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A novel score based on serum apolipoprotein A-1 and C-reactive protein is a prognostic biomarker in hepatocellular carcinoma patients.
Mao, M, Wang, X, Sheng, H, Liu, Y, Zhang, L, Dai, S, Chi, PD
BMC cancer. 2018;(1):1178
Abstract
BACKGROUND The aim of this study was to propose a prognostic scoring system based on preoperative serum apolipoprotein A-1 and C-reactive protein (ApoA-1 and CRP, AC score) levels and to evaluate the prognostic value of these markers in patients with hepatocellular carcinoma (HCC). METHODS In all, 539 consecutive cases diagnosed with HCC from 2009 to 2012 at Sun Yat-sen University Cancer Center were analysed. The characteristics and levels of pretreatment lipids (ApoA-1, apolipoprotein B (Apo-B), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TGs)) and CRP were reviewed and determined by univariate and multivariate Cox hazard models. Then, the AC score was proposed, which combines two independent risk factors (ApoA-1 and CRP). RESULTS The optimal cut-off points in our study were determined according to established reference ranges. Patients with decreased ApoA-1 levels (< 1.090 g/L) and increased CRP levels (≥3.00 mg/L) exhibited a significantly poor overall survival (OS) and disease-free survival (DFS). The AC score was calculated as follows: patients with decreased ApoA-1 and elevated CRP were given a score of 3, patients with only one of these abnormalities were given a score of 2, and those with no abnormalities were given a score of 1. Patients with a higher AC score showed more progressive disease and a poorer prognosis. This was observed not only in the entire cohort (for OS, P < 0.001; for DFS, P < 0.001) but also in the subgroups stratified by pathological stage (stage I-II and stage III-IV). The discriminatory ability of the AC score in HCC was assessed according to the AUC values. The AUC value of the AC score (AUC: 0.676, 95% CI: 0.629-0.723, P < 0.001) was higher than that of AFP. In addition, the combination of the AFP and AC scores (AUC: 0.700, 95% CI: 0.655-0.745, P < 0.001) was superior to the AFP and AC scores alone. CONCLUSIONS The AC score is a significant valuable predictor of OS and DFS and could more accurately differentiate the prognosis of HCC patients. As this study is a retrospective analysis, the value of the AC score should be validated in large prospective trials.
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HDL cholesterol efflux normalised to apoA-I is associated with future development of type 2 diabetes: from the CORDIOPREV trial.
Blanco-Rojo, R, Perez-Martinez, P, Lopez-Moreno, J, Martinez-Botas, J, Delgado-Lista, J, van-Ommen, B, Yubero-Serrano, E, Camargo, A, Ordovas, JM, Perez-Jimenez, F, et al
Scientific reports. 2017;(1):12499
Abstract
This prospective study evaluated whether baseline cholesterol efflux is associated with future development of type 2 diabetes (T2DM) in cardiovascular patients. We measured cholesterol efflux in all CORDIOPREV study (NCT00924937) participants free of T2DM at baseline (n = 462) and assessed its relationship with T2DM incidence during a 4.5 years of follow-up. Cholesterol efflux was quantified by incubation of cholesterol-loaded THP-1 cells with the participants' apoB-depleted plasma. Disposition index was estimated as beta-cell function indicator. During follow-up 106 individuals progressed to T2DM. The cholesterol efflux/apoA-1 ratio was inversely associated with T2DM development independently of traditional risk factors (model-1, OR: 0.647, 95%CI: 0.495-0.846), and after additional adjustment for glycaemic parameters (model-2, OR: 0.670, 95%CI: 0.511-0.878). When cumulative incidence of diabetes was analysed by quartiles of cholesterol efflux/apoA-I, incidence of T2DM was reduced by 54% in subjects who were in the higher cholesterol efflux/apoA-I quartile compared to subjects in the lowest quartile (p = 0.018 and p = 0.042 for model-1 and 2). Moreover, participants who were in the higher cholesterol efflux/apoA-I presented significantly higher disposition index (β = 0.056, SE = 0.026; p = 0.035). In conclusion, HDL-cholesterol efflux normalised to apoA-I was inversely associated with T2DM development in cardiovascular patients. This association was independent of several T2DM risk factors, and may be related to a preserved beta-cell function.
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Lifestyle and Dietary Determinants of Serum Apolipoprotein A1 and Apolipoprotein B Concentrations: Cross-Sectional Analyses within a Swedish Cohort of 24,984 Individuals.
