression is accompanied by reduced formation of cholesteryl esters and perhaps by impairment of reverse cholesterol transport. The latter is reportedly accompanied by lower serum high-density lipoprotein cholesterol (HDL-C). The aim of this study was to examine whether (i) major depression is accompanied by lower serum HDL-C or by abnormal levels of serum total cholesterol, triglycerides, low-density lipoprotein-C (LDL-C) or vitamin E, (ii) suicidal attempts are related to lower serum HDL-C and (iii) there are significant associations between serum HDL-C and immune/inflammatory markers. A total of 36 subjects with major depression, of whom 28 patients showed treatment resistance, as well as 28 normal control subjects, had blood sampled for the assay of the above lipids, serum zinc (Zn), albumin (Alb) and flow cytometric determination of the T-helper/T-suppressor (CD4+/CD8+) T-cell ratio. In total, 28 depressed subjects had repeated measures of these variables both before and after treatment with antidepressants. Serum HDL-C and total cholesterol, as well as the HDL-C/cholesterol ratio, were significantly lower in subjects with major depression than in normal controls. Serum HDL-C levels were significantly lower in depressed men who had at some time made serious suicidal attempts than in those without such suicidal behaviour. Treatment with antidepressants for 5 weeks did not significantly alter either serum HDL-C or other lipid variables. Serum HDL-C levels were significantly and negatively correlated with the (CD4+/CD8+) T-cell ratio, and positively correlated with serum Alb and Zn. These results suggest that (i) lower serum HDL-C levels are a marker for major depression and suicidal behaviour in depressed men, (ii) lower serum HDL-C levels are probably
Thacker, Seth G.; Rousset, Xavier; Esmail, Safiya; Zarzour, Abdalrahman; Jin, Xueting; Collins, Heidi L.; Sampson, Maureen; Stonik, John; Demosky, Stephen; Malide, Daniela A.; Freeman, Lita; Vaisman, Boris L.; Kruth, Howard S.; Adelman, Steven J.; Remaley, Alan T.
LCAT, a plasma enzyme that esterifies cholesterol, has been proposed to play an antiatherogenic role, but animal and epidemiologic studies have yielded conflicting results. To gain insight into LCAT and the role of free cholesterol (FC) in atherosclerosis, we examined the effect of LCAT over- and underexpression in diet-induced atherosclerosis in scavenger receptor class B member I-deficient [Scarab(−/−)] mice, which have a secondary defect in cholesterol esterification. Scarab(−/−)×LCAT-null [Lcat(−/−)] mice had a decrease in HDL-cholesterol and a high plasma ratio of FC/total cholesterol (TC) (0.88 ± 0.033) and a marked increase in VLDL-cholesterol (VLDL-C) on a high-fat diet. Scarab(−/−)×LCAT-transgenic (Tg) mice had lower levels of VLDL-C and a normal plasma FC/TC ratio (0.28 ± 0.005). Plasma from Scarab(−/−)×LCAT-Tg mice also showed an increase in cholesterol esterification during in vitro cholesterol efflux, but increased esterification did not appear to affect the overall rate of cholesterol efflux or hepatic uptake of cholesterol. Scarab(−/−)×LCAT-Tg mice also displayed a 51% decrease in aortic sinus atherosclerosis compared with Scarab(−/−) mice (P < 0.05). In summary, we demonstrate that increased cholesterol esterification by LCAT is atheroprotective, most likely through its ability to increase HDL levels and decrease pro-atherogenic apoB-containing lipoprotein particles. PMID:25964513
Liu, Chao; Gaudet, Daniel; Miller, Yury I
Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency.
Liu, Chao; Gaudet, Daniel; Miller, Yury I.
Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency. PMID:28107429
Nobbs, B T; Smith, J M; Walker, A W
Enzymic procedures for the determination of plasma cholesterol, using cholesterol esterase and cholesterol oxidase, have been adapted to the Vickers D-300, Vickers M,-300, and Vitatron AKES discrete analysers. The results obtained by these methods have been compared to those obtained by manual and continuous flow Liebermann-Burchard methods. The enzymic methods were found to be accurate, precise and of adequate sensitivity.
Thayer, Julian F; Fischer, Joachim E
The aim of this study was to assess the relationship between autonomic nervous system activity as indexed by measures of heart rate variability and overnight urinary norepinephrine, and plasma cholesterol levels in a large sample of working adults. The study population comprised 611 apparently healthy employees of an airplane manufacturing plant in Southern Germany. Heart rate variability was calculated as beat-to-beat intervals over the course of one 24-hour weekday measured with an ambulatory ECG recorder. Overnight urine collection and blood samples were also obtained. We found an inverse association between indices of vagally-mediated heart rate variability and plasma levels of total cholesterol, low density lipoprotein (LDL), and the ratio of LDL to high density lipoprotein (HDL) that remained significant in multivariate models after controlling for relevant covariates including norepinephrine. Urinary norepinephrine was not significantly related to any measure of cholesterol in multivariate models. We report here for the first time, in a large sample of healthy human adults, evidence supporting the hypothesis of a clinically relevant inverse relationship between measures of plasma cholesterol and vagally-mediated heart rate variability after controlling for sympathetic nervous system activity. This suggests an important role for the vagal control of plasma cholesterol levels in cardiovascular disease. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Annema, Wijtske; Dikkers, Arne; de Boer, Jan Freark; Gautier, Thomas; Rensen, Patrick C N; Rader, Daniel J; Tietge, Uwe J F
ApoE plays an important role in lipoprotein metabolism. This study investigated the effects of adenovirus-mediated human apoE overexpression (AdhApoE3) on sterol metabolism and in vivo reverse cholesterol transport (RCT). In wild-type mice, AdhApoE3 resulted in decreased HDL cholesterol levels and a shift toward larger HDL in plasma, whereas hepatic cholesterol content increased (P < 0.05). These effects were dependent on scavenger receptor class B type I (SR-BI) as confirmed using SR-BI-deficient mice. Kinetic studies demonstrated increased plasma HDL cholesteryl ester catabolic rates (P < 0.05) and higher hepatic selective uptake of HDL cholesteryl esters in AdhApoE3-injected wild-type mice (P < 0.01). However, biliary and fecal sterol output as well as in vivo macrophage-to-feces RCT studied with (3)H-cholesterol-loaded mouse macrophage foam cells remained unchanged upon human apoE overexpression. Similar results were obtained using hApoE3 overexpression in human CETP transgenic mice. However, blocking ABCA1-mediated cholesterol efflux from hepatocytes in AdhApoE3-injected mice using probucol increased biliary cholesterol secretion (P < 0.05), fecal neutral sterol excretion (P < 0.05), and in vivo RCT (P < 0.01), specifically within neutral sterols. These combined data demonstrate that systemic apoE overexpression increases i) SR-BI-mediated selective uptake into the liver and ii) ABCA1-mediated efflux of RCT-relevant cholesterol from hepatocytes back to the plasma compartment, thereby resulting in unchanged fecal mass sterol excretion and overall in vivo RCT.
Fernandez, Maria Luz; Murillo, Ana Gabriela
It is well known that plasma lipids, waist circumference (WC) and blood pressure (BP) increase following menopause. In addition, there is a perceived notion that plasma high-density lipoprotein-cholesterol (HDL-C) concentrations also decrease in postmenopausal women. In this cross-sectional study, we evaluated plasma lipids, fasting glucose, anthropometrics and BP in 88 post and 100 pre-menopausal women diagnosed with metabolic syndrome. No differences were observed in plasma low-density lipoprotein-cholesterol cholesterol, triglycerides, fasting glucose or systolic and diastolic BP between groups. However, plasma HDL-C was higher (p < 0.01) in postmenopausal women and the percentage of women who had low HDL (<50 mg/dL) was higher (p < 0.01) among premenopausal women. In addition, negative correlations were found between WC and HDL-C (r = −0.148, p < 0.05) and BMI and HDL-C (r = −0.258, p < 0.01) for all subjects indicating that increases in weight and abdominal fat have a deleterious effect on plasma HDL-C. Interestingly, there was a positive correlation between age and plasma HDL-C (r = 0.237 p < 0.01). The results from this study suggest that although HDL is decreased by visceral fat and overall weight, low HDL is not a main characteristic of metabolic syndrome in postmenopausal women. Further, HDL appears to increase, not decrease, with age. PMID:27417608
Fernandez, Maria Luz; Murillo, Ana Gabriela
It is well known that plasma lipids, waist circumference (WC) and blood pressure (BP) increase following menopause. In addition, there is a perceived notion that plasma high-density lipoprotein-cholesterol (HDL-C) concentrations also decrease in postmenopausal women. In this cross-sectional study, we evaluated plasma lipids, fasting glucose, anthropometrics and BP in 88 post and 100 pre-menopausal women diagnosed with metabolic syndrome. No differences were observed in plasma low-density lipoprotein-cholesterol cholesterol, triglycerides, fasting glucose or systolic and diastolic BP between groups. However, plasma HDL-C was higher (p < 0.01) in postmenopausal women and the percentage of women who had low HDL (<50 mg/dL) was higher (p < 0.01) among premenopausal women. In addition, negative correlations were found between WC and HDL-C (r = -0.148, p < 0.05) and BMI and HDL-C (r = -0.258, p < 0.01) for all subjects indicating that increases in weight and abdominal fat have a deleterious effect on plasma HDL-C. Interestingly, there was a positive correlation between age and plasma HDL-C (r = 0.237 p < 0.01). The results from this study suggest that although HDL is decreased by visceral fat and overall weight, low HDL is not a main characteristic of metabolic syndrome in postmenopausal women. Further, HDL appears to increase, not decrease, with age.
Orsoni, Alexina; Saheb, Samir; Levels, Johannes H. M.; Dallinga-Thie, Geesje; Atassi, Marielle; Bittar, Randa; Robillard, Paul; Bruckert, Eric; Kontush, Anatol; Carrié, Alain; Chapman, M. John
Subnormal HDL-cholesterol (HDL-C) and apolipoprotein (apo)AI levels are characteristic of familial hypercholesterolemia (FH), reflecting perturbed intravascular metabolism with compositional anomalies in HDL particles, including apoE enrichment. Does LDL-apheresis, which reduces HDL-cholesterol, apoAI, and apoE by adsorption, induce selective changes in HDL subpopulations, with relevance to atheroprotection? Five HDL subpopulations were fractionated from pre- and post-LDL-apheresis plasmas of normotriglyceridemic FH subjects (n = 11) on regular LDL-apheresis (>2 years). Apheresis lowered both plasma apoE (−62%) and apoAI (−16%) levels, with preferential, genotype-independent reduction in apoE. The mass ratio of HDL2:HDL3 was lowered from ∼1:1 to 0.72:1 by apheresis, reflecting selective removal of HDL2 mass (80% of total HDL adsorbed). Pre-LDL-apheresis, HDL2 subpopulations were markedly enriched in apoE, consistent with ∼1 copy of apoE per 4 HDL particles. Large amounts (50-66%) of apoE-HDL were removed by apheresis, preferentially in the HDL2b subfraction (−50%); minor absolute amounts of apoE-HDL were removed from HDL3 subfractions. Furthermore, pre-β1-HDL particle levels were subnormal following removal (−53%) upon apheresis, suggesting that cellular cholesterol efflux may be defective in the immediate postapheresis period. In LDL-receptor (LDL-R) deficiency, LDL-apheresis may enhance flux through the reverse cholesterol transport pathway and equally attenuate potential biglycan-mediated deposition of apoE-HDL in the arterial matrix. PMID:21957200
Silva, Vanessa M; Vinagre, Carmen G C; Dallan, Luis A O; Chacra, Ana P M; Maranhão, Raul C
Metabolic syndrome (MetS) refers to states of insulin resistance that predispose to development of cardiovascular disease and type 2 diabetes (T2DM). The aim was to investigate whether plasma lipids and lipid metabolism differ in MetS patients compared to those with T2DM with poor glycemic control (glycated hemoglobin > 7.0). Eighteen patients with T2DM, 18 with MetS and 14 controls, paired for age (40-70 years) and body mass index (BMI), were studied. Plasma lipids and the kinetics of a triacylglycerol-rich emulsion labeled with [(3)H]-triolein ([(3)H]-TAG) and [(14)C]-cholesteryl esters ([(14)C]-CE) injected intravenously followed by one-hour blood sampling were determined. Lipid transfers from an artificial nanoemulsion donor to high-density lipoprotien (HDL) were assayed in vitro. Low-density lipoprotein (LDL) and HDL cholesterol (mg/dl) were not different in T2DM (128 ± 7; 42 ± 7) and MetS (142 ± 6; 39 ± 3), but triacylglycerols were even higher in MetS (215 ± 13) than in T2DM (161 ±11, p < 0.05). Fractional clearance rate (FCR, in min(1)) of [(3)H]-TAG and [(14)C]-CE were equal in T2DM (0.008 ± 0.018; 0.005 ± 0.024) and MetS (0.010 ± 0.016; 0.006 ± 0.013), and both were reduced compared to controls. The transfer of non-esterified cholesterol, phospholipids and triacylglycerols to HDL was higher in MetS and T2DM than in controls (p < 0.01). Cholesteryl ester transfer and HDL size were equal in all groups. Results imply that MetS is equal to poorly controlled T2DM concerning the disturbances of plasma lipid metabolism examined here, and suggest that there are different thresholds for the insulin action on glucose and lipids. These findings highlight the magnitude of the lipid disturbances in MetS, and may have implications in the prevention of cardiovascular diseases.
Background The search for sickle cell disease (SCD) prognosis biomarkers is a challenge. These markers identification can help to establish further therapy, later severe clinical complications and with patients follow-up. We attempted to study a possible involvement of levels of high-density lipoprotein cholesterol (HDL-C) in steady-state children with SCD, once that this lipid marker has been correlated with anti-inflammatory, anti-oxidative, anti-aggregation, anti-coagulant and pro-fibrinolytic activities, important aspects to be considered in sickle cell disease pathogenesis. Methods We prospectively analyzed biochemical, inflammatory and hematological biomarkers of 152 steady-state infants with SCD and 132 healthy subjects using immunochemistry, immunoassay and electronic cell counter respectively. Clinical data were collected from patient medical records. Results Of the 152 infants investigated had a significant positive association of high-density lipoprotein cholesterol with hemoglobin (P < 0.001), hematocrit (P < 0.001) and total cholesterol (P < 0.001) and a negative significant association with reticulocytes (P = 0.046), leukocytes (P = 0.015), monocytes (P = 0.004) and platelets (P = 0.005), bilirubins [total bilirubin (P < 0.001), direct bilirubin (P < 0.001) and indirect bilirubin (P < 0.001], iron (P < 0.001), aminotransferases [aspartate aminotransferase (P = 0.004), alanine aminotransferase (P = 0.035)], lactate dehydrogenase (P < 0.001), urea (P = 0.030), alpha 1-antitrypsin (P < 0.001), very low-density lipoprotein cholesterol (P = 0.003), triglycerides (P = 0.005) and hemoglobin S (P = 0.002). Low high-density lipoprotein cholesterol concentration was associated with the history of cardiac abnormalities (P = 0.025), pneumonia (P = 0.033) and blood transfusion use (P = 0.025). Lipids and inflammatory markers were associated with the presence of cholelithiasis. Conclusions We hypothesize that some SCD patients can have a specific dyslipidemic
Warnick, G R; Mayfield, C; Benderson, J; Chen, J S; Albers, J J
Two methods using commercial kits for high density lipoprotein (HDL) cholesterol quantitation were compared with the Lipid Research Clinics (LRC) procedures. HDL cholesterol quantitations on 50 patient specimens by the Lancer HDL cholesterol Rapid Stat Kit (Lancer) with phosphotungstate-Mg2+ precipitation and enzymic cholesterol assay averaged 424 mg/L, and by a method with dextran sulfate-Mn2+-polyethylene glycol (dextran sulfate) precipitation and enzymic cholesterol assay averaged 474 mg/L. By comparison, the LRC method (heparin-Mn2+ precipitation combined with a Liebermann-Burchard reagent cholesterol assay) averaged 478 mg/L. Supernates obtained by the three precipitation methods had similar cholesterol values when analyzed by the LRC assay, suggesting that the observed differences were primarily due to differences between the cholesterol assays. Results were consistent with underestimation by the enzymic assay of cholesterol in the supernates, offset by a positive interference of Mn2+ in the dextran sulfate-produced supernates. Among-day CVs of 4-5% were observed for the Lancer method, and 6-7% for the dextran sulfate method. Sedimentation of precipitates in hypertriglyceridemic specimens was excellent by both methods.
