BackgroundThe prevalence of abdominal obesity and type 2 diabetes mellitus (T2DM) is a public health challenge. New solutions need to be developed to help patients implement lifestyle changes.ObjectiveThe objective of the study was to evaluate a fully automated Web-based intervention designed to help users improve their dietary habits and increase their physical activity.MethodsThe Accompagnement Nutritionnel de l’Obésité et du Diabète par E-coaching (ANODE) study was a 16-week, 1:1 parallel-arm, open-label randomized clinical trial. Patients with T2DM and abdominal obesity (n=120, aged 18-75 years) were recruited. Patients in the intervention arm (n=60) had access to a fully automated program (ANODE) to improve their lifestyle. Patients were asked to log on at least once per week. Human contact was limited to hotline support in cases of technical issues. The dietetic tool provided personalized menus and a shopping list for the day or the week. Stepwise physical activity was prescribed. The control arm (n=60) received general nutritional advice. The primary outcome was the change of the dietary score (International Diet Quality Index; DQI-I) between baseline and the end of the study. Secondary endpoints included changes in body weight, waist circumference, hemoglobin A1c (HbA1c) and measured maximum oxygen consumption (VO2 max).ResultsThe mean age of the participants was 57 years (standard deviation [SD] 9), mean body mass index was 33 kg/m² (SD 4), mean HbA1c was 7.2% (SD 1.1), and 66.7% (80/120) of participants were women. Using an intention-to-treat analysis, the DQI-I score (54.0, SD 5.7 in the ANODE arm; 52.8, SD 6.2 in the control arm; P=.28) increased significantly in the ANODE arm compared to the control arm (+4.55, SD 5.91 vs -1.68, SD 5.18; between arms P<.001). Body weight, waist circumference, and HbA1c changes improved significantly in the intervention.ConclusionsAmong patients with T2DM and abdominal obesity, the use of a fully automated Web-based program resulted in a significant improvement in dietary habits and favorable clinical and laboratory changes. The sustainability of these effects remains to be determined.Trial RegistrationClinicalTrials.gov NCT02343107; http://clinicaltrials.gov/ct2/show/NCT02343107 (Archived by WebCite at http://www.webcitation.org/6uVMKPRzs)

Objective-Low high-density lipoprotein (HDL) cholesterol levels are frequently observed in familial hypercholesterolemia (FH) and might be associated with functional alterations of HDL particles that may influence their efficaciousness in the reverse cholesterol transport pathway. Methods and Results-We evaluated key steps of the reverse cholesterol transport, ie, cellular free cholesterol efflux, cholesteryl ester transfer protein-mediated cholesteryl ester (CE) transfer from HDL to apolipoprotein B-containing lipoproteins, and hepatic HDL-CE uptake, in patients displaying FH (nϭ12) and in healthy normolipidemic control subjects (nϭ12). Large HDL2 particles isolated from FH patients displayed a reduced capacity to mediate free cholesterol efflux via both scavenger receptor-BI-and ABCG1-dependent pathways. A significant inverse relationship between scavenger receptor-BI-dependent HDL2 efflux capacity and carotid intima-media thickness (rϭϪ0.473; Pϭ0.0186), as well as between ABCG1-dependent HDL2 efflux capacity and carotid intima-media thickness (rϭϪ0.485; Pϭ0.0212), was detected. We also observed an elevated cholesteryl ester transfer protein-mediated CE transfer from HDL2 and HDL3 particles to low-density lipoprotein and a reduced capacity of HDL particles to deliver CEs to the liver. Conclusion-We demonstrated that the centripetal movement of cholesterol from peripheral tissues, including the vessel wall, to feces is defective in FH, thereby emphasizing its atherogenicity. Key Words: ABC transporter Ⅲ lipoproteins Ⅲ macrophages Ⅲ metabolism Ⅲ receptors F amilial hypercholesterolemia (FH) is a common inherited dominant autosomal disorder caused by mutations in the gene encoding the low-density lipoprotein (LDL) receptor. 1 These mutations lead to a reduced number of functional LDL receptors, resulting in diminished cellular uptake of LDL particles, LDL accumulation, and increased plasma levels of total cholesterol, LDL cholesterol, and premature atherosclerosis. 2,3 Within the arterial wall, macrophages take up modified LDL through a variety of scavenger receptors, mainly scavenger receptor (SR)-A and CD36, accumulate cholesteryl esters (CEs), and are progressively converted into lipid-rich foam cells that represent the hallmark of the atherosclerotic plaque. 4 Excess cholesterol in macrophages is eliminated via the process of reverse cholesterol transport (RCT), a pathway by which cholesterol from peripheral tissues is transported to the liver for biliary excretion. 5 During the past few years, the atheroprotective role of RCT has been clearly demonstrated in humans. 6 The first step in this pathway is the efflux of cholesterol from cells to extracellular acceptors, such as high-density lipoprotein (HDL) and apolipoprotein AI (apoAI). Cellular cholesterol efflux to lipid-free or lipid-poor apoAI occurs through a transporter belonging to the ATP binding cassette (ABC) family, ABCA1, 7 whereas free cholesterol efflux to mature HDL particles involves both ABCG1 8 and SR-BI. 9 The low HDL cholesterol levels...

