HDL-free cholesterol influx into macrophages and transfer to LDL correlate with HDL-free cholesterol content.

High-density lipoprotein (HDL)-free cholesterol (FC) transfers to other lipoproteins and cells, the former by a spontaneous mechanism and the latter by both spontaneous and receptor-mediated mechanisms. Macrophages are an important cell type in all stages of atherosclerotic cardiovascular disease (ASCVD), and the magnitude of FC efflux from macrophages to HDL, a metric of HDL function, inversely associated with several metrics of ASCVD. Very high plasma HDL concentrations are associated with increased all-cause and ASCVD mortality, suggesting that the reverse process, FC influx from HDL into macrophages, is atherogenic.

Long-term sustained effects of the Look AHEAD lifestyle intervention on body composition among adults with type 2 diabetes.

Objective: The objective of the study was to test whether there are sustained effects of the Look AHEAD intensive lifestyle intervention (ILI), versus diabetes support and education (DSE), on weight and body composition 12 to 16 years after randomization.

Methods: Participants were a subset of enrollees in the Look AHEAD dual-energy x-ray absorptiometry substudy who completed the final visit, composed of men (DSE = 99; ILI = 94) and women (DSE = 134; ILI = 135) with type 2 diabetes and mean (SD) age 57.2 (6.

The pathophysiology of excess plasma-free cholesterol.

Purpose Of Review: Several large studies have shown increased mortality due to all-causes and to atherosclerotic cardiovascular disease. In most clinical settings, plasma HDL-cholesterol is determined as a sum of free cholesterol and cholesteryl ester, two molecules with vastly different metabolic itineraries. We examine the evidence supporting the concept that the pathological effects of elevations of plasma HDL-cholesterol are due to high levels of the free cholesterol component of HDL-C.

An ERK5-NRF2 Axis Mediates Senescence-Associated Stemness and Atherosclerosis.

Background: ERK5 (extracellular signal-regulated kinase 5) is a dual kinase transcription factor containing an N-terminal kinase domain and a C-terminal transcriptional activation domain. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions about the role of the catalytic activity of ERK5 in proliferation and inflammation.

Poloxamer 407 Induces Hypertriglyceridemia but Decreases Atherosclerosis in Ldlr Mice.

Background: Hypertriglyceridemia (HTG) increases the risk for atherosclerotic cardiovascular disease, but underlying mechanisms are incompletely understood. Circulating monocytes play an important role in atherogenesis by infiltrating arterial walls, where they differentiate into macrophages. We tested the hypothesis that HTG is mechanistically linked to atherogenesis by altering the monocyte phenotype and infiltration into atherosclerotic lesions in a model of diet-induced atherogenesis in Ldlr mice.

Free Cholesterol Bioavailability and Atherosclerosis.

Purpose Of Review: As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis.

High Free Cholesterol Bioavailability Drives the Tissue Pathologies in Scarb1 Mice.

Objective: Overall and atherosclerosis-associated mortality is elevated in humans with very high HDL (high-density lipoprotein) cholesterol concentrations. Mice with a deficiency of the HDL receptor, Scarb1 (scavenger receptor class B type 1), are a robust model of this phenotype and exhibit several additional pathologies. We hypothesized that the previously reported high plasma concentration of free cholesterol (FC)-rich HDL in Scarb1-/- mice produces a state of high HDL-FC bioavailability that increases whole-body FC and dysfunction in multiple tissue sites.

High-density lipoproteins, reverse cholesterol transport and atherogenesis.

Plasma HDL-cholesterol concentrations correlate negatively with the risk of atherosclerotic cardiovascular disease (ASCVD). According to a widely cited model, HDL elicits its atheroprotective effect through its role in reverse cholesterol transport, which comprises the efflux of cholesterol from macrophages to early forms of HDL, followed by the conversion of free cholesterol (FCh) contained in HDL into cholesteryl esters, which are hepatically extracted from the plasma by HDL receptors and transferred to the bile for intestinal excretion. Given that increasing plasma HDL-cholesterol levels by genetic approaches does not reduce the risk of ASCVD, the focus of research has shifted to HDL function, especially in the context of macrophage cholesterol efflux.

Physico-chemical and physiological determinants of lipo-nanoparticle stability.

Liposome-based nanoparticles (NPs) comprised mostly of phospholipids (PLs) have been developed to deliver diagnostic and therapeutic agents. Whereas reassembled plasma lipoproteins have been tested as NP carriers of hydrophobic molecules, they are unstable because the components can spontaneously transfer to other PL surfaces-cell membranes and lipoproteins-and can be degraded by plasma lipases. Here we review two strategies for NP stabilization.

Within-Trial Cost-Effectiveness of a Structured Lifestyle Intervention in Adults With Overweight/Obesity and Type 2 Diabetes: Results From the Action for Health in Diabetes (Look AHEAD) Study.

Objective: To assess the cost-effectiveness (CE) of an intensive lifestyle intervention (ILI) compared with standard diabetes support and education (DSE) in adults with overweight/obesity and type 2 diabetes, as implemented in the Action for Health in Diabetes study.

Research Design And Methods: Data were from 4,827 participants during their first 9 years of study participation from 2001 to 2012. Information on Health Utilities Index Mark 2 (HUI-2) and HUI-3, Short-Form 6D (SF-6D), and Feeling Thermometer (FT), cost of delivering the interventions, and health expenditures was collected during the study.

Intensive Weight Loss Intervention and Cancer Risk in Adults with Type 2 Diabetes: Analysis of the Look AHEAD Randomized Clinical Trial.

Objective: This study was designed to determine whether intensive lifestyle intervention (ILI) aimed at weight loss lowers cancer incidence and mortality.