Pozzi, Fernanda S; Maranhão, Raul C; Guedes, Lissiane K; Borba, Eduardo F; Laurindo, Ieda M M; Bonfa, Eloisa; Vinagre, Carmen G
Rheumatoid arthritis (RA) is a systemic inflammatory disease associated with cardiovascular risk, but with normal plasma lipids. The aim was to investigate low-density lipoprotein (LDL) and high-density lipoprotein (HDL) metabolism in RA patients using radioactive nanoemulsions resembling an LDL lipid structure (LDE) as metabolic probes. Thirty patients with RA, 16 in remission and 14 in high activity, and 30 healthy controls were studied. LDE labeled with (14)C-cholesteryl ester ((14)C-CE) and (3)H-unesterified cholesterol ((3)H-UC) was intravenously injected followed by 24-hour plasma sampling. Fractional clearance rates (FCR, h(-1)) were calculated by compartmental analysis. Lipid transfers to HDL were assayed by incubating plasma samples with a donor nanoemulsion labeled with radioactive lipids; % lipids transferred to HDL were quantified after chemical precipitation. LDL cholesterol, triglycerides, unesterified cholesterol, and oxidized LDL were equal in RA and controls, and HDL cholesterol was even higher in RA. Compared with controls, apolipoprotein B was lower, apolipoprotein A1 was equal, and apolipoprotein E was higher in RA. Decay curves of LDE labels were faster in RA patients than in controls ((14)C-CE: 0.072 ± 0.066 and 0.038 ± 0.027, P = .0115; (3)H-UC: 0.066 ± 0.042 and 0.035 ± 0.039; P < .0044). FCRs were equal in 2 RA subgroups. Transfer of UC, triglycerides, and phospholipids to HDL was equal between RA and controls, but CE transfer was lower in RA. HDL size was smaller in RA patients than in controls (8.5 ± 0.5 nm; 9.2 ± 0.8 nm, P < .0001). RA patients were more efficient in removing atherogenic LDL from plasma, as indicated by higher CE and UC FCR, with in lower apolipoprotein B. This was unexpected because of the higher cardiovascular risk in RA. Copyright © 2015 National Lipid Association. Published by Elsevier Inc. All rights reserved.
Leduc, Magalie S; Blair, Rachael Hageman; Verdugo, Ricardo A; Tsaih, Shirng-Wern; Walsh, Kenneth; Churchill, Gary A; Paigen, Beverly
A higher incidence of coronary artery disease is associated with a lower level of HDL-cholesterol. We searched for genetic loci influencing HDL-cholesterol in F2 mice from a cross between MRL/MpJ and SM/J mice. Quantitative trait loci (QTL) mapping revealed one significant HDL QTL (Apoa2 locus), four suggestive QTL on chromosomes 10, 11, 13, and 18 and four additional QTL on chromosomes 1 proximal, 3, 4, and 7 after adjusting HDL for the strong Apoa2 locus. A novel nonsynonymous polymorphism supports Lipg as the QTL gene for the chromosome 18 QTL, and a difference in Abca1 expression in liver tissue supports it as the QTL gene for the chromosome 4 QTL. Using weighted gene co-expression network analysis, we identified a module that after adjustment for Apoa2, correlated with HDL, was genetically determined by a QTL on chromosome 11, and overlapped with the HDL QTL. A combination of bioinformatics tools and systems genetics helped identify several candidate genes for both the chromosome 11 HDL and module QTL based on differential expression between the parental strains, cis regulation of expression, and causality modeling. We conclude that integrating systems genetics to a more-traditional genetics approach improves the power of complex trait gene identification.
Hasvold, Pål; Thuresson, Marcus; Sundström, Johan; Hammar, Niklas; Kjeldsen, Sverre E; Johansson, Gunnar; Holme, Ingar; Bodegård, Johan
Statin-induced changes in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) are unrelated. Many patients initiated on statins experience a paradoxical decrease in HDL-C. The aim of this study was to evaluate the association between a decrease in HDL-C and risk of major adverse cardiovascular events (MACE). Data from 15,357 primary care patients initiated on statins during 2004-2009 were linked with data from mandatory national hospital, drug-dispensing, and cause-of-death registers, and were grouped according to HDL-C change: decreased ≥0.1 mmol/L, unchanged ±0.1 or ≥0.1 mmol/L increased. To evaluate the association between decrease in HDL-C and risk of MACE, a sample of propensity score-matched patients from the decreased and unchanged groups was created, using the latter group as reference. MACE was defined as myocardial infarction, unstable angina pectoris, ischaemic stroke, or cardiovascular mortality. Cox proportional hazards models were used to estimate relative risks. HDL-C decreased in 20%, was unchanged in 58%, and increased in 22% of patients initiated on statin treatment (96% treated with simvastatin). The propensity score-matched sample comprised 5950 patients with mean baseline HDL-C and LDL-C of 1.69 and 4.53 mmol/L, respectively. HDL-C decrease was associated with 56% higher MACE risk (hazard ratio 1.56; 95% confidence interval 1.12-2.16; p < 0.01) compared with the unchanged HDL-C group. Paradoxical statin-induced reduction in HDL-C was relatively common and was associated with increased risk of MACE.
O'Donovan, Gary; Stensel, David; Hamer, Mark; Stamatakis, Emmanuel
The objective of this study was to investigate associations between leisure-time physical activity, low high-density lipoprotein cholesterol (HDL-C) and mortality. Self-reported leisure-time physical activity, HDL-C concentration, and mortality were assessed in 37,059 adults in Health Survey for England and Scottish Health Survey. Meeting physical activity guidelines was defined as ≥150 min wk(-1) of moderate-intensity activity, ≥75 min wk(-1) of vigorous-intensity activity, or equivalent combinations. Low HDL-C was defined as <1.03 mmol L(-1). Cox proportional hazard models were adjusted for age, sex, smoking, total cholesterol, systolic blood pressure, body mass index, longstanding illness, and socioeconomic status. There were 2250 deaths during 326,016 person-years of follow-up. Compared with those who met physical activity guidelines and whose HDL-C was normal (reference group), all-cause mortality risk was not elevated in those who met physical activity guidelines and whose HDL-C concentration was low (hazard ratio: 1.07; 95% confidence interval: 0.75, 1.53). Compared with the reference group, all-cause mortality risk was elevated in those who did not meet physical activity guidelines and whose HDL-C was normal (1.37; 1.16, 1.61), and in those who did not meet physical activity guidelines and whose HDL-C was low (1.65; 1.37, 1.98). Cardiovascular disease mortality hazard ratios were similar, although confidence intervals were wider. There was no statistically significant evidence of biological interaction between physical inactivity and low HDL-C. This novel study supports the notion that leisure-time physical activity be recommended in those with low HDL-C concentration who may be resistant to the HDL-raising effect of exercise training.
Rosales, Corina; Tang, Daming; Gillard, Baiba K; Courtney, Harry S; Pownall, Henry J
Recombinant streptococcal serum opacity factor (rSOF) mediates the in vitro disassembly of human plasma high-density lipoprotein (HDL) into lipid-free apolipoprotein (apo) A-I, a neo-HDL that is cholesterol poor, and a cholesteryl ester-rich microemulsion (CERM) containing apoE. Given the occurrence of apoE on the CERM, we tested the hypothesis that rSOF injection into mice would reduce total plasma cholesterol clearance via apoE-dependent hepatic low-density lipoprotein receptors (LDLR). rSOF (4 μg) injection into wild-type C57BL/6J mice formed neo-HDL, CERM, and lipid-free apoA-I, as observed in vitro, and reduced plasma total cholesterol (-43%, t(1/2)=44±18 minutes) whereas control saline injections had a negligible effect. Similar experiments with apoE(-/-) and LDLR(-/-) mice reduced plasma total cholesterol ≈0% and 20%, respectively. rSOF was potent; injection of 0.18 μg of rSOF produced 50% of maximum reduction of plasma cholesterol 3 hours postinjection, corresponding to a ≈0.5-mg human dose. Most cholesterol was cleared hepatically (>99%), with rSOF treatment increasing clearance by 65%. rSOF injection into mice formed a CERM that was cleared via hepatic LDLR that recognize apoE. This reaction could provide an alternative mechanism for reverse cholesterol transport.
Ridker, Paul M; Genest, Jacques; Boekholdt, S Matthijs; Libby, Peter; Gotto, Antonio M; Nordestgaard, Børge G; Mora, Samia; MacFadyen, Jean G; Glynn, Robert J; Kastelein, John J P
HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events. We addressed, using the JUPITER trial cohort, whether this association remains when LDL-cholesterol concentrations are reduced to the very low ranges with high-dose statin treatment. Participants in the randomised placebo-controlled JUPITER trial were adults without diabetes or previous cardiovascular disease, and had baseline concentrations of LDL cholesterol of less than 3.37 mmol/L and high-sensitivity C-reactive protein of 2 mg/L or more. Participants were randomly allocated by a computer-generated sequence to receive rosuvastatin 20 mg per day or placebo, with participants and adjudicators masked to treatment assignment. In the present analysis, we divided the participants into quartiles of HDL-cholesterol or apolipoprotein A1 and sought evidence of association between these quartiles and the JUPITER primary endpoint of first non-fatal myocardial infarction or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT00239681. For 17,802 patients in the JUPITER trial, rosuvastatin 20 mg per day reduced the incidence of the primary endpoint by 44% (p<0.0001). In 8901 (50%) patients given placebo (who had a median on-treatment LDL-cholesterol concentration of 2.80 mmol/L [IQR 2.43-3.24]), HDL-cholesterol concentrations were inversely related to vascular risk both at baseline (top quartile vs bottom quartile hazard ratio [HR] 0.54, 95% CI 0.35-0.83, p=0.0039) and on-treatment (0.55, 0.35-0.87, p=0.0047). By contrast, among the 8900 (50%) patients given rosuvastatin 20 mg (who had a median on-treatment LDL-cholesterol concentration of 1.42 mmol/L [IQR 1.14-1.86]), no significant relationships were noted between quartiles of HDL-cholesterol concentration and vascular risk either at baseline (1.12, 0.62-2.03, p=0.82) or on-treatment (1.03, 0.57-1.87, p=0.97). Our analyses
Previous studies indicate that reduced concentrations of circulating high-density lipoprotein (HDL) particles can be superior to HDL-cholesterol (HDL-C) levels as a predictor of cardiovascular disease. Measurements of HDL particle numbers, therefore, bear a potential for the improved assessment of cardiovascular risk. Furthermore, such measurement can be relevant for the evaluation of novel therapeutic approaches targeting HDL. Modern in-depth analyses of HDL particle profile may further improve evaluation of cardiovascular risk. Although clinical relevance of circulating concentrations of HDL subpopulations to cardiovascular disease remains controversial, the negative relationship between the number of large HDL particles and cardiovascular disease suggests that assessment of HDL particle profile can be clinically useful. Reduced mean HDL size is equally associated with cardiovascular disease in large-scale clinical studies. Since HDL-C is primarily carried in the circulation by large, lipid-rich HDL particles, the inverse relationship between HDL size and cardiovascular risk can be secondary to those established for plasma levels of HDL particles, HDL-C, and large HDL. The epidemiological data thereby suggest that HDL particle number may represent a more relevant therapeutic target as compared to HDL-C.
Hermans, Michel P; Amoussou-Guenou, K Daniel; Bouenizabila, Evariste; Sadikot, Shaukat S; Ahn, Sylvie A; Rousseau, Michel F
The role of high-density lipoprotein cholesterol (HDL-C) as modifiable risk factor for cardiovascular (CV) disease is increasingly debated, notwithstanding the finding that small-dense and dysfunctional HDL are associated with the metabolic syndrome and T2DM. In order to better clarify the epidemiological risk related to HDL of different size/density, without resorting to direct measures, it would seem appropriate to adjust HDL-C to the level of its main apolipoprotein (apoA-I), thereby providing an [HDL-C/apoA-I] ratio. The latter allows not only to estimate an average size for HDLs, but also to derive indices on particle number, cholesterol load, and density. So far, the potential usefulness of this ratio in diabetes is barely addressed. To this end, we sorted 488 male patients with T2DM according to [HDL-C/apoA-I] quartiles (Q), to determine how the ratio relates to cardiometabolic risk, β-cell function, glycaemic control, and micro- and macrovascular complications. Five lipid parameters were derived from the combined determination of HDL-C and apoA-I, namely HDL size; particle number; cholesterol load/particle; apoA-I/particle; and particle density. An unfavorable cardiometabolic profile characterized patients from QI and QII, in which HDLs were pro-atherogenic, denser and apoA-I-depleted. By contrast, QIII patients had an [HDL-C/apoA-I] ratio close to that of non-diabetic controls. QIV patients had better than average HDL size and composition, and in those patients whose [HDL-C/apoA-I] ratio was above normal, a more favorable phenotype was observed regarding lifestyle, anthropometry, metabolic comorbidities, insulin sensitivity, MetS score/severity, glycaemic control, and target-organ damage pregalence in small or large vessels. In conclusion, [HDL-C/apoA-I] and the resulting indices of HDL composition and functionality predict macrovascular risk and β-cell function decline, as well as overall microangiopathic risk, suggesting that this ratio could serve
Turak, Osman; Afşar, Barış; Ozcan, Fırat; Öksüz, Fatih; Mendi, Mehmet Ali; Yayla, Çagrı; Covic, Adrian; Bertelsen, Nathan; Kanbay, Mehmet
Triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) has been suggested as a simple method to identify unfavorable cardiovascular outcomes in the general population. The effect of the TG/HDL-C ratio on essential hypertensive patients is unclear. About 900 consecutive essential hypertensive patients (mean age 52.9±12.6 years, 54.2% male) who visited our outpatient hypertension clinic were analyzed. Participants were divided into quartiles based on baseline TG/HDL-C ratio and medical records were obtained periodically for the occurrence of fatal events and composite major adverse cardiovascular events (MACEs) including transient ischemic attack, stroke, aortic dissection, acute coronary syndrome, and death. Participants were followed for a median of 40 months (interquartile range, 35-44 months). Overall, a higher quartile of TG/HDL-C ratio at baseline was significantly linked with higher incidence of fatal and nonfatal cardiovascular events. Using multivariate Cox regression analysis, plasma TG/HDL-C ratio was independently associated with increased risk of fatal events (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.13-1.37; P≤.001] and MACEs (HR, 1.13; 95% CI, 1.06-1.21; P≤.001). Increased plasma TG/HDL-C ratio was associated with more fatal events and MACEs in essential hypertensive patients. © 2015 Wiley Periodicals, Inc.