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We evaluated the impact of gender differences in both the quantitative and qualitative features of HDL subspecies on cellular free cholesterol efflux through the scavenger receptor class B type I (SR-BI), ABCA1, and ABCG1 pathways. For that purpose, healthy subjects (30 men and 26 women) matched for age, body mass index, triglyceride, apolipoprotein A-I, and high density lipoprotein-cholesterol (HDL-C) levels were recruited. We observed a significant increase (114%; P , 0.03) in the capacity of whole sera from women to mediate cellular free cholesterol efflux via the SR-BI-dependent pathway compared with sera from men. Such enhanced efflux capacity resulted from a significant increase in plasma levels of large cholesteryl ester-rich HDL 2 particles (120%; P , 0.04) as well as from an enhanced capacity (114%; P , 0.03) of these particles to mediate cellular free cholesterol efflux via SR-BI. By contrast, plasma from men displayed an enhanced free cholesterol efflux capacity (131%; P , 0.001) via the ABCA1 transporter pathway compared with that from women, which resulted from a 2.4-fold increase in the plasma level of preb particles (P , 0.008). Moreover, in women, SR-BI-mediated cellular free cholesterol efflux was significantly correlated with plasma HDL-C (r 5 0.72, P , 0.0001), whereas this relationship was not observed in men. In conclusion, HDL-C level may not represent the absolute indicator of the efficiency of the initial step of the reverse cholesterol

Objective-The purpose of this study was to evaluate the impact of torcetrapib on atherogenic TG-rich lipoprotein subfractions in the postprandial phase in Type IIB hyperlipidemia. Methods and Results-The quantitative and qualitative features of the postprandial profile of TG-rich lipoproteins were determined at baseline, after treatment for 6 weeks with 10 mg/d atorvastatin, and subsequently with an atorvastatin/ torcetrapib combination (10/60 mg/d) in Type IIB patients (nϭ18). After ingestion of a standardized mixed meal, TG-rich lipoprotein subfractions were evaluated over 8 hours after each experimental period. On a background of atorvastatin, torcetrapib significantly attenuated the incremental postprandial area under the curve (iAUC 0 to 8 hours) for VLDL-1 (Ϫ40%), and the AUC 0 to 8 hours for VLDL-2 (-53%), with minor effect on chylomicron iAUC (Ϫ24%); concomitantly, the CE/TG ratio in both VLDL-1 and VLDL-2 was significantly reduced (Ϫ27% to Ϫ42%). Such reduction was attributable to torcetrapib-mediated attenuation of postprandial CE transfer to Chylomicrons (Ϫ17%) and VLDL-1 (Ϫ33%). Marked reduction in postprandial VLDL-1 levels was associated with apoE enrichment. Key Words: CETP Ⅲ Torcetrapib Ⅲ high-density lipoprotein Ⅲ postprandial hypertriglyceridemia P ostprandial hypertriglyceridemia represents an independent risk factor for premature coronary artery disease (CAD). Indeed, it is now established that remnants of triglyceride-rich lipoproteins, principally chylomicrons and VLDL, may penetrate the arterial intima, with retention by the extracellular matrix and ensuing cholesterol accumulation. 1 Postprandial lipoprotein metabolism is characterized by transient accumulation of intestinally-derived Chylomicrons (CM) and hepatically-derived very low density lipoproteins (VLDL) and their remnants. Hydrolysis of the triglyceride core of CM and VLDL by lipoprotein lipase facilitates the delivery of free fatty acids to muscle and adipose tissue, with formation of CM-and VLDL-remnants which are efficiently removed from the circulation by receptor-mediated pathways in the liver. 2 During lipolysis of postprandial triglyceride-rich lipoproteins, an excess of surface components containing apolipoproteins, unesterified cholesterol, and phospholipids is generated and sequesters to HDL potentially via the action of hepatic lipase and PLTP, thereby increasing the total circulating HDL pool and enhancing the transformation of small HDL3 to large CE-rich HDL2 particles. 3 Equally, CETP mediates heterotransfer of cholesteryl esters and triglycerides between HDL on the one hand, and apoBcontaining lipoproteins on the other; such transfer is accelerated under postprandial conditions with CE enrichment of triglyceride-rich lipoprotein particles, and transient transformation of CE-enriched HDL into TG-enriched particles which become a substrate for hepatic lipase. 4 -6 In this way, HDL particle size is modulated. 6 Dyslipidemic states associated with premature atherosclerotic disease and high cardiovascular risk are asso...