Methods: Data from the Look AHEAD trial were examined to investigate whether participants randomized to ILI designed for weight loss would have reduced overall cancer incidence, obesity-related cancer incidence, and cancer mortality, as compared with the diabetes support and education (DSE) comparison group. This analysis included 4,859 participants without a cancer diagnosis at baseline except for nonmelanoma skin cancer.

Highly conserved amino acid residues in apolipoprotein A1 discordantly induce high density lipoprotein assembly in vitro and in vivo.

Objective: Apolipoprotein A1 (APOA1) is essential to reverse cholesterol transport, a physiologically important process that protects against atherosclerotic cardiovascular disease. APOA1 is a 28 kDa protein comprising multiple lipid-binding amphiphatic helices initialized by proline residues, which are conserved across multiple species. We tested the hypothesis that the evolutionarily conserved residues are essential to high density lipoprotein (HDL) function.

The Alcohol-High-Density Lipoprotein Athero-Protective Axis.

Ingestion of alcohol is associated with numerous changes in human energy metabolism, especially that of plasma lipids and lipoproteins. Regular moderate alcohol consumption is associated with reduced atherosclerotic cardiovascular disease (ASCVD), an effect that has been attributed to the concurrent elevations of plasma high-density lipoprotein-cholesterol (HDL-C) concentrations. More recent evidence has accrued against the hypothesis that raising plasma HDL concentrations prevents ASCVD so that other metabolic processes associated with alcohol consumption have been considered.

Weight Change 2 Years After Termination of the Intensive Lifestyle Intervention in the Look AHEAD Study.

Objective: This study evaluated weight changes after cessation of the 10-year intensive lifestyle intervention (ILI) in the Look AHEAD (Action for Health in Diabetes) study. It was hypothesized that ILI participants would be more likely to gain weight during the 2-year observational period following termination of weight-loss-maintenance counseling than would participants in the diabetes support and education (DSE) control group.

Methods: Look AHEAD was a randomized controlled trial that compared the effects of ILI and DSE on cardiovascular morbidity and mortality in participants with overweight/obesity and type 2 diabetes.

Dietary Alcohol and Fat Differentially Affect Plasma Cholesteryl Ester Transfer Activity and Triglycerides in Normo- and Hypertriglyceridemic Subjects.

Moderate alcohol consumption is associated with increased plasma high-density lipoprotein (HDL)-cholesterol concentrations and reduced risk for cardiovascular disease. Plasma cholesteryl ester transfer activity (CETA) mediates the exchange of HDL-cholesteryl ester (CE) for the triacylglycerol (TAG) of very-low-density lipoproteins. We compared the effects of oral challenges of Alcohol, saturated fat (SAT), and (Alcohol + SAT) on plasma CETA, cholesterol, nonesterified fatty acids (NEFA), and TAG among normo-triglyceridemic (NTG) and mildly hypertriglyceridemic (HTG) volunteers having a range of plasma TAG concentrations.

History of Cardiovascular Disease, Intensive Lifestyle Intervention, and Cardiovascular Outcomes in the Look AHEAD Trial.

Objective: To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063).

Replacing Saturated Fat With Unsaturated Fat in Western Diet Reduces Foamy Monocytes and Atherosclerosis in Male Mice.

Objective: A Mediterranean diet supplemented with olive oil and nuts prevents cardiovascular disease in clinical studies, but the underlying mechanisms are incompletely understood. We investigated whether the preventive effect of the diet could be due to inhibition of atherosclerosis and foamy monocyte formation in mice fed with a diet in which milkfat in a Western diet (WD) was replaced with extra-virgin olive oil and nuts (EVOND). Approach and Results: mice were fed EVOND or a Western diet for 3 (or 6) months.

Revisiting Reverse Cholesterol Transport in the Context of High-Density Lipoprotein Free Cholesterol Bioavailability.

Dysregulated free cholesterol (FC) metabolism has been implicated in nearly all stages of atherosclerosis, the underlying cause of most cardiovascular disease. According to a widely cited model, the burden of macrophage FC in the arterial wall is relieved by transhepatic reverse cholesterol transport (RCT), which comprises three successive steps: (1) macrophage FC efflux to high-density lipoprotein (HDL) and/or its major protein, apolipoprotein AI; (2) FC esterification by lecithin:cholesterol acyltransferase (LCAT); and (3) HDL-cholesteryl ester (CE) uptake via the hepatic HDL-receptor, scavenger receptor class B type 1 (SR-B1). Recent studies have challenged the validity of this model, most notably the role of LCAT, which appears to be of minor importance.

Cholesterol: Can't Live With It, Can't Live Without It.

Given its role in many biochemical processes essential to life, cholesterol remains a topic of intense research. Of all the plasma lipids, cholesterol is distinctive because it is a precursor to steroidogenic molecules, some of which regulate metabolism, and its blood concentration in the form of low- and high-density lipoprotein cholesterol (HDL-C) are positive and negative risk factors for atherosclerotic cardiovascular disease (ASCVD). New research, however, has challenged the widely held belief that high HDL-C levels are atheroprotective and is showing that both low and high plasma HDL-C levels confer an increased risk of ASCVD.

Somatic Editing of Ldlr With Adeno-Associated Viral-CRISPR Is an Efficient Tool for Atherosclerosis Research.

Objective- Atherosclerosis studies in Ldlr knockout mice require breeding to homozygosity and congenic status on C57BL6/J background, a process that is both time and resource intensive. We aimed to develop a new method for generating atherosclerosis through somatic deletion of Ldlr in livers of adult mice. Approach and Results- Overexpression of PCSK9 (proprotein convertase subtilisin/kexin type 9) is currently used to study atherosclerosis, which promotes degradation of LDLR (low-density lipoprotein receptor) in the liver.