Berrougui, Hicham; Ikhlef, Souad; Khalil, Abdelouahed
Results of the present work give evidence from the beneficial role of extra virgin olive of oil (EVOO) consumption towards oxidative stress and cardiovascular diseases. Polyphenols contained in EVOO are responsible for inhibiting lipoproteins oxidative damages and promoting reverse cholesterol transport process via ABCA1 pathway. PMID:26495005
Frank-Kamenetsky, Maria; Grefhorst, Aldo; Anderson, Norma N; Racie, Timothy S; Bramlage, Birgit; Akinc, Akin; Butler, David; Charisse, Klaus; Dorkin, Robert; Fan, Yupeng; Gamba-Vitalo, Christina; Hadwiger, Philipp; Jayaraman, Muthusamy; John, Matthias; Jayaprakash, K Narayanannair; Maier, Martin; Nechev, Lubomir; Rajeev, Kallanthottathil G; Read, Timothy; Röhl, Ingo; Soutschek, Jürgen; Tan, Pamela; Wong, Jamie; Wang, Gang; Zimmermann, Tracy; de Fougerolles, Antonin; Vornlocher, Hans-Peter; Langer, Robert; Anderson, Daniel G; Manoharan, Muthiah; Koteliansky, Victor; Horton, Jay D; Fitzgerald, Kevin
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. Here, we have developed active, cross-species, small interfering RNAs (siRNAs) capable of targeting murine, rat, nonhuman primate (NHP), and human PCSK9. For in vivo studies, PCSK9 and control siRNAs were formulated in a lipidoid nanoparticle (LNP). Liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50-70%. The reduction in PCSK9 transcript was associated with up to a 60% reduction in plasma cholesterol concentrations. These effects were shown to be mediated by an RNAi mechanism, using 5'-RACE. In transgenic mice expressing human PCSK9, siRNAs silenced the human PCSK9 transcript by >70% and significantly reduced PCSK9 plasma protein levels. In NHP, a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc, without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for 3 weeks after a single bolus i.v. administration. These results validate PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia.
Rice, Mary Berlik; Cavallari, Jenn; Fang, Shona; Christiani, David
Objective To investigate acute changes in circulating lipids after exposure to relatively high levels of particulate matter through welding. Methods Using a repeated measures panel study, lipid levels before and after welding and personal exposures to fine particulate matter (PM2.5) were measured in 36 male welders over 63 exposure and/or control days. Results There was a trend toward decrease in HDL (−2.3 mg/dL, P = 0.08) 18 hours after welding. This effect became significant (−2.6 mg/dL, P = 0.05) after adjustment for possible confounders. The effect was strongest (−4.3 mg/dL, P = 0.02) among welders who did not weld the day before the study. There were no significant changes in other lipids associated with welding or PM2.5 exposure. Conclusion Welding exposure was associated with an acute decrease in circulating HDL, which may relate to the inflammatory and proatherosclerotic effects of fine particle exposure. PMID:21187793
Holzinger, Emily R; Dudek, Scott M; Frase, Alex T; Krauss, Ronald M; Medina, Marisa W; Ritchie, Marylyn D
Technology is driving the field of human genetics research with advances in techniques to generate high-throughput data that interrogate various levels of biological regulation. With this massive amount of data comes the important task of using powerful bioinformatics techniques to sift through the noise to find true signals that predict various human traits. A popular analytical method thus far has been the genome-wide association study (GWAS), which assesses the association of single nucleotide polymorphisms (SNPs) with the trait of interest. Unfortunately, GWAS has not been able to explain a substantial proportion of the estimated heritability for most complex traits. Due to the inherently complex nature of biology, this phenomenon could be a factor of the simplistic study design. A more powerful analysis may be a systems biology approach that integrates different types of data, or a meta-dimensional analysis. For this study we used the Analysis Tool for Heritable and Environmental Network Associations (ATHENA) to integrate high-throughput SNPs and gene expression variables (EVs) to predict high-density lipoprotein cholesterol (HDL-C) levels. We generated multivariable models that consisted of SNPs only, EVs only, and SNPs + EVs with testing r-squared values of 0.16, 0.11, and 0.18, respectively. Additionally, using just the SNPs and EVs from the best models, we generated a model with a testing r-squared of 0.32. A linear regression model with the same variables resulted in an adjusted r-squared of 0.23. With this systems biology approach, we were able to integrate different types of high-throughput data to generate meta-dimensional models that are predictive for the HDL-C in our data set. Additionally, our modeling method was able to capture more of the HDL-C variation than a linear regression model that included the same variables.
Ganjali, Shiva; Blesso, Christopher N; Banach, Maciej; Pirro, Matteo; Majeed, Muhammed; Sahebkar, Amirhossein
Curcumin, a bioactive polyphenol, is a yellow pigment of the Curcuma longa (turmeric) plant. Curcumin has many pharmacologic effects including antioxidant, anti-carcinogenic, anti-obesity, anti-angiogenic and anti-inflammatory properties. Recently, it has been found that curcumin affects lipid metabolism, and subsequently, may alleviate hyperlipidemia and atherosclerosis. Plasma HDL cholesterol (HDL-C) is an independent negative risk predictor of cardiovascular disease (CVD). However, numerous clinical and genetic studies have yielded disappointing results about the therapeutic benefit of raising plasma HDL-C levels. Therefore, research efforts are now focused on improving HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to heterogeneity in composition. Consistent with its complexity in composition and metabolism, a wide range of biological activities is reported for HDL, including antioxidant, anti-glycation, anti-inflammatory, anti-thrombotic, anti-apoptotic and immune modulatory activities. Protective properties of curcumin may influence HDL functionality; therefore, we reviewed the literature to determine whether curcumin can augment HDL function. In this review, we concluded that curcumin may modulate markers of HDL function, such as apo-AI, CETP, LCAT, PON1, MPO activities and levels. Curcumin may subsequently improve conditions in which HDL is dysfunctional and may have potential as a therapeutic drug in future. Further clinical trials with bioavailability-improved formulations of curcumin are warranted to examine its effects on lipid metabolism and HDL function. Copyright © 2017 Elsevier Ltd. All rights reserved.
McGue, M; Rao, D C; Iselius, L; Russell, J M
A path model and associated statistical method for the analysis of data on twin families are introduced and applied to high density lipoprotein cholesterol (HDL-c) observations in the Swedish Twin Family Study. The proposed path model incorporates both genetic and environmental sources of familial resemblance, maternal environmental effects, intergenerational differences in heritabilities, marital resemblance due to either primary or secondary phenotypic homogamy, and twin residual environmental correlations. Application of the model to HDL-c levels resulted in parameter estimates consistent with those reported in earlier reviews and in the analysis of nuclear family and twin data. Genetic heritability was estimated as h2 = .363 +/- .243, cultural heritability as c2 = .187 +/- .082, and the proportion of phenotypic variance due to residual environmental effects as r2 = .450 +/- .207. Although the parameter estimates were comparable, the statistical tests of hypotheses were, relative to other designs, of low statistical power. It appears that environmental indices are necessary for powerful tests of hypotheses. PMID:4050793
Lahoz-Tornos, Álvaro; Vilchez-Aguilera, Juan A; Hernandez-Romero, Diana; Romero-Aniorte, Ana I; Orenes-Piñero, Esteban; Jara-Rubio, Ruben; Del Saz-Ortiz, Ana; Arribas-Leal, José María; García-Alberola, Arcadio; Valdés-Chávarri, Mariano; Marín-Ortuño, Francisco
Atrial fibrillation (AF) has an incidence rate of approximately 30% and is the most frequent arrhythmia following heart surgery. Factors such as inflammation, the presence of heart fibrosis, stress and cardiomyocyte apoptosis, have all been associated with AF. We believe that atrial remodelling is a pre-existent process in patients with post-surgical AF. We have analyzed the factors related to the incidence of atrial fibrillation in the period after heart surgery. We included consecutive, hemodynamically stable patients with a sinusal rhythm who were subjected to programmed heart surgery with extracorporeal circulation. An assessment was made of the fall in atrial fibrillation after surgery using prolonged electrocardiographic monitoring. A total of 100 patients were included in the study and were subjected to either coronary revascularisation surgery (59) or aortic valve substitution due to severe aortic stenosis (41). Postoperative AF occurred in 29 patients who received predominantly more valve surgery than coronary surgery. The following factors were predictive of postoperative AF in the multivariate analysis: Male sex; beta-blocker therapy for chronic disease; the use of intraoperative; fibrinogen perfusion; low HDL cholesterol values; and high sensitive troponin T values, in the preoperative period. HDL cholesterol and high sensitive troponin T can be useful biomarkers to predict the occurrence of AF after surgery. The early identification of these patients who develop of FA allows us to take preventive measures to minimize the negative effects. Copyright © 2013 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. All rights reserved.
Kunutsor, Setor K; Zaccardi, Francesco; Karppi, Jouni; Kurl, Sudhir; Laukkanen, Jari A
Low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c), which are components of total cholesterol, have each been suggested to be linked to the risk of sudden cardiac death (SCD). However, the relationship between LDL-c/HDL-c ratio and the risk of SCD has not been previously investigated. We aimed to assess the associations of LDL-c, HDL-c, and the ratio of LDL-c/HDL-c with the risk of SCD. Serum lipoprotein concentrations were assessed at baseline in the Finnish Kuopio Ischemic Heart Disease prospective cohort study of 2,616 men aged 42-61 years at recruitment. Hazard ratios (HRs) (95% confidence intervals [CI]) were assessed. During a median follow-up of 23.0 years, a total of 228 SCDs occurred. There was no significant evidence of an association of LDL-c or HDL-c with the risk of SCD. In analyses adjusted for age, examination year, body mass index, systolic blood pressure, smoking, alcohol consumption, physical activity, years of education, diabetes, previous myocardial infarction, family history of coronary heart disease, and serum high sensitivity C-reactive protein, there was approximately a two-fold increase in the risk of SCD (HR 1.94, 95% CI 1.21-3.11; p=0.006), comparing the top (＞4.22) versus bottom (≤2.30) quintile of serum LDL-c/HDL-c ratio. In this middle-aged male population, LDL-c or HDL-c was not associated with the risk of SCD. However, a high serum LDL-c/HDL-c ratio was found to be independently associated with an increased risk of SCD. Further research is warranted to understand the mechanistic pathways underlying this association.
Gadi, Ramprasad; Amanullah, Aman; Figueredo, Vincent M
It has long been recognized that elevated levels of low-density lipoprotein cholesterol (LDL-C) increase the risk of cardiovascular disease (CHD) and that pharmacologic therapy to decrease LDL-C significantly reduces cardiovascular events. Despite the effectiveness of statins for CHD risk reduction, even optimal LDL-lowering therapy alone fails to avert 60% to 70% of CHD cases. A low plasma concentration of high-density lipoprotein cholesterol (HDL-C) is also associated with increased risk of CHD. However, the convincing epidemiologic data linking HDL cholesterol (HDL-C) to CHD risk in an inverse correlation has not yet translated into clinical trial evidence supporting linearity between HDL-C increases and CHD risk reduction. It is becoming clear that a functional HDL is a more desirable target than simply increasing HDL-C levels. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights, in turn, have fueled the development of new HDL-targeted drugs, which can be classified according to four different therapeutic approaches: directly augmenting the concentration of apolipoprotein A-I (apo A-I), the major protein constituent of HDL; indirectly augmenting the concentration of apo A-I and HDL cholesterol; mimicking the functionality of apo A-I and enhancing reverse cholesterol transport. This review discusses the latest in novel HDL directed therapeutic strategies.
Kim, Nam-Young; Kim, Kyu-Il
We conducted two studies to determine the effect of gender, gonadectomy (GDX) on growth and plasma cholesterol levels in pigs. In experiment 1, five sham-operated and five GDX female Landrace pigs (26 kg) were allowed to have free access to water and feed up to market weight (approximately 100 kg). Body weight and feed consumption were recorded biweekly, and daily body weight gain, daily feed intake and feed efficiency (gain/feed) were calculated during the feeding period. In experiment 2, 10 male (26 kg) and 10 female (26 kg) Landrace pigs were used; five male and five female pigs were assigned to sham-operated or GDX. Pigs were allowed to have free access to water and a diet without added cholesterol (Table 1) until they were 6 months old (male 104 and female 98 kg) and thereafter they were fed a hypercholesterolemic diet (Table 1) containing 0.5% cholesterol and 0.1% cholate for 10 days. GDX of female pigs increased average daily gain (P<0.05), compared with their sham-operated counterparts during the growing-finishing period, but had no effect (P>0.05) on feed efficiency. Plasma cholesterol levels in pigs fed a hypercholesterolemic diet for 10 days were much higher (P<0.05) in females than in males (161 vs 104 mg/100 mL plasma), and were increased by GDX only in male pigs. HDL-cholesterol/LDL+VLDL-cholesterol ratio appeared to be higher in males than in females, and was not influenced by GDX in either sex. Results suggested that the lower growth rate of female pigs than their male counterparts is attributable to the ovarian activity, and the lower plasma cholesterol level in male than in female pigs fed a hypercholesterolemic diet is due to the testicular activity. PMID:20016700
A systematic review and meta-analysis of randomized controlled trials of the effect of konjac glucomannan, a viscous soluble fiber, on LDL cholesterol and the new lipid targets non-HDL cholesterol and apolipoprotein B.
Ho, Hoang Vi Thanh; Jovanovski, Elena; Zurbau, Andreea; Blanco Mejia, Sonia; Sievenpiper, John L; Au-Yeung, Fei; Jenkins, Alexandra L; Duvnjak, Lea; Leiter, Lawrence; Vuksan, Vladimir
Background: Evidence from randomized controlled trials (RCTs) suggests the consumption of konjac glucomannan (KJM), a viscous soluble fiber, for improving LDL-cholesterol concentrations. It has also been suggested that the cholesterol-lowering potential of KJM may be greater than that of other fibers. However, trials have been relatively scarce and limited in sample size and duration, and the effect estimates have been inconsistent. The effect of KJM on new lipid targets of cardiovascular disease (CVD) risk is also unknown.Objective: This systematic review and meta-analysis aimed to assess the effect of KJM on LDL cholesterol, non-HDL cholesterol, and apolipoprotein B.Design: Medline, Embase, CINAHL, and the Cochrane Central databases were searched. We included RCTs with a follow-up of ≥3 wk that assessed the effect of KJM on LDL cholesterol, non-HDL cholesterol, or apolipoprotein B. Data were pooled by using the generic inverse-variance method with random-effects models and expressed as mean differences (MDs) with 95% CIs. Heterogeneity was assessed by the Cochran Q statistic and quantified by the I(2) statistic.Results: Twelve studies (n = 370), 8 in adults and 4 in children, met the inclusion criteria. KJM significantly lowered LDL cholesterol (MD: -0.35 mmol/L; 95% CI: -0.46, -0.25 mmol/L) and non-HDL cholesterol (MD: -0.32 mmol/L; 95% CI: -0.46, -0.19 mmol/L). Data from 6 trials suggested no impact of KJM on apolipoprotein B.Conclusions: Our findings support the intake of ∼3 g KJM/d for reductions in LDL cholesterol and non-HDL cholesterol of 10% and 7%, respectively. The information may be of interest to health agencies in crafting future dietary recommendations related to reduction in CVD risk. This study was registered at clinicaltrials.gov as NCT02068248. © 2017 American Society for Nutrition.
Exercise attenuates the increase in plasma monounsaturated fatty acids and high-density lipoprotein cholesterol but not high-density lipoprotein 2b cholesterol caused by high-oleic ground beef in women.