Frondelius, K, Borg, M, Ericson, U, Borné, Y, Melander, O, Sonestedt, E
Nutrients. 2017;(3)
Abstract
Low serum apolipoprotein (Apo) A1 concentrations and high serum ApoB concentrations may be better markers of the risk of cardiovascular disease than high-density lipoprotein (HDL) and low-density lipoprotein (LDL). However, the associations between modifiable lifestyle factors and Apo concentrations have not been investigated in detail. Therefore, this study investigated the associations between Apo concentrations and education, lifestyle factors and dietary intake (macronutrients and 34 food groups). These cross-sectional associations were examined among 24,984 individuals in a Swedish population-based cohort. Baseline examinations of the cohort were conducted between 1991 and 1996. Dietary intake was assessed using a modified diet history method. The main determinants of high ApoA1 concentrations (r between 0.05 and 0.25) were high alcohol consumption, high physical activity, non-smoking, and a low body mass index (BMI), and the main determinants of high ApoB concentrations were smoking and a high BMI. The intake of sucrose and food products containing added sugar (such as pastries, sweets, chocolate, jam/sugar and sugar-sweetened beverages) was negatively correlated with ApoA1 concentrations and positively correlated with ApoB concentrations and the ApoB/ApoA1 ratio, whereas the intake of fermented dairy products, such as fermented milk and cheese, was positively correlated with ApoA1 concentrations and negatively correlated with the ApoB/ApoA1 ratio. These results indicate that smoking, obesity, low physical activity, low alcohol consumption and a diet high in sugar and low in fermented dairy products are correlated with an unfavorable Apo profile.
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Extended-release niacin increases anti-apolipoprotein A-I antibodies that block the antioxidant effect of high-density lipoprotein-cholesterol: the EXPLORE clinical trial.
Batuca, JR, Amaral, MC, Favas, C, Paula, FS, Ames, PRJ, Papoila, AL, Delgado Alves, J
British journal of clinical pharmacology. 2017;(5):1002-1010
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Abstract
AIMS: Extended-release niacin (ERN) is the most effective agent for increasing high-density lipoprotein-cholesterol (HDL-C). Having previously identified anti-HDL antibodies, we investigated whether ERN affected the antioxidant capacity of HDL and whether ERN was associated with the production of antibodies against HDL (aHDL) and apolipoprotein A-I (aApoA-I). METHODS Twenty-one patients older than 18 years, with HDL-C ≤40 mg dl-1 (men) or ≤50 mg dl-1 (women) were randomly assigned to receive daily ERN (n = 10) or placebo (n = 11) for two sequential 12-week periods, with 4 weeks of wash-out before cross-over. Primary outcome was change of paraoxonase-1 (PON1) activity and secondary outcomes were changes in aHDL and aApoA-I antibodies. Clinical Trial Unique Identifier: EudraCT 2006-006889-42. RESULTS The effect of ERN on PON1 activity was nonsignificant (coefficient estimate 20.83 U l-1 , 95% confidence interval [CI] -9.88 to 51.53; P = 0.184). ERN was associated with an increase in HDL-C levels (coefficient estimate 5.21 mg dl-1 , 95% CI 1.16 to 9.25; P = 0.012) and its subclasses HDL2 (coefficient estimate 2.46 mg dl-1 , 95% CI 0.57 to 4.34; P = 0.011) and HDL3 (coefficient estimate 2.73 mg dl-1 , 95% CI 0.47 to 4.98; P = 0.018). ERN was significantly associated with the production of aApoA-I antibodies (coefficient estimate 0.25 μg ml-1 , 95% CI 0.09-0.40; P = 0.001). aApoA-I titres at baseline were correlated with decreased PON activity. CONCLUSIONS The rise in HDL-C achieved with ERN was not matched by improved antioxidant capacity, eventually hampered by the emergence of aApoA-I antibodies. These results may explain why Niacin and other lipid lowering agents fail to reduce cardiovascular risk.
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Insulin-Mediated Downregulation of Apolipoprotein A-I Gene in Human Hepatoma Cell Line HepG2: The Role of Interaction Between FOXO1 and LXRβ Transcription Factors.
