Hugh Barrett

Dyslipidemia in visceral obesity: mechanisms, implications, and therapy.

Visceral obesity is frequently associated with high plasma triglycerides and low plasma high density lipoprotein-cholesterol (HDL-C), and with high plasma concentrations of apolipoprotein B (apoB)-containing lipoproteins. Atherogenic dyslipidemia in these patients may be caused by a combination of overproduction of very low density lipoprotein (VLDL) apoB-100, decreased catabolism of apoB-containing particles, and increased catabolism of HDL-apoA-I particles. These abnormalities may be consequent on a global metabolic effect of insulin resistance. Weight reduction, increased physical activity, and moderate alcohol intake are first-line therapies to improve lipid abnormalities in visceral obesity. These lifestyle changes can effectively reduce plasma triglycerides and low density lipoprotein-cholesterol (LDL-C), and raise HDL-C. Kinetic studies show that in visceral obesity, weight loss reduces VLDL-apoB secretion and reciprocally upregulates LDL-apoB catabolism, probably owing to reduced visceral fat mass, enhanced insulin sensitivity and decreased hepatic lipogenesis. Adjunctive pharmacologic treatments, such as HMG-CoA reductase inhibitors, fibric acid derivatives, niacin (nicotinic acid), or fish oils, may often be required to further correct the dyslipidemia. Therapeutic improvements in lipid and lipoprotein profiles in visceral obesity can be achieved by several mechanisms of action, including decreased secretion and increased catabolism of apoB, as well as increased secretion and decreased catabolism of apoA-I. Clinical trials have provided evidence supporting the use of HMG-CoA reductase inhibitors and fibric acid derivatives to treat dyslipidemia in patients with visceral obesity, insulin resistance and type 2 diabetes mellitus. Since drug monotherapy may not adequately optimize dyslipoproteinemia, dual pharmacotherapy may be required, such as HMG-CoA reductase inhibitor/fibric acid derivative, HMG-CoA reductase inhibitor/niacin and HMG-CoA reductase inhibitor/fish oils combinations. Newer therapies, such as cholesterol absorption inhibitors, cholesteryl ester transfer protein antagonists and insulin sensitizers, could also be employed alone or in combination with other agents to optimize treatment. The basis for a multiple approach to correcting dyslipoproteinemia in visceral obesity and the metabolic syndrome relies on understanding the mechanisms of action of the individual therapeutic components.

Kinetic studies of lipoprotein metabolism in the metabolic syndrome including effects of nutritional interventions

Nutritional interventions may favourably regulate dyslipoproteinemia and, hence, decrease cardiovascular disease risk. Lipoprotein kinetic studies afford a powerful approach to understanding and defining the mechanisms by which such interventions modulate lipoprotein metabolism. Stable isotope tracers and compartment models are now commonly employed for such studies. We review the recent application of tracer methodologies to the study of dyslipoproteinemia in the metabolic syndrome. We also focus on the effects of nutritional intervention studies that have addressed the effects of weight loss, n-3 fatty acids, plant sterols and alcohol on very low density lipoprotein, LDL and HDL metabolism. The potential for statin treatment as an adjunct to dietary modification is also discussed. New tracer methodologies are discussed, specifically those referring to reverse cholesterol transport. The nutritional interventions discussed in this review are readily transferable into clinical preventive practice. The potential benefits to be gained by weight loss and fish oil supplementation in the metabolic syndrome extend beyond their specific and positive effects on lipoprotein metabolism. Furthermore, recent developments in tracer methodologies afford new tools for probing the in-vivo pathways of lipoprotein metabolism in future studies.

Plasma Kinetics of Cholesteryl Ester Transfer Protein in the Rabbit Effects of Dietary Cholesterol

The plasma kinetics of recombinant human cholesteryl ester transfer protein (rCETP) were studied in six rabbits before and after cholesterol feeding (0.5% wt/wt). The rCETP, labeled with the use of the Bolton Hunter reagent, was shown to retain neutral lipid transfer activity. After intravenous infusion, labeled rCETP associated with rabbit lipoproteins to an extent similar to endogenous rabbit CETP (62% to 64% HDL associated). The plasma kinetics of CETP, modeled with the use of SAAM-II, conformed to a two-pool model, likely representing free and loosely HDL-associated CETP (fast pool) and a tightly apo (apolipoprotein) AI-associated (slow pool) CETP. The plasma residency time (chow diet) of the fast pool averaged 7.1 hours and of the slow pool, 76.3 hours. The production rate (PR) into and the fractional catabolic rate (FCR) of the fast pool were 20 and 10 times the PR and FCR, respectively, of the slow pool. In response to cholesterol feeding, CETP PR, FCR, and plasma mass increased by 416%, 60%, and 230%, respectively. There was a strong correlation (r = .95, P = .003) between the increase in rabbit plasma CETP and the modeled increase in CETP PR in response to cholesterol feeding, suggesting that labeled human rCETP is a satisfactory tracer for rabbit plasma CETP. CETP is catabolized by distinct pools, likely corresponding to an apo AI-associated (slow) pool and a free and/or loosely HDL-associated (fast) pool. Factors that alter the affinity of CETP for HDL would be predicted to result in altered CETP catabolism. The effect of dietary cholesterol on plasma CETP mass can be explained largely by the effects on CETP synthesis, consistent with the observed effects of cholesterol on tissue mRNA levels.