Gilmore, L Anne; Crouse, Stephen F; Carbuhn, Aaron; Klooster, Jennifer; Calles, José Antonio Elias; Meade, Thomas; Smith, Stephen B
We hypothesized that dietary monounsaturated fatty acids (MUFA) and exercise increase high-density lipoprotein cholesterol (HDL-C) by independent mechanisms, so there would be additive effects between a single, intensive session of exercise and high-MUFA ground beef on HDL-C and blood risk factors for cardiovascular disease. Seventeen postmenopausal women completed a 2-way crossover design in which they consumed five 114-g ground beef patties per week for two 6-week periods separated by a 4-week washout (habitual diet) period. The ground beef patties contained 21% total fat with either 9.97 (low-MUFA) or 12.72 (high-MUFA) g total MUFA. Blood was taken at entry, at the end of each 6-week diet period, after the 4-week washout period, and 24 hours after aerobic exercise sessions (75% VO₂peak, 2.07 MJ). After the ground beef intervention, the high-MUFA ground beef increased plasma palmitoleic acid and oleic acid, low-density lipoprotein (LDL) particle density, HDL-C, and HDL2b-C (all P < .05), whereas the low-MUFA ground beef increased LDL density. After the washout (habitual diet) period, the single exercise session increased serum LDL cholesterol, HDL-C, and HDL2a and decreased TAG and oleic acid. After the low-MUFA ground beef diet, exercise increased LDL size and HDL density and decreased LDL density and very low-density lipoprotein cholesterol, but had no effect on HDL-C fractions. After the high-MUFA ground beef intervention, exercise decreased palmitioleic acid, oleic acid, HDL-C, and HDL2a-C, but not HDL2b-C. Contrary to our hypothesis, the effects of exercise and a high-MUFA diet were not additive; instead, exercise attenuated the effects of the high-MUFA ground beef on HDL-C and plasma MUFAs. The differential effects of high-MUFA ground beef and exercise on HDL2a-C and HDL2b-C indicate that diet and exercise affect HDL-C by different mechanisms.
Redondo, Santiago; Martínez-González, José; Urraca, Concha; Tejerina, Teresa
Epidemiologic studies indicate a strong inverse correlation between plasma levels of high-density lipoproteins (HDL) and cardiovascular disease (CVD). The most relevant cardioprotective mechanism mediated by HDL is thought to be reverse cholesterol transport (RCT). New insights in HDL biology and RCT have allowed the development of promising agents aimed to increase HDL function and promote atherosclerosis regression. In this regard, apo-AI analogs and CETP inhibitors dalcetrapib and anacetrapib have aroused a great interest and opened new expectations in the treatment of CVD.
Kabagambe, Edmond K; Ordovas, Jose M; Hopkins, Paul N; Tsai, Michael Y; Arnett, Donna K
Trans fatty acids (TFA) lower HDL and increase triglyceride concentrations while polyunsaturated fatty acids (PUFA) lower triglycerides and may decrease HDL concentrations. The effect of the interaction between trans fat and PUFA on lipids is uncertain. Men and women (n = 1032) in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study were included. Fatty acids in erythrocyte membranes were measured with gas chromatography while data on potential confounders were obtained from questionnaires. To test the interaction between total erythrocyte PUFA (ePUFA) and TFA (eTFA) on lipid concentrations we distributed eTFA into tertiles and dichotomized ePUFA at the median concentration. For the 1(st), 2(nd) and 3(rd) tertiles of eTFA, multivariate-adjusted means±s.e.m for HDL were 46.2±1.1, 46.3±1.1 and 45.5±1.0 mg/dL among those with low ePUFA, respectively, while they were 50.0±1.1, 46.9±1.1 and 44.7±1.1 mg/dL among those with high ePUFA, respectively (P for interaction = 0.01). For the 1(st), 2(nd) and 3(rd) tertiles of eTFA, multivariate-adjusted means±s.e.m for triglycerides were 178.6±11.3, 144.7±10.9 and 140.8±10.6, respectively, among those with low ePUFA, while they were 133.8±11.3, 145.7±10.9 and 149.3±11.5, respectively, among those with high ePUFA (P for interaction = 0.005). Results for VLDL were similar to those for triglycerides. No significant interactions were observed for LDL or total cholesterol. The relation between trans fat and HDL, VLDL and triglycerides may depend on PUFA. The benefit of avoiding trans fat may be greater among individuals with higher PUFA intake. Supplementation with PUFA among individuals with relatively high trans fat intake may have limited benefits on lipid profiles.
Kabagambe, Edmond K.; Ordovas, Jose M.; Hopkins, Paul N.; Tsai, Michael Y.; Arnett, Donna K.
Background Trans fatty acids (TFA) lower HDL and increase triglyceride concentrations while polyunsaturated fatty acids (PUFA) lower triglycerides and may decrease HDL concentrations. The effect of the interaction between trans fat and PUFA on lipids is uncertain. Methods Men and women (n = 1032) in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study were included. Fatty acids in erythrocyte membranes were measured with gas chromatography while data on potential confounders were obtained from questionnaires. To test the interaction between total erythrocyte PUFA (ePUFA) and TFA (eTFA) on lipid concentrations we distributed eTFA into tertiles and dichotomized ePUFA at the median concentration. Results For the 1st, 2nd and 3rd tertiles of eTFA, multivariate-adjusted means±s.e.m for HDL were 46.2±1.1, 46.3±1.1 and 45.5±1.0 mg/dL among those with low ePUFA, respectively, while they were 50.0±1.1, 46.9±1.1 and 44.7±1.1 mg/dL among those with high ePUFA, respectively (P for interaction = 0.01). For the 1st, 2nd and 3rd tertiles of eTFA, multivariate-adjusted means±s.e.m for triglycerides were 178.6±11.3, 144.7±10.9 and 140.8±10.6, respectively, among those with low ePUFA, while they were 133.8±11.3, 145.7±10.9 and 149.3±11.5, respectively, among those with high ePUFA (P for interaction = 0.005). Results for VLDL were similar to those for triglycerides. No significant interactions were observed for LDL or total cholesterol. Conclusions The relation between trans fat and HDL, VLDL and triglycerides may depend on PUFA. The benefit of avoiding trans fat may be greater among individuals with higher PUFA intake. Supplementation with PUFA among individuals with relatively high trans fat intake may have limited benefits on lipid profiles. PMID:23077615
Christoffersen, Christina; Benn, Marianne; Christensen, Pernille M; Gordts, Philip L S M; Roebroek, Anton J M; Frikke-Schmidt, Ruth; Tybjaerg-Hansen, Anne; Dahlbäck, Björn; Nielsen, Lars B
ApoM is mainly associated with HDL. Nevertheless, we have consistently observed positive correlations of apoM with plasma LDL cholesterol in humans. Moreover, LDL receptor deficiency is associated with increased plasma apoM in mice. Here, we tested the idea that plasma apoM concentrations are affected by the rate of LDL receptor-mediated clearance of apoB-containing particles. We measured apoM in humans each carrying one of three different LDL receptor mutations (n = 9) or the apoB3500 mutation (n = 12). These carriers had increased plasma apoM (1.34 ± 0.13 µM, P = 0.003, and 1.23 ± 0.10 µM, P = 0.02, respectively) as compared with noncarriers (0.93 ± 0.04 µM). When we injected human apoM-containing HDL into Wt (n = 6) or LDL receptor-deficient mice (n = 6), the removal of HDL-associated human apoM was delayed in the LDL receptor-deficient mice. After 2 h, 54 ± 5% versus 90 ± 8% (P < 0.005) of the initial amounts of human apoM remained in the plasma of Wt and LDL receptor-deficient mice, respectively. Finally, we compared the turnover of radio-iodinated LDL and plasma apoM concentrations in 45 normocholesterolemic humans. There was a negative correlation between plasma apoM and the fractional catabolic rate of LDL (r = -0.38, P = 0.009). These data suggest that the plasma clearance of apoM, despite apoM primarily being associated with HDL, is influenced by LDL receptor-mediated clearance of apoB-containing particles.
Briand, François; Thieblemont, Quentin; Muzotte, Elodie; Burr, Noémie; Urbain, Isabelle; Sulpice, Thierry; Johns, Douglas G
Cholesteryl ester transfer protein (CETP) inhibitors dalcetrapib and anacetrapib differentially alter LDL- and HDL-cholesterol levels, which might be related to the potency of each drug to inhibit CETP activity. We evaluated the effects of both drugs at similar levels of CETP inhibition on macrophage-to-feces reverse cholesterol transport (RCT) in hamsters. In normolipidemic hamsters, both anacetrapib 30 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~60%. After injection of 3H-cholesteryl oleate labeled HDL, anacetrapib and dalcetrapib reduced HDL-cholesteryl esters fractional catabolic rate (FCR) by 30% and 26% (both P<0.001 vs. vehicle) respectively, but only dalcetrapib increased HDL-derived 3H-tracer fecal excretion by 30% (P<0.05 vs. vehicle). After 3H-cholesterol labeled macrophage intraperitoneal injection, anacetrapib stimulated 3H-tracer appearance in HDL, but both drugs did not promote macrophage-derived 3H-tracer fecal excretion. In dyslipidemic hamsters, both anacetrapib 1 mg/kg QD and dalcetrapib 200 mg/kg BID inhibited CETP activity by ~65% and reduced HDL-cholesteryl ester FCR by 36% (both P<0.001 vs. vehicle), but only anacetrapib increased HDL-derived 3H-tracer fecal excretion significantly by 39%. After 3H-cholesterol labeled macrophage injection, only anacetrapib 1 mg/kg QD stimulated macrophage-derived 3H-tracer appearance in HDL. These effects remained weaker than those observed with anacetrapib 60 mg/kg QD, which induced a maximal inhibition of CETP and stimulation of macrophage-derived 3H-tracer fecal excretion. In contrast, dalcetrapib 200 mg/kg BID reduced macrophage-derived 3H-tracer fecal excretion by 23% (P<0.05 vs. vehicle). In conclusion, anacetrapib and dalcetrapib differentially alter HDL metabolism and RCT in hamsters. A stronger inhibition of CETP may be required to promote macrophage-to-feces reverse cholesterol transport in dyslipidemic hamsters. Copyright © 2014 Elsevier B.V. All rights reserved.
Diaz, M; Lopez, F; Hernandez, F; Urbina, J A
L-Carnitine plays an important role in the mitochondrial uptake of long-chain fatty acids in mammals. It has recently been shown that this compound has a marked hypo-cholesterolemic effect when used in conjunction with lipid-rich diets. The aim of this study was to investigate the effects of L-carnitine on the fatty acid composition of plasma lipoproteins in rabbits fed with different diets. Four different groups were investigated: group I (standard diet), group II (standard diet supplemented with L-carnitine at 80 mg/kg), group III (standard diet supplemented with 0.5% cholesterol), and group IV (standard diet supplemented with 0.5% cholesterol plus L-carnitine at 80 mg/kg). The feeding period was 126 d. Total plasma cholesterol was indistinguishable in groups I and II, but increased nearly 40-fold in group III. This increment was reduced by 50% in group IV. Correspondingly, total cholesterol content in lipoprotein fractions [very low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL) separated by agarose gel chromatography was the same for groups I and II, while for animals fed a cholesterol-rich diet (III) total cholesterol in VLDL + LDL increased nearly 100-fold when compared with groups I and II but, again, the increment was reduced by 50% in group IV. In contrast, total cholesterol in HDL increased only fivefold for both groups III and IV when compared with groups I and II, indicating no effects of L-carnitine on this parameter. The reduction of total cholesterol in VLDL + LDL particles in animals fed a cholesterol-rich diet plus L-carnitine was associated with a marked decrease in the ratio of cholesteryl ester to free cholesterol and a dramatic increase in their phospholipid content; opposite effects were observed for HDL. L-Carnitine induced a marked decrease in the saturated to unsaturated C16 + C18 fatty acid ratio in cholesteryl esters associated with VLDL and LDL from animals fed with both normal and cholesterol
Suzuki, S; Nishio, S-i; Ishii, H; Sato, A; Takeda, T; Komatsu, M
The present study was performed to develop a simple procedure for assessment of body temperature and to determine whether postprandial thermoregulation is related to metabolic regulation in diabetic patients. We examined 101 male and female subjects with diabetes. Axillary temperature was measured prior to and after all meals (3 meals per day) and self-recorded for 1 week. The averages were calculated. Positive postprandial thermoregulation (PPT) was defined as a pattern in which each of 3 average postprandial temperatures was higher than the corresponding 3 preprandial temperatures. Negative postprandial thermoregulation (NPT) was defined as the pattern except for PPT. A significant increase in postprandial temperature was observed. With the exception of high-density lipoprotein (HDL)-cholesterol levels, there were no relationships between the categorized postprandial thermoregulation and other factors, including age, sex, body mass index, thyroid function, HbA1c, diabetic complications, lipid metabolism, and calorie intake. Logistic analysis indicated an independent positive relation between HDL-cholesterol and PPT. A simple method for measurement of body temperature indicated that HDL-cholesterol level was predominantly associated with thermic effects of food in diabetic patients, while other metabolic factors showed no such relations. HDL-cholesterol may affect the postprandial regulation of body temperature in diabetic patients. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.
Coutinho, Eponina R; Macedo, Geísa M; Campos, Florisbela S; Bandeira, Francisco A
Type-2 diabetic patients exhibit postprandial hypertriglyceridemia, a risk factor for atherosclerosis. Several inflammatory markers are also risk factors for atherosclerosis, such as ultrasensitive C-reactive protein (CRP) and number of leukocytes. There is a relationship between the increase in triglycerides and that of leukocytes in the postprandial period. Our objective was to evaluate whether the lipid changes in the postprandial period are related to changes in the inflammatory markers of atherogenesis in type-2 diabetic patients. Lipids, ultrasensitive CRP, and leukocyte count were analyzed during fasting and after a meal containing 56 g of fat. There was a decrease in HDL-cholesterol at five hours in the control group and at three and five hours in the diabetic group, and an increase in triglycerides at both three and five hours in the two groups, the latter being more evident at five hours in the diabetic patients. The decrease in HDL-cholesterol in the diabetic patients was inversely proportional to waist circumference, waist hip ratio, and body mass index (BMI). The number of leukocytes showed an increase in both groups at both times, being more apparent at five hours. There were no differences in lipids or markers between the groups. The fall in postprandial HDL-cholesterol correlated with visceral obesity in the group with type-2 diabetes. Hypertriglyceridemia and lowered HDL-cholesterol in the postprandial period were accompanied by a rise in the number of leukocytes in both healthy and type-2 diabetic subjects.
Chen, Suet Nee; Cilingiroglu, Mehmet; Todd, Josh; Lombardi, Raffaella; Willerson, James T; Gotto, Antonio M; Ballantyne, Christie M; Marian, AJ
Background Plasma level of high-density lipoprotein-cholesterol (HDL-C), a heritable trait, is an important determinant of susceptibility to atherosclerosis. Non-synonymous and regulatory single nucleotide polymorphisms (SNPs) in genes implicated in HDL-C synthesis and metabolism are likely to influence plasma HDL-C, apolipoprotein A-I (apo A-I) levels and severity of coronary atherosclerosis. Methods We genotyped 784 unrelated Caucasian individuals from two sets of populations (Lipoprotein and Coronary Atherosclerosis Study- LCAS, N = 333 and TexGen, N = 451) for 94 SNPs in 42 candidate genes by 5' nuclease assays. We tested the distribution of the phenotypes by the Shapiro-Wilk normality test. We used Box-Cox regression to analyze associations of the non-normally distributed phenotypes (plasma HDL-C and apo A-I levels) with the genotypes. We included sex, age, body mass index (BMI), diabetes mellitus (DM), and cigarette smoking as covariates. We calculated the q values as indicators of the false positive discovery rate (FDR). Results Plasma HDL-C levels were associated with sex (higher in females), BMI (inversely), smoking (lower in smokers), DM (lower in those with DM) and SNPs in APOA5, APOC2, CETP, LPL and LIPC (each q ≤0.01). Likewise, plasma apo A-I levels, available in the LCAS subset, were associated with SNPs in CETP, APOA5, and APOC2 as well as with BMI, sex and age (all q values ≤0.03). The APOA5 variant S19W was also associated with minimal lumen diameter (MLD) of coronary atherosclerotic lesions, a quantitative index of severity of coronary atherosclerosis (q = 0.018); mean number of coronary artery occlusions (p = 0.034) at the baseline and progression of coronary atherosclerosis, as indicated by the loss of MLD. Conclusion Putatively functional variants of APOA2, APOA5, APOC2, CETP, LPL, LIPC and SOAT2 are independent genetic determinants of plasma HDL-C levels. The non-synonymous S19W SNP in APOA5 is also an independent determinant of plasma
Boekholdt, S Matthijs; Arsenault, Benoit J; Hovingh, G Kees; Mora, Samia; Pedersen, Terje R; Larosa, John C; Welch, K M A; Amarenco, Pierre; Demicco, David A; Tonkin, Andrew M; Sullivan, David R; Kirby, Adrienne; Colhoun, Helen M; Hitman, Graham A; Betteridge, D John; Durrington, Paul N; Clearfield, Michael B; Downs, John R; Gotto, Antonio M; Ridker, Paul M; Kastelein, John J P
It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.81-0.86 per 1 standard deviation increment), as were apoA-I levels (HR, 0.79; 95% CI, 0.72-0.82). This association was also observed among patients achieving on-statin low-density lipoprotein cholesterol levels <50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR, 0.98; 95% CI, 0.94-1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR, 0.93; 95% CI, 0.90-0.97). Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low low-density lipoprotein cholesterol. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.