Shavva, VS, Bogomolova, AM, Nikitin, AA, Dizhe, EB, Tanyanskiy, DA, Efremov, AM, Oleinikova, GN, Perevozchikov, AP, Orlov, SV
Journal of cellular biochemistry. 2017;(2):382-396
Abstract
Apolipoprotein A-I (ApoA-I) is a key component of high density lipoproteins which possess anti-atherosclerotic and anti-inflammatory properties. Insulin is a crucial mediator of the glucose and lipid metabolism that has been implicated in atherosclerotic and inflammatory processes. Important mediators of insulin signaling such as Liver X Receptors (LXRs) and Forkhead Box A2 (FOXA2) are known to regulate apoA-I expression in liver. Forkhead Box O1 (FOXO1) is a well-known target of insulin signaling and a key mediator of oxidative stress response. Low doses of insulin were shown to activate apoA-I expression in human hepatoma HepG2 cells. However, the detailed mechanisms for these processes are still unknown. We studied the possible involvement of FOXO1, FOXA2, LXRα, and LXRβ transcription factors in the insulin-mediated regulation of apoA-I expression. Treatment of HepG2 cells with high doses of insulin (48 h, 100 nM) suppresses apoA-I gene expression. siRNAs against FOXO1, FOXA2, LXRβ, or LXRα abrogated this effect. FOXO1 forms a complex with LXRβ and insulin treatment impairs FOXO1/LXRβ complex binding to hepatic enhancer and triggers its nuclear export. Insulin as well as LXR ligand TO901317 enhance the interaction between FOXA2, LXRα, and hepatic enhancer. These data suggest that high doses of insulin downregulate apoA-I gene expression in HepG2 cells through redistribution of FOXO1/LXRβ complex, FOXA2, and LXRα on hepatic enhancer of apoA-I gene. J. Cell. Biochem. 118: 382-396, 2017. © 2016 Wiley Periodicals, Inc.
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Association of High-Density Lipoprotein-Cholesterol Versus Apolipoprotein A-I With Risk of Coronary Heart Disease: The European Prospective Investigation Into Cancer-Norfolk Prospective Population Study, the Atherosclerosis Risk in Communities Study, and the Women's Health Study.
van Capelleveen, JC, Bochem, AE, Boekholdt, SM, Mora, S, Hoogeveen, RC, Ballantyne, CM, Ridker, PM, Sun, W, Barter, PJ, Tall, AR, et al
Journal of the American Heart Association. 2017;(8)
Abstract
BACKGROUND The contribution of apolipoprotein A-I (apoA-I) to coronary heart disease (CHD) risk stratification over and above high-density lipoprotein cholesterol (HDL-C) is unclear. We studied the associations between plasma levels of HDL-C and apoA-I, either alone or combined, with risk of CHD events and cardiovascular risk factors among apparently healthy men and women. METHODS AND RESULTS HDL-C and apoA-I levels were measured among 17 661 participants of the EPIC (European Prospective Investigation into Cancer)-Norfolk prospective population study. Hazard ratios for CHD events and distributions of risk factors were calculated by quartiles of HDL-C and apoA-I. Results were validated using data from the ARIC (Atherosclerosis Risk in Communities) and WHS (Women's Health Study) cohorts, comprising 15 494 and 27 552 individuals, respectively. In EPIC-Norfolk, both HDL-C and apoA-I quartiles were strongly and inversely associated with CHD risk. Within HDL-C quartiles, higher apoA-I levels were not associated with lower CHD risk; in fact, CHD risk was higher within some HDL-C quartiles. ApoA-I levels were associated with higher levels of CHD risk factors: higher body mass index, HbA1c, non-HDL-C, triglycerides, apolipoprotein B, systolic blood pressure, and C-reactive protein, within fixed HDL-C quartiles. In contrast, HDL-C levels were consistently inversely associated with overall CHD risk and CHD risk factors within apoA-I quartiles (P<0.001). These findings were validated in the ARIC and WHS cohorts. CONCLUSIONS Our findings demonstrate that apoA-I levels do not offer predictive information over and above HDL-C. In fact, within some HDL-C quartiles, higher apoA-I levels were associated with higher risk of CHD events, possibly because of the unexpected higher prevalence of cardiovascular risk factors in association with higher apoA-I levels. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00000479.
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RVX 208: A novel BET protein inhibitor, role as an inducer of apo A-I/HDL and beyond.
Ghosh, GC, Bhadra, R, Ghosh, RK, Banerjee, K, Gupta, A
Cardiovascular therapeutics. 2017;(4)
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Low-density cholesterol (LDL) has been the prime target of currently available lipid-lowering therapies although current research is expanding the focus beyond LDL lowering and has included high-density cholesterol (HDL) also as the target. Bromo and extra-terminal (BET) proteins are implicated in the regulation of transcription of several regulatory genes and regulation of proinflammatory pathways. As atherosclerosis is an inflammatory pathway and studies showed that BET inhibition has a role in inhibiting inflammation, the concept of BET inhibition came in the field of atherosclerosis. RVX 208 is a novel, orally active, BET protein inhibitor and the only BET inhibitor currently available in the field of atherosclerosis. RVX 208 acts primarily by increasing apo A-I (apolipoprotein A-I) and HDL levels. RVX 208 has a novel action of increasing larger, more cardio-protective HDL particles. Post hoc analysis of Phase II trials also showed that RVX 208 reduced major adverse cardiovascular events (MACE) in treated patients, over and above that of apo A-I/HDL increasing action. This MACE reducing actions of RVX 208 were largely due to its novel anti-inflammatory actions. Currently, a phase III trial, BETonMACE, is recruiting patients to look for the effects of RVX 208 in patients with increased risk of atherosclerotic cardiovascular disease. So BET inhibitors act in multiple ways to inhibit and modulate atherosclerosis and would be an emerging and potential option in the management of multifactorial disease like coronary artery disease by inhibiting a single substrate. But we need long-term phase III trial data's to look for effects on real-world patients.