TRL, IDL, and LDL Apolipoprotein B-100 and HDL Apolipoprotein A-I Kinetics as a Function of Age and Menopausal Status

Objective—To determine mechanisms contributing to the altered lipoprotein profile associated with aging and menopause, apolipoprotein B-100 (apoB-100) and apoA-I kinetic behavior was assessed. Methods and Results—Eight premenopausal (25±3 years) and 16 postmenopausal (65±6 years) women consumed for 6 weeks a standardized Western diet, at the end of which a primed-constant infusion of deuterated leucine was administered in the fed state to determine the kinetic behavior of triglyceride-rich lipoprotein (TRL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB-100, and high-density lipoprotein (HDL) apoA-I. Data were fit to a multicompartmental model using SAAM II to calculate fractional catabolic rate (FCR) and production rate (PR). Total cholesterol, LDL cholesterol (LDL-C), TRL-C, and triglyceride levels were higher (50%, 55%, 130%, and 232%, respectively) in the postmenopausal compared with the premenopausal women, whereas HDL-C levels were similar. Plasma TRL, IDL, and LDL–apoB-100 levels and pool sizes (PS) were significantly higher in the postmenopausal than premenopausal women. These differences were accounted for by lower TRL, IDL, and LDL apoB-100 FCR (P<0.05), with no difference in PR. There was no significant difference between groups in HDL-C levels or apoA-I kinetic parameters. Plasma TRL-C concentrations were negatively correlated with TRL apoB-100 FCR (r=−0.46; P<0.05) and positively correlated with PR (r=0.62; P<0.01). Plasma LDL-C concentrations were negatively correlated with LDL apoB-100 FCR (r=−0.70; P<0.001) but not PR. Conclusions—The mechanism for the increase in TRL and LDL apoB-100 PS observed in the postmenopausal women was determined predominantly by decreased TRL and LDL catabolism rather than increased production. No differences were observed in HDL apoA-I kinetics between groups.

Impact of a Digital Activity Tracker-Based Workplace Activity Program on Health and Wellbeing

Chronic disease is endemic within the Australian community. 3.6 million Australians have diabetes or pre-diabetes with the number increasing by 7% each year. Fifty three percent of Australians have one or more chronic diseases. Increasing levels of activity has proved relatively straightforward, especially through workplace physical activity interventions. What is still not certain are the short, and long-term, health benefits arising from these workplace activity challenges. Research into workplace activity challenges is beset with a number of methodological obstacles that may, in part, explain why consistent outcomes have not been found from studies of this type. The aim of this study was to assess whether participation in a 16-week activity challenge would result in measurable changes in lipid profile, blood glucose, renal function, blood pressure, weight and health and well being as measured using a health and wellbeing assessment. The study demonstrated that participants could increase their levels of activity and maintain at least 10,000 steps a day for a period of 16 weeks. The study also identified that participants in teams were significantly more active than those participating as individuals. Furthermore, attrition from the activity challenge was greater amongst participants not in a team. This demonstrated the importance of social interactions, support and possibly other factors that being part of a group brought to the experience of participating in the activity challenge. In addition to the above, the challenge resulted in reductions in non-HDL cholesterol, and triglyceride concentrations and health and well being score.

Impact of commonly prescribed exercise interventions on platelet activation in physically inactive and overweight men

The exercise paradox infers that, despite the well‐established cardioprotective effects of repeated episodic exercise (training), the risk of acute atherothrombotic events may be transiently increased during and soon after an exercise bout. However, the acute impact of different exercise modalities on platelet function has not previously been addressed. We hypothesized that distinct modalities of exercise would have differing effects on in vivo platelet activation and reactivity to agonists which induce monocyte‐platelet aggregate (MPA) formation. Eight middle‐aged (53.5 ± 1.6 years) male participants took part in four 30 min experimental interventions (aerobic AE, resistance RE, combined aerobic/resistance exercise CARE, or no‐exercise NE), in random order. Blood samples were collected before, immediately after, and 1 h after each intervention, and incubated with one of three agonists of physiologically/clinically relevant pathways of platelet activation (thrombin receptor activating peptide‐6 TRAP, arachidonic acid AA, and cross‐linked collagen‐related peptide xCRP). In the presence of AA, TRAP, and xCRP, both RE and CARE evoked increases in MPAs immediately post‐exercise (P < 0.01), whereas only AA significantly increased MPAs immediately after AE (P < 0.01). These increases in platelet activation post‐exercise were transient, as responses approached pre‐exercise levels by 1 h. These are the first data to suggest that exercise involving a resistance component in humans may transiently increase platelet‐mediated thrombotic risk more than aerobic modalities.