Ikura, Kazuki; Hanai, Ko; Shinjyo, Takamichi; Uchigata, Yasuko
We examined whether HDL cholesterol levels are a predictor for an incidence of lower-extremity amputation (LEA) and wound-related death in patients with diabetic foot ulcers (DFUs). This was a single-center, observational, longitudinal historical cohort study of 163 Japanese ambulatory patients with DFUs, 45 woman and 118 men, with a mean (standard deviation) age of 62 (14) years. The primary composite endpoint was defined as the worst of the following outcomes for each individual; (1) minor amputation, defined as amputation below the ankle, (2) major amputation, defined as amputation above the ankle, and (3) wound-related death. During the median follow-up period of 5.1 months, 67 patients (41.1%) reached the endpoint (43 minor amputations, 16 major amputations, and 8 wound-related deaths). In the univariate Cox proportional hazard model analysis, lower HDL cholesterol levels (mmol/L) were significantly associated with the incidence of the primary composite endpoint (hazard ratio 0.16 [95% CI 0.08-0.32], p < 0.001). In the multivariate Cox proportional hazard model analysis using a stepwise variable-selecting procedure, HDL cholesterol levels in addition to the presence of ankle brachial index <0.9 or ≥1.4 and serum albumin levels were selected as independent risk factors for the incidence of the endpoint (hazard ratio 0.30 [95% CI 0.14-0.63], p = 0.002). Similar results were obtained when HDL cholesterol levels were treated as a categorical variable (≥1.03 mmol/L or less). HDL cholesterol levels might be a novel clinical predictor for the incidence of LEA and wound-related death in patients with DFUs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Figueroa, Catalina; Droppelmann, Katherine; Quiñones, Verónica; Amigo, Ludwig; Mendoza, Camila; Serrano, Valentina; Véjar, Margarita; Maiz, Alberto; Rigotti, Attilio
Plasma high density lipoproteins (HDL) are involved in reverse cholesterol transport mediated by the scavenger receptor class B type I (SR-BI). Nicotinic acid increases HDL cholesterol levels, even though its specific impact on SR-BI dependent-cellular cholesterol transport remains unknown. To determine the effect of nicotinic acid on HDL particle functionality in cholesterol efflux and uptake mediated by SR-BI in cultured cells in hypoalphalipoproteinemic patients. In a pilot study, eight patients with low HDL (≤ 40 mg/dL) were treated with extended release nicotinic acid. HDL cholesterol and phospholipid levels, HDL2 and HDL3 fractions and HDL particle sizes were measured at baseline and post-therapy. Before and after nicotinic acid treatment, HDL particles were used for cholesterol transport studies in cells transfected with SR-BI. Nicotinic acid treatment raised total HDL cholesterol and phospholipids, HDL2 levels as well as HDL particle size. Nicotinic acid significantly increased HDL cholesterol efflux and uptake capacity mediated by SR-BI in cultured cells. Nicotinic acid therapy increases SR-BI-dependent HDL cholesterol transport in cultured cells, establishing a new cellular mechanism by which this lipid-lowering drug appears to modulate HDL metabolism in patients with hypoalphalipoproteinemia.
Maccari, S; Bassi, C; Zanoni, P; Plancher, A C
We examined total cholesterolemia, triglyceridemia, high density lipoproteins- (HDL) cholesterolemia, apolipoproteins A1 and B, body mass index, albuminemia and alanine aminotransferase in 60 heroin addicts. After comparing 23 control subjects with the heroin addicts the result was that the latter have significantly lower mean values of total cholesterolemia and of HDL-cholesterolemia and higher values of triglyceridemia. They also have significantly higher prevalences of cases of hypocholesterolemia and of hypo-HDL-cholesterolemia. Within the addict group there is no linear correlation between total cholesterolemia and body mass index; there is, however, an inverse linear correlation between total cholesterolemia and alanine aminotransferase. Therefore, the alterations found in the lipid pattern of heroin addicts are not due to malnutrition but hypothetically to liver diseases which are frequent in these patients.
Puri, Rishi; Nissen, Steven E; Shao, Mingyuan; Elshazly, Mohamed B; Kataoka, Yu; Kapadia, Samir R; Tuzcu, E Murat; Nicholls, Stephen J
Non-high-density lipoprotein cholesterol (non-HDLC) levels reflect the full burden of cholesterol transported in atherogenic lipoproteins. Genetic studies suggest a causal association between elevated triglycerides (TGs)-rich lipoproteins and atherosclerosis. We evaluated associations between achieved non-HDLC and TG levels on changes in coronary atheroma volume. Data were analyzed from 9 clinical trials involving 4957 patients with coronary disease undergoing serial intravascular ultrasonography to assess changes in percent atheroma volume (ΔPAV) and were evaluated against on-treatment non-HDLC and TG levels. The effects of lower (<100 mg/dL) versus higher (≥100 mg/dL) achieved non-HDLC levels and lower (<200 mg/dL) versus higher (≥200 mg/dL) achieved TG levels were evaluated in populations with variable on-treatment low-density lipoprotein cholesterol (LDLC) ≥70 mg/dL and C-reactive protein ≥2 mg/L and in patients with or without diabetes mellitus. On-treatment non-HDLC levels linearly associated with ΔPAV. Overt PAV progression (ΔPAV>0) was associated with achieved TG levels >200 mg/dL, respectively. Lower on-treatment non-HDLC and TG levels associated with significant PAV regression compared with higher non-HDLC and TG levels across all levels of LDLC and C-reactive protein and irrespective of diabetic status (P<0.001 across all comparisons). ΔPAV were more strongly influenced by changes in non-HDLC (β=0.62; P<0.001) compared with changes in LDLC (β=0.51; P<0.001). Kaplan-Meier sensitivity analyses demonstrated significantly greater major adverse cardiovascular event rates in those with higher versus lower non-HDLC and TG levels, with an earlier separation of the non-HDLC compared with the LDLC curve. Achieved non-HDLC levels seem more closely associated with coronary atheroma progression than LDLC. Plaque progression associates with achieved TGs, but only above levels of 200 mg/dL. These observations support a more prominent role for non
Mark, Laszlo; Vallejo-Vaz, Antonio J; Reiber, Istvan; Paragh, György; Kondapally Seshasai, Sreenivasa Rao; Ray, Kausik K
Non-HDL cholesterol represents the pro-atherogenic, apo-B-containing lipoprotein fraction of circulating lipids, and represents a secondary target for CVD prevention in people with diabetes. We therefore assessed the proportion of individuals with diabetes and CVD who attain a non-HDL-C goal of <2.6 mmol/L, the extent to which triglycerides influence this goal attainment, and their relationship with HDL-C and triglyceride-rich lipoproteins (TRL). Of 2674 diabetic subjects with baseline CVD in the Hungarian MULTI-GAP programme (mean age 64.8 years, mean HbA1c 7.2%), an LDL-C goal <1.8 and non-HDL-C goal <2.6 mmol/L was attained in 13.5% and 17.7% individuals, respectively. Non-HDL-C goal attainment declined at higher triglyceride concentrations; and graphically this relationship appeared to be continuously and inversely associated with triglyceride concentrations. In contrast, the relationship between LDL-C goal attainment was inversely and continuously associated with triglyceride levels up to about 2.5 mmol/L, after which the graphical appearance plateaued such that no further difference in LDL-C were observed beyond triglyceride levels of 2.5 mmol/L. With increasing triglyceride concentrations, non-HDL-C increased continuously, HDL-C decreased initially but later plateaued (at 1.5-2.0 [men] or 2.0-2.5 mmol/L [women]), LDL-C levels plateaued at about 2.0-2.5 mmol/L, and TRL-cholesterol (non-HDL-C minus LDL-C) rose continuously. In multivariable-adjusted models, elevated triglyceride concentrations, non-specialist care and uncontrolled blood pressure were inversely associated with non-HDL-C goal attainment. Triglyceride levels were more strongly associated with non-HDL-C than with LDL-C goal attainment (ORs per 1-SD increase in log-triglycerides was 0.74, 95% CI 0.61-0.89, for LDL-C goal attainment, and 0.49, 95% CI 0.38-0.61, for non-HDL-C goal attainment). Non-HDL-C goal attainment was suboptimal in people with diabetes and co-existing CVD. This was most
Das, Akash; Brown, Michael S; Anderson, Donald D; Goldstein, Joseph L; Radhakrishnan, Arun
When human fibroblasts take up plasma low density lipoprotein (LDL), its cholesterol is liberated in lysosomes and eventually reaches the endoplasmic reticulum (ER) where it inhibits cholesterol synthesis by blocking activation of SREBPs. This feedback protects against cholesterol overaccumulation in the plasma membrane (PM). But how does ER know whether PM is saturated with cholesterol? In this study, we define three pools of PM cholesterol: (1) a pool accessible to bind 125I-PFO*, a mutant form of bacterial Perfringolysin O, which binds cholesterol in membranes; (2) a sphingomyelin(SM)-sequestered pool that binds 125I-PFO* only after SM is destroyed by sphingomyelinase; and (3) a residual pool that does not bind 125I-PFO* even after sphingomyelinase treatment. When LDL-derived cholesterol leaves lysosomes, it expands PM's PFO-accessible pool and, after a short lag, it also increases the ER's PFO-accessible regulatory pool. This regulatory mechanism allows cells to ensure optimal cholesterol levels in PM while avoiding cholesterol overaccumulation. DOI: http://dx.doi.org/10.7554/eLife.02882.001 PMID:24920391
Sugar-Sweetened Beverage Intake Is Positively Associated with Baseline Triglyceride Concentrations, and Changes in Intake Are Inversely Associated with Changes in HDL Cholesterol over 12 Months in a Multi-Ethnic Sample of Children.
Van Rompay, Maria I; McKeown, Nicola M; Goodman, Elizabeth; Eliasziw, Misha; Chomitz, Virginia R; Gordon, Catherine M; Economos, Christina D; Sacheck, Jennifer M
Intake of sugar-sweetened beverages (SSBs) is linked to greater cardiometabolic risk in adults. Although longitudinal evidence is sparse among children, SSB intake reduction is targeted to reduce cardiometabolic risk factors in this group. We investigated characteristics associated with consumption of SSBs in a multi-ethnic sample of children/adolescents and measured cross-sectional and longitudinal associations between SSB intake and plasma HDL cholesterol and triglycerides (TGs) over 12 mo. In a diverse cohort of children aged 8-15 y, cross-sectional associations (n = 613) between baseline SSB intake and blood lipid concentrations and longitudinal associations (n = 380) between mean SSB intake, changes in SSB intake, and lipid changes over 12 mo were assessed with multivariable linear regression. Greater SSB intake was associated with lower socioeconomic status, higher total energy intake, lower fruit/vegetable intake, and more sedentary time. In cross-sectional analysis, greater SSB intake was associated with higher plasma TG concentrations among consumers (62.4, 65.3, and 71.6 mg/dL in children who consumed >0 but <2, ≥2 but <7, and ≥7 servings/wk, respectively; P-trend: 0.03); plasma HDL cholesterol showed no cross-sectional association. In the longitudinal analysis, mean SSB intake over 12 mo was not associated with lipid changes; however, the 12-mo increase in plasma HDL-cholesterol concentration was greater among children who decreased their intake by ≥1 serving/wk (4.6 ± 0.8 mg/dL) compared with children whose intake stayed the same (2.0 ± 0.8 mg/dL) or increased (1.5 ± 0.8 mg/dL; P = 0.02). In a multi-ethnic sample of children, intake of SSBs was positively associated with TG concentrations among consumers, and changes in SSB intake were inversely associated with HDL cholesterol concentration changes over 12 mo. Further research in large diverse samples of children is needed to study the public health implications of reducing SSB intake among
Sugar-Sweetened Beverage Intake Is Positively Associated with Baseline Triglyceride Concentrations, and Changes in Intake Are Inversely Associated with Changes in HDL Cholesterol over 12 Months in a Multi-Ethnic Sample of Children123
Van Rompay, Maria I; McKeown, Nicola M; Goodman, Elizabeth; Eliasziw, Misha; Chomitz, Virginia R; Gordon, Catherine M; Economos, Christina D; Sacheck, Jennifer M
Background: Intake of sugar-sweetened beverages (SSBs) is linked to greater cardiometabolic risk in adults. Although longitudinal evidence is sparse among children, SSB intake reduction is targeted to reduce cardiometabolic risk factors in this group. Objective: We investigated characteristics associated with consumption of SSBs in a multi-ethnic sample of children/adolescents and measured cross-sectional and longitudinal associations between SSB intake and plasma HDL cholesterol and triglycerides (TGs) over 12 mo. Methods: In a diverse cohort of children aged 8–15 y, cross-sectional associations (n = 613) between baseline SSB intake and blood lipid concentrations and longitudinal associations (n = 380) between mean SSB intake, changes in SSB intake, and lipid changes over 12 mo were assessed with multivariable linear regression. Results: Greater SSB intake was associated with lower socioeconomic status, higher total energy intake, lower fruit/vegetable intake, and more sedentary time. In cross-sectional analysis, greater SSB intake was associated with higher plasma TG concentrations among consumers (62.4, 65.3, and 71.6 mg/dL in children who consumed >0 but <2, ≥2 but <7, and ≥7 servings/wk, respectively; P-trend: 0.03); plasma HDL cholesterol showed no cross-sectional association. In the longitudinal analysis, mean SSB intake over 12 mo was not associated with lipid changes; however, the 12-mo increase in plasma HDL-cholesterol concentration was greater among children who decreased their intake by ≥1 serving/wk (4.6 ± 0.8 mg/dL) compared with children whose intake stayed the same (2.0 ± 0.8 mg/dL) or increased (1.5 ± 0.8 mg/dL; P = 0.02). Conclusions: In a multi-ethnic sample of children, intake of SSBs was positively associated with TG concentrations among consumers, and changes in SSB intake were inversely associated with HDL cholesterol concentration changes over 12 mo. Further research in large diverse samples of children is needed to study the
Tuvdendorj, Demidmaa; Munoz, Alejandro O; Ruiz-Barros, Viviana; Schwarz, Jean-Marc; Montalto, Giuseppe; Chandalia, Manisha; Sowers, Lawrence C; Rizzo, Manfredi; Murphy, Elizabeth J; Abate, Nicola