Objective-We aim to identify the impact of endogenous cholesteryl ester transfer protein (CETP) activity on plasma capacity to mediate free cholesterol efflux from human macrophages. Methods and Results-Endogenous plasma CETP activity was measured in a population of 348 women. We defined a low CETP group corresponding to subjects displaying an endogenous plasma CETP activity within the first tertile and a high CETP group corresponding to subjects with an endogenous plasma CETP activity within the third tertile. Subjects from the high CETP activity group displayed a significant increase in the capacity of their plasma (+8.2%; P=0.001) to mediate cholesterol efflux from human acute monocytic leukemia cell line human macrophages and from ATP-binding cassette transporter A1-dependent pathway (+23.4%; P=0.0001) as compared with those from the low CETP activity group. Multivariate analyses revealed that the impact of CETP activity was independent of plasma lipids levels. Pre-β1-high-density lipoprotein concentrations were significantly elevated (+29.6%; P=0.01) in the high CETP activity group as compared with the low CETP activity group. A positive correlation between pre-β1-high-density lipoprotein levels and plasma efflux efficiency from human acute monocytic leukemia cell line human macrophages was observed (r=0.29, P=0.02). Conclusion-CETP

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This article is available online at http://www.jlr.org Supplementary key words ATP binding cassette transporter G1 • high density lipoprotein • cellular cholesterol effl ux • scavenger receptor class B, type I Elevated postprandial hypertriglyceridemia is a characteristic metabolic disorder associated with increased cardiovascular risk ( 1 ). After ingestion of dietary fat, an increase in plasma triglyceridemia is observed, refl ecting transient accumulation of plasma triglyceride-rich lipoproteins (TRL) of intestinal and hepatic origin, namely, apoB48-containing chylomicrons (CM), apoB100-containing very low density lipoprotein (VLDL), and their remnants. The systemic accumulation of these particles represents a pro-atherogenic consequence of the postprandial period, as they can penetrate the arterial intima at sites of endothelial dysfunction, with retention by the extracellular matrix, thereby contributing to cholesterol accumulation and plaque formation ( 2 ). During the postprandial phase, plasma cholesteryl ester transfer protein (CETP) activity is enhanced as a result of an increase in circulating cholesteryl ester (CE) acceptors and/or CETP concentrations ( 3, 4 ). On a quantitative basis, both CM and large VLDL-1 particles represent the preferential acceptors of CE from HDL among TRL during the postprandial phase ( 5 ). This process favors CE enrichment of TRL Abstract Lipid and cholesterol metabolism in the postprandial phase is associated with both quantitative and qualitative remodeling of HDL particle subspecies that may infl uence 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) effl ux, 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 effl ux 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 effl ux via the ABCA1-dependent pathway was signifi cantly 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 effl ux 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. -Julia, Z., E. Duchene, N. Fournier, N. Bellanger, M. J. Chapman, W. Le Goff, and M...