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The HDL cholesterol/apolipoprotein A-I ratio: an indicator of cardiovascular disease.
Rhee, EJ, Byrne, CD, Sung, KC
Current opinion in endocrinology, diabetes, and obesity. 2017;(2):148-153
Abstract
PURPOSE OF REVIEW In multiple studies, the HDL cholesterol (HDL-C) concentration has been shown to be inversely associated with cardiovascular disease (CVD) and CVD risk. Based on this observation, increasing the plasma HDL-C concentration is thought to be a desirable strategy, in the 21st century, for decreasing the burden of CVD. RECENT FINDINGS Recent studies have shown that powerful HDL-C concentration-increasing drugs are ineffective for decreasing CVD. Increasing evidence now shows that HDL is an unstable and heterogeneous particle, and that 'HDL particle functionality' is far more important in atheroprotection than is the HDL-C level, alone. Apolipoprotein A-I (apoA-I) is the major protein component of HDL, and increasing evidence suggests that the ratio of HDL-C to apoA-I may give additional insight as a risk marker not just for CVD but also for all-cause and cancer mortality. SUMMARY In this review, we discuss the importance of HDL composition, apoA-I levels, and the HDL-C/apoA-I ratio for predicting CVD and mortality outcomes.
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Inclusion of Almonds in a Cholesterol-Lowering Diet Improves Plasma HDL Subspecies and Cholesterol Efflux to Serum in Normal-Weight Individuals with Elevated LDL Cholesterol.
Berryman, CE, Fleming, JA, Kris-Etherton, PM
The Journal of nutrition. 2017;(8):1517-1523
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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 circulating HDL subpopulation distribution and improve cholesterol efflux in normal-weight individuals with elevated LDL cholesterol. This trial was registered at clinicaltrials.gov as NCT01101230.
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Apolipoprotein A-I exchange is impaired in metabolic syndrome patients asymptomatic for diabetes and cardiovascular disease.
Borja, MS, Hammerson, B, Tang, C, Savinova, OV, Shearer, GC, Oda, MN
PloS one. 2017;(8):e0182217
Abstract
OBJECTIVE We tested the hypothesis that HDL-apolipoprotein A-I exchange (HAE), a measure of high-density lipoprotein (HDL) function and a key step in reverse cholesterol transport (RCT), is impaired in metabolic syndrome (MetSyn) patients who are asymptomatic for diabetes and cardiovascular disease. We also compared HAE with cell-based cholesterol efflux capacity (CEC) to address previous reports that CEC is enhanced in MetSyn populations. METHODS HAE and ABCA1-specific CEC were measured as tests of HDL function in 60 MetSyn patients and 14 normolipidemic control subjects. Predictors of HAE and CEC were evaluated with multiple linear regression modeling using clinical markers of MetSyn and CVD risk. RESULTS HAE was significantly reduced in MetSyn patients (49.0 ± 10.9% vs. 61.2 ± 6.1%, P < 0.0001), as was ABCA1-specific CEC (10.1 ± 1.6% vs. 12.3 ± 2.0%, P < 0.002). Multiple linear regression analysis identified apoA-I concentration as a significant positive predictor of HAE, and MetSyn patients had significantly lower HAE per mg/dL of apoA-I (P = 0.004). MetSyn status was a negative predictor of CEC, but triglyceride (TG) was a positive predictor of CEC, with MetSyn patients having higher CEC per mg/dL of TG, but lower overall CEC compared to controls. CONCLUSIONS MetSyn patients have impaired HAE that contributes to reduced capacity for ABCA1-mediated CEC. MetSyn status is inversely correlated with CEC but positively correlated with TG, which explains the contradictory results from earlier MetSyn studies focused on CEC. HAE and CEC are inhibited in MetSyn patients over a broad range of absolute apoA-I and HDL particle levels, supporting the observation that this patient population bears significant residual cardiovascular disease risk.