Low concentrations of plasma HDL-C are associated with the development of atherosclerotic cardiovascular diseases and type 2 diabetes. Here we aimed to explore the relationship between the in vivo fractional synthesis of triglycerides (fTG) in subcutaneous (s.q.) abdominal adipose tissue (AT), HDL-C concentrations and HDL particle size composition in non-diabetic humans. The fTG in s.q. abdominal AT was measured in 16 non-diabetic volunteers (7 women, 9 men; Age: 49 ± 20 years; BMI: 31 ± 5 kg/m; Fasting Plasma Glucose: 90 ± 10 mg/dl) after (2)H2O labeling. HDL-C concentration and subclasses, large (L-HDL), intermediate (I-HDL) and small (S-HDL) were measured. Linear regression analyses demonstrated significant associations of fTG with plasma concentration of HDL-C (r = 0.625,p = 0.009) and percent contribution of L-HDL (r = 0.798,p < 0.001), I-HDL (r = -0.765,p < 0.001) and S-HDL (r = -0.629, p = 0.009). When analyses were performed by gender, the associations remained significant in women (HDL-C: r = 0.822,p = 0.023; L-HDL: r = 0.892,p = 0.007; I-HDL: r = -0.927,p = 0.003) but not men. Our study demonstrated an in vivo association between subcutaneous abdominal adipose tissue lipid dynamics and HDL parameters in humans, but this was true for women not men. Positive association with L-HDL and negative with I-HDL suggest that subcutaneous abdominal adipose tissue lipid dynamics may play an important role in production of mature functional HDL particles. Further studies evaluating the mechanism responsible for these associations and the observed gender differences are important and warranted to identify potential novel targets of intervention to increase the production of atheroprotective subclasses of HDL-Cs and thus decreasing the risks of development of atherosclerotic conditions. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Wolfs, Marcel G M; Rensen, Sander S; Bruin-Van Dijk, Elinda J; Verdam, Froukje J; Greve, Jan-Willem; Sanjabi, Bahram; Bruinenberg, Marcel; Wijmenga, Cisca; van Haeften, Timon W; Buurman, Wim A; Franke, Lude; Hofker, Marten H
Excessive accumulation of body fat, in particular in the visceral fat depot, is a major risk factor to develop a variety of diseases such as type 2 diabetes. The mechanisms underlying the increased risk of obese individuals to develop co-morbid diseases are largely unclear.We aimed to identify genes expressed in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) that are related to blood parameters involved in obesity co-morbidity, such as plasma lipid and glucose levels, and to compare gene expression between the fat depots. Whole-transcriptome SAT and VAT gene expression levels were determined in 75 individuals with a BMI >35 kg/m2. Modules of co-expressed genes likely to be functionally related were identified and correlated with BMI, plasma levels of glucose, insulin, HbA1c, triglycerides, non-esterified fatty acids, ALAT, ASAT, C-reactive protein, and LDL- and HDL cholesterol. Of the approximately 70 modules identified in SAT and VAT, three SAT modules were inversely associated with plasma HDL-cholesterol levels, and a fourth module was inversely associated with both plasma glucose and plasma triglyceride levels (p < 5.33 x 10(-5)). These modules were markedly enriched in immune and metabolic genes. In VAT, one module was associated with both BMI and insulin, and another with plasma glucose (p < 4.64 x 10(-5)). This module was also enriched in inflammatory genes and showed a marked overlap in gene content with the SAT modules related to HDL. Several genes differentially expressed in SAT and VAT were identified. In obese subjects, groups of co-expressed genes were identified that correlated with lipid and glucose metabolism parameters; they were enriched with immune genes. A number of genes were identified of which the expression in SAT correlated with plasma HDL cholesterol, while their expression in VAT correlated with plasma glucose. This underlines both the singular importance of these genes for lipid and glucose metabolism and the specific
Chechi, Kanta; Blanchard, Pierre-Gilles; Mathieu, Patrick; Deshaies, Yves; Richard, Denis
Recent evidence indicates that epicardial adipose tissue (EAT) expresses uncoupling protein-1 (UCP1), a marker of brown adipocytes. However, the putative effects of the presence of brown adipocytes in EAT remain unknown. The mRNA expression of genes related to brown adipocyte-mediated thermogenesis was measured in the fat samples collected from the epicardial-, mediastinal- and subcutaneous-depots of patients undergoing coronary artery bypass grafting. Both univariate and multivariate analyses were then utilized to determine any association between gene expression and the anthropometrics and fasting blood chemistries of these patients. EAT exhibited significantly higher expression of UCP1 and cytochrome c oxidase subunit-IV (COX-IV) compared to mediastinal- and subcutaneous-fat depots (P ≤ 0.05). EAT expression of UCP1 (r=0.50), COX-IV (r=0.37) and lipoprotein lipase (LPL) (r=0.58) positively associated with circulating levels of HDL-cholesterol (P ≤ 0.05). In addition, EAT expression of LPL, acyl coA dehydrogenase-short, -medium and -long chain genes associated negatively with circulating TG levels (P ≤ 0.05). Abundance of UCP-1 in the EAT relative to other fat depots confirms the presence of brown adipocytes in human EAT. Furthermore, the correlations among the EAT expression of thermogenesis-related genes with the circulating HDL and TG levels indicate that presence of active brown adipocytes shares a functional association with the circulating plasma lipids in humans. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Barona, Jacqueline; Fernandez, Maria Luz
The associations between dietary cholesterol and heart disease are highly controversial. While epidemiological studies and clinical interventions have shown the lack of correlation between cholesterol intake and cardiovascular disease (CVD) risk, there is still concern among health practitioners and the general population regarding dietary cholesterol. In this review, several clinical studies utilizing cholesterol challenges are analyzed in terms of changes that occur in lipoprotein metabolism resulting from excess consumption of cholesterol. Dietary cholesterol has been shown to increase both LDL and HDL in those individuals who respond to a cholesterol challenge without altering the LDL cholesterol/HDL cholesterol ratio, a key marker of CVD risk. Further, dietary cholesterol has been shown to increase only HDL with no changes in LDL with average cholesterol consumption and during weight loss interventions. Ingestion of cholesterol has also been shown to increase the size of both LDL and HDL particles with the associated implications of a less atherogenic LDL particle as well as more functional HDL in reverse cholesterol transport. Other changes observed in lipoprotein metabolism are a greater number of large LDL and decreases in small LDL subfractions. All this information put together points to specific roles of dietary cholesterol in substantially altering intravascular processing of lipoproteins as well as reverse cholesterol transport.
Barona, Jacqueline; Fernandez, Maria Luz
The associations between dietary cholesterol and heart disease are highly controversial. While epidemiological studies and clinical interventions have shown the lack of correlation between cholesterol intake and cardiovascular disease (CVD) risk, there is still concern among health practitioners and the general population regarding dietary cholesterol. In this review, several clinical studies utilizing cholesterol challenges are analyzed in terms of changes that occur in lipoprotein metabolism resulting from excess consumption of cholesterol. Dietary cholesterol has been shown to increase both LDL and HDL in those individuals who respond to a cholesterol challenge without altering the LDL cholesterol/HDL cholesterol ratio, a key marker of CVD risk. Further, dietary cholesterol has been shown to increase only HDL with no changes in LDL with average cholesterol consumption and during weight loss interventions. Ingestion of cholesterol has also been shown to increase the size of both LDL and HDL particles with the associated implications of a less atherogenic LDL particle as well as more functional HDL in reverse cholesterol transport. Other changes observed in lipoprotein metabolism are a greater number of large LDL and decreases in small LDL subfractions. All this information put together points to specific roles of dietary cholesterol in substantially altering intravascular processing of lipoproteins as well as reverse cholesterol transport. PMID:23016129
Mostafa, Samiul A; Davies, Melanie J; Morris, Danielle H; Yates, Tom; Srinivasan, Balasubramanian Thiagarajan; Webb, David; Brady, Emer; Khunti, Kamlesh
There is recent interest surrounding the use of the triglyceride-to-HDL cholesterol ratio as a surrogate marker of insulin resistance in clinical practice, as it may identify people at high risk of developing diabetes or its complications. However, it has been suggested using this lipid ratio may not be appropriate for measuring insulin resistance in African-Americans, particularly women. We investigated if this inconsistency extended to South Asian women in a UK multi-ethnic cohort of White Europeans and South Asians. Cross-sectional analysis was done of 729 participants from the ADDITION-Leicester study from 2005 to 2009. The association between tertiles of triglyceride-to-HDL cholesterol ratio to fasting insulin, homeostatic model of assessment for insulin resistance (HOMA1-IR), quantitative insulin sensitivity check index (QUICKI) and glucose: insulin ratio was examined with adjustment for confounding variables. Incremental tertiles of the triglyceride-to-HDL cholesterol ratio demonstrated a significant positive association with levels of fasting insulin, HOMA1-IR, glucose: insulin ratio and a negative association with QUICKI in White European men (n = 255) and women (n = 250) and South Asian men (n = 124) (all p<0.05), but not South Asian women (n = 100). A significant interaction was demonstrated between sex and triglyceride-to-HDL cholesterol ratio tertiles in South Asians only (p<0.05). The area under the receiver operating characteristic curve for triglyceride-to-HDL cholesterol ratio to detect insulin resistance, defined as the cohort HOMA1-IR ≥ 75(th) percentile (3.08), was 0.74 (0.67 to 0.81), 0.72 (0.65 to 0.79), 0.75 (0.66 to 0.85) and 0.67 (0.56 to 0.78) in White European men and women, South Asian men and women respectively. The optimal cut-points for detecting insulin resistance were 0.9-1.7 in mmol/l (2.0-3.8 in mg/dl) for the triglyceride-to-HDL ratio. In South Asian women the triglyceride-to-HDL cholesterol ratio was not associated with
Salto, Lorena M; Bu, Liming; Beeson, W Lawrence; Firek, Anthony; Cordero-MacIntyre, Zaida; De Leon, Marino
The alanine to threonine amino acid substitution at codon 54 (Ala54Thr) of the intestinal fatty acid binding protein (FABP2) has been associated with elevated levels of insulin and blood glucose as well as with dyslipidemia. The aim of this study was to characterize the effect of this FABP2 polymorphism in Mexican-Americans with type 2 diabetes (T2D) in the context of a three-month intervention to determine if the polymorphism differentially modulates selected clinical outcomes. For this study, we genotyped 43 participant samples and performed post-hoc outcome analysis of the profile changes in fasting blood glucose, HbA1c, insulin, lipid panel and body composition, stratified by the Ala54Thr polymorphism. Our results show that the Thr54 allele carriers (those who were heterozygous or homozygous for the threonine-encoding allele) had lower HDL cholesterol and higher triglyceride levels at baseline compared to the Ala54 homozygotes (those who were homozygous for the alanine-encoding allele). Both groups made clinically important improvements in lipid profiles and glycemic control as a response to the intervention. Whereas the Ala54 homozygotes decreased HDL cholesterol in the context of an overall total cholesterol decrease, Thr54 allele carriers increased HDL cholesterol as part of an overall total cholesterol decrease. We conclude that the Ala54Thr polymorphism of FABP2 modulates HDL cholesterol in Mexican-Americans with T2D and that Thr54 allele carriers may be responsive in interventions that include dietary changes.
Salto, Lorena M.; Bu, Liming; Beeson, W. Lawrence; Firek, Anthony; Cordero-MacIntyre, Zaida; De Leon, Marino
The alanine to threonine amino acid substitution at codon 54 (Ala54Thr) of the intestinal fatty acid binding protein (FABP2) has been associated with elevated levels of insulin and blood glucose as well as with dyslipidemia. The aim of this study was to characterize the effect of this FABP2 polymorphism in Mexican-Americans with type 2 diabetes (T2D) in the context of a three-month intervention to determine if the polymorphism differentially modulates selected clinical outcomes. For this study, we genotyped 43 participant samples and performed post-hoc outcome analysis of the profile changes in fasting blood glucose, HbA1c, insulin, lipid panel and body composition, stratified by the Ala54Thr polymorphism. Our results show that the Thr54 allele carriers (those who were heterozygous or homozygous for the threonine-encoding allele) had lower HDL cholesterol and higher triglyceride levels at baseline compared to the Ala54 homozygotes (those who were homozygous for the alanine-encoding allele). Both groups made clinically important improvements in lipid profiles and glycemic control as a response to the intervention. Whereas the Ala54 homozygotes decreased HDL cholesterol in the context of an overall total cholesterol decrease, Thr54 allele carriers increased HDL cholesterol as part of an overall total cholesterol decrease. We conclude that the Ala54Thr polymorphism of FABP2 modulates HDL cholesterol in Mexican-Americans with T2D and that Thr54 allele carriers may be responsive in interventions that include dietary changes. PMID:26703680
Pownall, Henry J.; Courtney, Harry S.; Gillard, Baiba K.; Massey, John B.
Serum opacity factor from Streptococcus pyogenes transfers the cholesteryl esters (CE) of ~100,000 plasma high density lipoprotein particles (HDL) to a CE-rich microemulsion (CERM) while forming neo HDL, a cholesterol-poor HDL-like particle. HDL, neo HDL, and CERM are distinct. Neo HDL is lower in free cholesterol and has lower surface and total microviscosities than HDL; the surface polarity of neo HDL and HDL are similar. CERM is much larger than HDL and richer in cholesterol and CE. Although the surface microviscosity of HDL is higher than that of CERM, they have similar total microviscosities because cholesterol partitions into the neutral lipid core. Because of its unique surface properties apo E preferentially associates with the CERM. In contrast, the composition and properties of neo HDL make it a potential acceptor of cellular cholesterol and its esterification. Thus, neo HDL and CERM are possible vehicles for improving cholesterol transport to the liver. PMID:18838065
Pownall, Henry J; Courtney, Harry S; Gillard, Baiba K; Massey, John B
Serum opacity factor from Streptococcus pyogenes transfers the cholesteryl esters (CE) of approximately 100,000 plasma high-density lipoprotein particles (HDL) to a CE-rich microemulsion (CERM) while forming neo HDL, a cholesterol-poor HDL-like particle. HDL, neo HDL, and CERM are distinct. Neo HDL is lower in free cholesterol and has lower surface and total microviscosities than HDL; the surface polarity of neo HDL and HDL are similar. CERM is much larger than HDL and richer in cholesterol and CE. Although the surface microviscosity of HDL is higher than that of CERM, they have similar total microviscosities because cholesterol partitions into the neutral lipid core. Because of its unique surface properties apo E preferentially associates with the CERM. In contrast, the composition and properties of neo HDL make it a potential acceptor of cellular cholesterol and its esterification. Thus, neo HDL and CERM are possible vehicles for improving cholesterol transport to the liver.
Huang, L S; Voyiaziakis, E; Markenson, D F; Sokol, K A; Hayek, T; Breslow, J L
apo B is a structural constituent of several classes of lipoprotein particles, including chylomicrons, VLDL, and LDL. To better understand the role of apo B in the body, we have used gene targeting in embryonic stem cells to create a null apo B allele in the mouse. Homozygous apo B deficiency led to embryonic lethality, with resorption of all embryos by gestational day 9. Heterozygotes showed an increased tendency to intrauterine death with some fetuses having incomplete neural tube closure and some live-born heterozygotes developing hydrocephalus. The majority of male heterozygotes were sterile, although the genitourinary system and sperm were grossly normal. Viable heterozygotes had normal triglycerides, but total, LDL, and HDL cholesterol levels were decreased by 37, 37, and 39%, respectively. Hepatic and intestinal apo B mRNA levels were decreased in heterozygotes, presumably contributing to the decreased LDL levels through decreased synthesis of apo B-containing lipoproteins. Kinetic studies indicated that heterozygotes had decreased transport rates of HDL cholesterol ester and apo A-I. As liver and intestinal apo A-I mRNA levels were unchanged, the mechanism for decreased apo A-I transport must be posttranscriptional. Heterozygotes also had normal cholesterol absorption and a normal response of the plasma lipoprotein pattern to chronic consumption of a high fat, high cholesterol, Western-type diet. In summary, we report a mouse model for apo B deficiency with several phenotypic features that were unexpected based on clinical studies of apo B-deficient humans, such as embryonic lethality in homozygotes and neural tube closure defects, male infertility, and a major defect in HDL production in heterozygotes. This model presents an opportunity to study the mechanisms underlying these phenotypic changes. Images PMID:7593600
Missimer, Amanda; DiMarco, Diana M; Andersen, Catherine J; Murillo, Ana Gabriela; Vergara-Jimenez, Marcela; Fernandez, Maria Luz
Eggs contain high quality protein, vitamins, minerals and antioxidants, yet regular consumption is still met with uncertainty. Therefore, the purpose of this study was to compare the effects of consuming two eggs per day or a heart-healthy oatmeal breakfast on biomarkers of cardiovascular disease (CVD) risk and satiety measures in a young, healthy population. Fifty subjects participated in a randomized crossover clinical intervention; subjects were randomly allocated to consume either two eggs or one packet of oatmeal per day for breakfast for four weeks. After a three-week washout period, participants were allocated to the alternative breakfast. Fasting blood samples were collected at the end of each intervention period to assess plasma lipids and plasma ghrelin. Subjects completed visual analog scales (VAS) concurrent to dietary records to assess satiety and hunger. Along with an increase in cholesterol intake, there were significant increases in both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol following the egg consumption period (p < 0.01). However, there was no difference in the LDL/HDL ratio, a recognized biomarker of CVD risk, nor in the plasma glucose, triglycerides or liver enzymes, between diet periods. Several self-reported satiety measures were increased following the consumption of eggs, which were associated with lower plasma ghrelin concentrations (p < 0.05). These results demonstrate that compared to an oatmeal breakfast, two eggs per day do not adversely affect the biomarkers associated with CVD risk, but increase satiety throughout the day in a young healthy population.
Jones, P J; Howell, T; MacDougall, D E; Feng, J Y; Parsons, W
To assess the short-term cholesterol-lowering potential of sitostanol-containing tall oil plant sterols, 22 subjects consumed fixed-food diets over two 10-day periods with or without 21.2 mg/kg body weight/d tall oil phytosterols (sitosterol 62%, sitostanol 21%, campesterol 16%, and campestanol 1%) in a randomized crossover study design. On day 10 of each diet, plasma lipoprotein cholesterol levels, plasma phytosterol concentrations, and cholesterol biosynthesis rates were determined. Total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels were lower (P < .01) after administration of tall oil phytosterol (4.7 +/- 0.3 and 3.0 +/- 0.3 mmol/L, respectively) versus placebo (5.0 +/- 0.3 and 3.2 +/- 0.3 mmol/L, respectively). Tall oil treatment had no effect on the plasma high-density lipoprotein (HDL) cholesterol level (1.1 +/- 0.1 mmol/L) versus placebo (1.1 +/- 0.1 mmol/L). Similarly, plasma triglyceride (TG) levels did not differ between tall oil (1.3 +/- 0.2 mmol/L) and placebo (1.4 +/- 0.2 mmol/L) treatments. Plasma campesterol (15.8 +/- 3.7 mmol/mol cholesterol) and sitosterol (6.0 +/- 2.1 mmol/mol cholesterol) levels were not different after tall oil treatment versus placebo treatment (15.4 +/- 2.3 and 6.4 +/- 2.0 mmol/mol cholesterol, respectively). Plasma sitostanol levels were essentially undetectable. No difference was observed in cholesterol biosynthesis between tall oil (0.045 +/- 0.004 pools/d) and placebo (0.034 +/- 0.004 pools/d) treatments; however, the effect of treatments in subjects with different cholesterol levels varied. In subjects with lower cholesterol values, the red blood cell cholesterol fractional synthesis rate (FSR) increased from 0.0291 +/- 0.0054 pools/d after placebo to 0.0509 +/- 0.0049 pools/d (P < .05) after phytosterol treatment. In subjects with higher cholesterol values, the red blood cell cholesterol FSR did not change significantly after treatment. These results demonstrate the short-term efficacy of tall
Shimizu, Yuji; Nakazato, Mio; Sekita, Takaharu; Koyamatsu, Jun; Kadota, Koichiro; Yamasaki, Hironori; Goto, Hisashi; Takamura, Noboru; Aoyagi, Kiyoshi; Maeda, Takahiro
Our previous study reported that categorizing diabetes patients according to the serum triglycerides-to-high-density lipoprotein cholesterol (TG-HDL) ratio is useful for estimating the risk of atherosclerosis, as a high TG-HDL ratio in patients with diabetes constitutes risk factors for atherosclerosis. Another study showed that a high hemoglobin level is associated with the risk of atherosclerosis. However, no previous studies have examined the association between the hemoglobin level and diabetes categorized by the TG-HDL ratio. In order to investigate these associations, we conducted a cross-sectional study of 3,733 (1,299 men and 2,434 women) Japanese participants 30-89 years of age undergoing a general health checkup. We investigated the association between the hemoglobin levels and the incidence of diabetes in all subjects, who were divided into tertiles according to the TG-HDL ratio. Diabetes was defined as an HbA1c (NGSP) level of ≥ 6.5% and/or the initiation of glucose-lowering or insulin therapy. Of the 265 diabetes patients identified in this study, 116 had a high TG-HDL ratio (high TG-HDL diabetes) and 71 had a low TG-HDL ratio (low TG-HDL diabetes). Independent from classical cardiovascular risk factors, the multivariate odds ratio of a 1 SD (standard deviation) increment in hemoglobin (1.30 g/dL for men, 1.16 g/dL for women) was 1.04 (95% confidence intervals (CI): 0.88-1.22) for all patients with diabetes, 1.44 (95%CI: 1.17-1.77) for the patients with high TG-HDL diabetes and 0.67 (95%CI: 0.54-0.83) for the patients with low TG-HDL diabetes. The hemoglobin level is positively associated with high TG-HDL diabetes and inversely associated with low TG-HDL diabetes. These findings suggest that measuring the hemoglobin level is clinically relevant for estimating the risk of atherosclerosis in patients with diabetes categorized according to the TG-HDL ratio.
Lange, Yvonne; Steck, Theodore L.
We review evidence that sterols can form stoichiometric complexes with certain bilayer phospholipids, and sphingomyelin in particular. These complexes appear to be the basis for the formation of condensed and ordered liquid phases, (micro)domains and/or rafts in both artificial and biological membranes. The sterol content of a membrane can exceed the complexing capacity of its phospholipids. The excess, uncomplexed membrane sterol molecules have a relatively high escape tendency, also referred to as fugacity or chemical activity (and, here, simply activity). Cholesterol is also activated when certain membrane intercalating amphipaths displace it from the phospholipid complexes. Active cholesterol projects from the bilayer and is therefore highly susceptible to attack by cholesterol oxidase. Similarly, active cholesterol rapidly exits the plasma membrane to extracellular acceptors such as cyclodextrin and high-density lipoproteins. For the same reason, the pool of cholesterol in the ER (endoplasmic reticulum) increases sharply when cell surface cholesterol is incremented above the physiological set-point; i.e., equivalence with the complexing phospholipids. As a result, the escape tendency of the excess cholesterol not only returns the plasma membrane bilayer to its set point but also serves as a feedback signal to intracellular homeostatic elements to down-regulate cholesterol accretion. PMID:18423408
Rayner, Katey J.; Esau, Christine C.; Hussain, Farah N.; McDaniel, Allison L.; Marshall, Stephanie M.; van Gils, Janine M.; Ray, Tathagat D.; Sheedy, Frederick J.; Goedeke, Leigh; Liu, Xueqing; Khatsenko, Oleg G.; Kaimal, Vivek; Lees, Cynthia J.; Fernandez-Hernando, Carlos; Fisher, Edward A.; Temel, Ryan E.; Moore, Kathryn J.
Cardiovascular disease (CVD) remains the leading cause of mortality in westernized countries, despite optimum medical therapy to lower LDL cholesterol. The pursuit of novel therapies to target this residual risk has focused on raising levels of HDL cholesterol in order to exploit its atheroprotective effects1. MicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and are thus a new class of targets for therapeutic intervention2. MicroRNA-33a and b (miR-33a/b) are intronic microRNAs embedded in the sterol response element binding protein genes SREBF2 and SREBF13–5, respectively, that repress expression of the cholesterol transporter ABCA1, a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL3–5 and protecting from atherosclerosis6, however extrapolation of these findings to humans is complicated by the fact that mice lack miR-33b which is present only in the SREBF1 gene of higher mammals. Here we show in African green monkeys that systemic delivery of an anti-miR oligonucleotide that targets both miR-33a and miR-33b increases hepatic expression of ABCA1 and induces a sustained increase in plasma HDL over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in the oxidation of fatty acids (CROT, CPT1A, HADHB, PRKAA1) and reduced genes involved in fatty acid synthesis (SREBF1, FASN, ACLY, ACACA), resulting in a marked suppression of plasma VLDL triglyceride levels, a finding not previously observed in mice. These data establish, in a model highly relevant to humans, that pharmacological inhibition of miR-33a and b is a promising therapeutic strategy to raise plasma HDL and lower VLDL triglycerides for the treatment of dyslipidemias that increase cardiovascular disease risk. PMID:22012398
Rayner, Katey J; Esau, Christine C; Hussain, Farah N; McDaniel, Allison L; Marshall, Stephanie M; van Gils, Janine M; Ray, Tathagat D; Sheedy, Frederick J; Goedeke, Leigh; Liu, Xueqing; Khatsenko, Oleg G; Kaimal, Vivek; Lees, Cynthia J; Fernandez-Hernando, Carlos; Fisher, Edward A; Temel, Ryan E; Moore, Kathryn J
Cardiovascular disease remains the leading cause of mortality in westernized countries, despite optimum medical therapy to reduce the levels of low-density lipoprotein (LDL)-associated cholesterol. The pursuit of novel therapies to target the residual risk has focused on raising the levels of high-density lipoprotein (HDL)-associated cholesterol in order to exploit its atheroprotective effects. MicroRNAs (miRNAs) have emerged as important post-transcriptional regulators of lipid metabolism and are thus a new class of target for therapeutic intervention. MicroRNA-33a and microRNA-33b (miR-33a/b) are intronic miRNAs whose encoding regions are embedded in the sterol-response-element-binding protein genes SREBF2 and SREBF1 (refs 3-5), respectively. These miRNAs repress expression of the cholesterol transporter ABCA1, which is a key regulator of HDL biogenesis. Recent studies in mice suggest that antagonizing miR-33a may be an effective strategy for raising plasma HDL levels and providing protection against atherosclerosis; however, extrapolating these findings to humans is complicated by the fact that mice lack miR-33b, which is present only in the SREBF1 gene of medium and large mammals. Here we show in African green monkeys that systemic delivery of an anti-miRNA oligonucleotide that targets both miR-33a and miR-33b increased hepatic expression of ABCA1 and induced a sustained increase in plasma HDL levels over 12 weeks. Notably, miR-33 antagonism in this non-human primate model also increased the expression of miR-33 target genes involved in fatty acid oxidation (CROT, CPT1A, HADHB and PRKAA1) and reduced the expression of genes involved in fatty acid synthesis (SREBF1, FASN, ACLY and ACACA), resulting in a marked suppression of the plasma levels of very-low-density lipoprotein (VLDL)-associated triglycerides, a finding that has not previously been observed in mice. These data establish, in a model that is highly relevant to humans, that pharmacological inhibition
Röhrl, Clemens; Stangl, Herbert
HDL removes excess cholesterol from peripheral tissues and delivers it to the liver and steroidogenic tissues via selective lipid uptake without catabolism of the HDL particle itself. In addition, endocytosis of HDL holo-particles has been debated for nearly 40 years. However, neither the connection between HDL endocytosis and selective lipid uptake, nor the physiological relevance of HDL uptake has been delineated clearly. This review will focus on HDL endocytosis and resecretion and its relation to cholesterol transfer. We will discuss the role of HDL endocytosis in maintaining cholesterol homeostasis in tissues and cell types involved in atherosclerosis, focusing on liver, macrophages and endothelium. We will critically summarize the current knowledge on the receptors mediating HDL endocytosis including SR-BI, F1-ATPase and CD36 and on intracellular HDL transport routes. Dependent on the tissue, HDL is either resecreted (retro-endocytosis) or degraded after endocytosis. Finally, findings on HDL transcytosis across the endothelial barrier will be summarized. We suggest that HDL endocytosis and resecretion is a rather redundant pathway under physiologic conditions. In case of disturbed lipid metabolism, however, HDL retro-endocytosis represents an alternative pathway that enables tissues to maintain cellular cholesterol homeostasis. PMID:23939397
Röhrl, Clemens; Stangl, Herbert
HDL removes excess cholesterol from peripheral tissues and delivers it to the liver and steroidogenic tissues via selective lipid uptake without catabolism of the HDL particle itself. In addition, endocytosis of HDL holo-particles has been debated for nearly 40years. However, neither the connection between HDL endocytosis and selective lipid uptake, nor the physiological relevance of HDL uptake has been delineated clearly. This review will focus on HDL endocytosis and resecretion and its relation to cholesterol transfer. We will discuss the role of HDL endocytosis in maintaining cholesterol homeostasis in tissues and cell types involved in atherosclerosis, focusing on liver, macrophages and endothelium. We will critically summarize the current knowledge on the receptors mediating HDL endocytosis including SR-BI, F1-ATPase and CD36 and on intracellular HDL transport routes. Dependent on the tissue, HDL is either resecreted (retro-endocytosis) or degraded after endocytosis. Finally, findings on HDL transcytosis across the endothelial barrier will be summarized. We suggest that HDL endocytosis and resecretion is a rather redundant pathway under physiologic conditions. In case of disturbed lipid metabolism, however, HDL retro-endocytosis represents an alternative pathway that enables tissues to maintain cellular cholesterol homeostasis.
Inonu Koseoglu, Handan; Pazarli, Ahmet Cemal; Kanbay, Asiye; Demir, Osman
Obstructive sleep apnea syndrome (OSAS) is an independent risk factor for cardiovascular disease (CVD). Although monocyte to high-density lipoprotein cholesterol ratio (MHR) is increasingly being implicated in cardiovascular morbidity and mortality, no study has attempted to determine the role of MHR in cardiovascular morbidity of patients with OSAS. We aimed to investigate the association between MHR and CVD in patients with OSAS and the relationship between severity of OSAS, polysomnographic parameters, and MHR. In this cohort study, patients who had undergone a full-night polysomnography for the diagnosis of OSAS were recruited. Included patients were grouped according to the apnea-hypopnea index (AHI) as mild (5-15), moderate (15-30), and severe (>30) OSAS. Patients with AHI < 5 served as the control group. The presence of heart failure, coronary artery disease, or arrhythmia was defined as CVD. A total of 1050 patients were included (131 controls, 222 mild, 228 moderate, and 469 severe OSAS). The severe group had higher MHR compared with the control and other OSAS groups (9.99, 12.11, 13.65, and 20.67 in control, mild, moderate, and severe OSAS groups, respectively, P < .001). The MHRs were significantly correlated with AHI, oxygen desaturation index, and minimum O2 saturation values ( P < .001). Values of MHR were significantly higher in patients with CVD compared with those without ( P < .001). Multiple regression analysis demonstrated that MHR is an independent predictor of CVD. The MHR is strongly associated with CVD and the severity of OSAS and might be used as a biomarker to predict CVD in patients with OSAS.
Radhakishun, Nalini; Blokhuis, Charlotte; van Vliet, Mariska; von Rosenstiel, Ines; Weijer, Olivier; Heymans, Martijn; Beijnen, Jos; Brandjes, Dees; Diamant, Michaela
The radical change of lifestyle during Ramadan fast has shown to affect cardiometabolic risk variables in adults. In youth, however, no studies are available. We aimed to evaluate the effect of Ramadan fast on Body Mass Index (BMI) and the cardiometabolic profile of obese adolescents. A prospective cohort study was conducted. We measured weight, height, body composition, blood pressure, heart rate, glucose, insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, triglycerides, and high sensitivity C-reactive protein (hs-CRP) levels before, during the last week of and at 6 weeks after Ramadan. Twenty-five obese adolescents were included. BMI and glucose metabolism did not change after Ramadan or at 6 week after cessation of Ramadan. At the end of Ramadan, a significant decrease in body fat percentage was observed, while significant increases in heart rate, total cholesterol, LDL cholesterol, HDL cholesterol, and hs-CRP were found (all P < 0.05). Six weeks after Ramadan, all parameters returned to baseline levels. In this sample of 25 ethnic obese adolescents transient cardiometabolic changes were observed during Ramadan fasting. Since most of these changes were reversible within 6 weeks, there seems no harm or benefit for obese adolescents to participate in Ramadan.
The association of coronary heart disease (CHD) with subpopulations of triglyceride (TG)-rich lipoproteins and high-density lipoproteins (HDL) is established in men, but has not been well characterized in women. Plasma HDL subpopulation concentrations, quantified by 2-dimensional gel electrophoresis...
Hayashi, Toshio; Kawashima, Seinosuke; Itoh, Hideki; Yamada, Nobuhiro; Sone, Hirohito; Watanabe, Hiroshi; Hattori, Yoshiyuki; Ohrui, Takashi; Yokote, Koutaro; Nomura, Hideki; Umegaki, Hiroyuki; Iguchi, Akihisa
To clarify the relationship between lipid levels and ischemic heart disease (IHD) and cerebrovascular disease (CVD) in diabetic individuals. The Japan Cholesterol and Diabetes Mellitus Study is a prospective cohort study of 4,014 type 2 diabetic patients (1,936 women; mean +/- SD age 67.4 +/- 9.5 years). Lipid and glucose levels and other factors were investigated in relation to occurrence of IHD or CVD. IHD and CVD occurred in 1.59 and 1.43% of participants, respectively, over a 2-year period. The relation of lower HDL or higher LDL cholesterol to occurrence of IHD in subjects <65 years old was significant. Lower HDL cholesterol was also significantly related to CVD in subjects >or=65 years old and especially in those >75 years old (n = 1,016; odds ratio 0.511 [95% CI 0.239-0.918]; P < 0.05). Stepwise multiple regression analysis with onset of CVD as a dependent variable showed the same result. Lower HDL cholesterol is an important risk factor for not only IHD but also CVD, especially in diabetic elderly individuals.
Kammerer, Candace M.; Rainwater, David L.; Gouin, Nicolas; Jasti, Madhuri; Douglas, Kory C.; Dressen, Amy S.; Ganta, Prasanth; VandeBerg, John L.; Samollow, Paul B.
Plasma cholesterol levels among individuals vary considerably in response to diet. However, the genes that influence this response are largely unknown. Non-HDL (V+LDL) cholesterol levels vary dramatically among gray, short-tailed opossums fed an atherogenic diet, and we previously reported that two quantitative trait loci (QTLs) influenced V+LDL cholesterol on two diets. We used hypothesis-free, genome-wide linkage analyses on data from 325 pedigreed opossums and located one QTL for V+LDL cholesterol on the basal diet on opossum chromosome 1q [logarithm of the odds (LOD) = 3.11, genomic P = 0.019] and another QTL for V+LDL on the atherogenic diet (i.e., high levels of cholesterol and fat) on chromosome 8 (LOD = 9.88, genomic P = 5 × 10−9). We then employed a novel strategy involving combined analyses of genomic resources, expression analysis, sequencing, and genotyping to identify candidate genes for the chromosome 8 QTL. A polymorphism in ABCB4 was strongly associated (P = 9 × 10−14) with the plasma V+LDL cholesterol concentrations on the high-cholesterol, high-fat diet. The results of this study indicate that genetic variation in ABCB4, or closely linked genes, is responsible for the dramatic differences among opossums in their V+LDL cholesterol response to an atherogenic diet. PMID:20650928
Kammerer, Candace M; Rainwater, David L; Gouin, Nicolas; Jasti, Madhuri; Douglas, Kory C; Dressen, Amy S; Ganta, Prasanth; Vandeberg, John L; Samollow, Paul B
Plasma cholesterol levels among individuals vary considerably in response to diet. However, the genes that influence this response are largely unknown. Non-HDL (V+LDL) cholesterol levels vary dramatically among gray, short-tailed opossums fed an atherogenic diet, and we previously reported that two quantitative trait loci (QTLs) influenced V+LDL cholesterol on two diets. We used hypothesis-free, genome-wide linkage analyses on data from 325 pedigreed opossums and located one QTL for V+LDL cholesterol on the basal diet on opossum chromosome 1q [logarithm of the odds (LOD) = 3.11, genomic P = 0.019] and another QTL for V+LDL on the atherogenic diet (i.e., high levels of cholesterol and fat) on chromosome 8 (LOD = 9.88, genomic P = 5 x 10(-9)). We then employed a novel strategy involving combined analyses of genomic resources, expression analysis, sequencing, and genotyping to identify candidate genes for the chromosome 8 QTL. A polymorphism in ABCB4 was strongly associated (P = 9 x 10(-14)) with the plasma V+LDL cholesterol concentrations on the high-cholesterol, high-fat diet. The results of this study indicate that genetic variation in ABCB4, or closely linked genes, is responsible for the dramatic differences among opossums in their V+LDL cholesterol response to an atherogenic diet.
Cetin, Mehmet Serkan; Ozcan Cetin, Elif Hande; Kalender, Erol; Aydin, Selahattin; Topaloglu, Serkan; Kisacik, Halil Lutfi; Temizhan, Ahmet
We aimed to investigate the usefulness of monocyte to HDL cholesterol ratio (MHR) in predicting coronary artery disease severity and future major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS). 2661 patient with ACS were enrolled and followed up during median 31.6 months. MHR were significantly positively correlated with neutrophil to lymphocyte ratio (r=0.438), CRP (r=0.394), Gensini (r=0.407), and SYNTAX score (r=0.333). During in-hospital and long-term follow-up, MACE, stent thrombosis, non-fatal MI, and mortality occurred more frequently in the third tertile group. Kaplan-Meier analysis revealed the higher occurrence of MACE in the third tertile group compared with other tertiles. Adjusting for other factors, a MHR value in the third tertile group was determined as an independent predictor of in-hospital and long-term MACE. MHR as a novel inflammation-based marker seemed to be an independent predictor of severity of coronary artery disease and future cardiovascular events in patients with ACS. MHR may utilise the identification of patients who are at higher risk for MACE and individualisation of targeted therapy. Copyright © 2016 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Ghorbanian, Bahloul; Ravassi, Aliasghar; Kordi, Mohammad Reza; Hedayati, Mahdi
Background Early obesity and its transfer to the adulthood, increases likelihood incidence of coronary artery disease (CAD). ATP-binding cassette transporter (ABCA1) as a member of the ABC transporters family plays a crucial role in reverse cholesterol transport and CAD prevention. Objective The current study aimed to investigate ABCA1 expression in lymphocytes, plasma apolipoprotein A-I and HDL-C in response to eight-week interval endurance rope training in overweight and obese boy adolescents. Patients and Methods Thirty students (17.3 ± 1.1 yr, 85.73 ± 11.68 kg and 28.41 ± 2.36 kg / m²) volunteered and were randomly assigned into training (n= 15) and control (n = 15) groups. Exercise protocol was interval endurance rope training (8 wk, 4 d/wk and 40 min/d). Cell hemolysis and sensitive Elisa method was used for Lymphocyte ABAC1 protein expression.t-test was employed. Results The independent-samples T-Test results showed that after 8 weeks IERT, the levels of lymphocyte ABCA1 expression (P = 0/001) and VO2max(P = 0/001) significantly increased and plasma levels of TG (P = 0.017), TC (P = 0.001), LDL-c/HDL-c (P = 0.026),TC/HDL-c (P = 0.002) and measures of BF% (P = 0/015) and BMI (P = 0.042) as anthropometric indicators significantly decreased. Changes of other variables such as increase in ApoA-I, HDL-c and decrease in LDL-c, body weight, were not significant. Conclusions The findings of this study proved that eight-week interval endurance rope training can have positive effects on lymphocyte ABCA1 protein expression (as gatekeeper of reverse cholesterol process) and lipid profiles among overweight and obese boy adolescents. PMID:23825977
Zuliani, Giovanni; Volpato, Stefano; Blè, Alessando; Bandinelli, Stefania; Corsi, Anna Maria; Lauretani, Fulvio; Paolisso, Giuseppe; Fellin, Renato; Ferrucci, Luigi
Background Low levels of high density lipoprotein cholesterol (HDL-C) are associated with increased incidence of coronary heart disease (CHD). A better understanding of the mechanisms leading to low HDL-C and CHD is essential for planning treatment strategies. Clinical studies have demonstrated that cytokines might affect both concentration and composition of plasma lipoproteins, including HDLs. Methods We investigated the possible association between low HDL-C levels, defined as ≤10th gender specific percentile, and circulating markers of inflammation (IL-1β, TNF-α, IL-6, IL-10, IL-18, and CRP) in a population of 1044 community dwelling older Italian subjects from the InChianti study. Results Using logistic regression analysis we demonstrated that IL-6 levels (III versus I tertile, OR: 2.10; 1.10–3.75), TG (III versus I tertile OR: 27.45; 8.47–88.93), fasting insulin (III versus I tertile OR: 2.84; 1.50–5.42), and age (OR: 1.038; 1.002–1.075) were associated with low HDL-C independent of smoking, BMI, waist circumference, hypertension, diabetes, physical activity, alcohol intake, oral hypoglycaemics, CRP, IL-18, and TNF-α levels. The adjusted attributable risk of low HDL-C in the exposed group (III tertile of IL-6) was 54%. Conclusions The present study provides the epidemiological evidence that besides triglycerides, fasting insulin, and age, IL-6 is one of the main correlates of low HDL-C levels in older individuals. PMID:16787648
Changes in lipid metabolism during last month of pregnancy and first two months of lactation in primiparous cows - analysis of apolipoprotein expression pattern and changes in concentration of total cholesterol, HDL, LDL, triglycerides.
Kurpińska, A K; Jarosz, A; Ożgo, M; Skrzypczak, W F
The final weeks of pregnancy and period of increasing lactation abound with adaptive changes in the intensity of metabolic processes. Maintaining the homeostasis of an organism in prepartum and postpartum periods is the key condition in maintaining the health of the mother and the fetus/calf. The aim of the study was to analyze physiological changes in lipid metabolism in cows during the last month of first pregnancy and in the first two months of lactation, based on the expression of identified apolipoproteins and changes in selected parameters of the lipid metabolism in peripheral blood plasma. Statistically significant changes in the expression of identified apolipoproteins were observed for apolipoprotein A-1 precursor, apolipoprotein A-IV precursor, apolipoprotein E precursor and apolipoprotein J precursor. The lowest expression of the apolipoproteins was noted around parturition and higher expression was observed during the final weeks of pregnancy and during lactation. Tendencies of changes in the concentration of total cholesterol, HDL and LDL were similar in blood plasma from analyzed cows - in the last month of pregnancy a decrease was observed and subsequently an increase in the first two months of lactation was noted. In contrast to abrupt changes observed for total cholesterol, HDL and LDL, changes in concentration of triglycerides were not that extensive and during lactation this parameter was rather stable. Evaluation of changes in the analyzed parameters may contribute to a better understanding of the changes in lipid metabolism occurring in the body of pregnant and lactating young cows.
There is great interest in developing new modes of therapy for atherosclerosis to treat coronary heart disease and stroke, particularly ones that involve modulation of high-density lipoproteins (HDLs). Here, we describe a new supramolecular chemotype for altering HDL morphology and function. Guided by rational design and SAR-driven peptide sequence enumerations, we have synthesized and determined the HDL remodeling activities of over 80 cyclic d,l-α-peptides. We have identified a few distinct sequence motifs that are effective in vitro in remodeling human and mouse plasma HDLs to increase the concentration of lipid-poor pre-beta HDLs, which are key initial acceptors of cholesterol in the reverse cholesterol transport (RCT) process, and concomitantly promote cholesterol efflux from macrophage cells. Functional assays with various control peptides, such as scrambled sequences, linear and enantiomeric cyclic peptide variants, and backbone-modified structures that limit peptide self-assembly, provide strong support for the supramolecular mode of action. Importantly, when the lead cyclic peptide c[wLwReQeR] was administered to mice (ip), it also promoted the formation of small, lipid-poor HDLs in vivo, displayed good plasma half-life (∼6 h), did not appear to have adverse side effects, and exerted potent anti-inflammatory effects in an acute in vivo inflammation assay. Given that previously reported HDL remodeling peptides have been based on α-helical apoA-I mimetic architectures, the present study, involving a new structural class, represents a promising step toward new potential therapeutics to combat atherosclerosis. PMID:28691076
Turner, Stephen D; Berg, Richard L; Linneman, James G; Peissig, Peggy L; Crawford, Dana C; Denny, Joshua C; Roden, Dan M; McCarty, Catherine A; Ritchie, Marylyn D; Wilke, Russell A
Genome-wide association studies (GWAS) are routinely being used to examine the genetic contribution to complex human traits, such as high-density lipoprotein cholesterol (HDL-C). Although HDL-C levels are highly heritable (h(2)∼0.7), the genetic determinants identified through GWAS contribute to a small fraction of the variance in this trait. Reasons for this discrepancy may include rare variants, structural variants, gene-environment (GxE) interactions, and gene-gene (GxG) interactions. Clinical practice-based biobanks now allow investigators to address these challenges by conducting GWAS in the context of comprehensive electronic medical records (EMRs). Here we apply an EMR-based phenotyping approach, within the context of routine care, to replicate several known associations between HDL-C and previously characterized genetic variants: CETP (rs3764261, p = 1.22e-25), LIPC (rs11855284, p = 3.92e-14), LPL (rs12678919, p = 1.99e-7), and the APOA1/C3/A4/A5 locus (rs964184, p = 1.06e-5), all adjusted for age, gender, body mass index (BMI), and smoking status. By using a novel approach which censors data based on relevant co-morbidities and lipid modifying medications to construct a more rigorous HDL-C phenotype, we identified an association between HDL-C and TRIB1, a gene which previously resisted identification in studies with larger sample sizes. Through the application of additional analytical strategies incorporating biological knowledge, we further identified 11 significant GxG interaction models in our discovery cohort, 8 of which show evidence of replication in a second biobank cohort. The strongest predictive model included a pairwise interaction between LPL (which modulates the incorporation of triglyceride into HDL) and ABCA1 (which modulates the incorporation of free cholesterol into HDL). These results demonstrate that gene-gene interactions modulate complex human traits, including HDL cholesterol.
Föger, B; Wohlfarter, T; Ritsch, A; Lechleitner, M; Miller, C H; Dienstl, A; Patsch, J R
The short-term effects of prolonged intense exercise on plasma lipid transport parameters including cholesterol, triglycerides (TGs), low-density lipoprotein (LD) cholesterol, high-density lipoprotein (HDL) cholesterol, and its subfractions HDL2 cholesterol and HDL3 cholesterol, on apolipoproteins (apos) A-I, A-II, and B, and on mass and activity of cholesteryl ester transfer protein (CETP) were studied in eight male endurance-trained athletes over the first week after a bicycle marathon. CETP mass concentration in plasma was quantified by a newly developed immunoradiometric assay (IRMA). Plasma concentrations of cholesterol, TGs, LDL cholesterol, apo B, CETP, and cholesteryl ester transfer activity (CETA) were significantly