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International Chair on Cardiometabolic Risk
My Healthy Waist

Editorial: Metabolic abnormalities in people with abdominal obesity: low levels of high-density lipoproteins

By Professor Philip J. Barter, MBBS, FRACP, PhD, The Heart Research Institute, Sydney, Australia

An inverse relationship between the level of high-density lipoprotein (HDL) cholesterol and the risk of developing premature cardiovascular disease (CVD) has been a consistent finding in prospective population studies. In several of these studies the level of HDL cholesterol has been the single most powerful lipid predictor of future CHD events. The increased CVD risk associated with low levels of HDL cholesterol persists even when the level of LDL cholesterol has been reduced to levels below 1.8 mmol/l (70 mg/dl) by treatment with statins. Furthermore, HDL raising interventions have been shown to be highly effective in reducing the development of atherosclerosis in a variety of animal models. More recently, this anti-atherogenic effect of HDLs has also been observed in humans in whom it has been shown that infusions of reconstituted HDLs reduce the atheroma burden in coronary arteries as revealed by intravascular ultrasound. There are several well-documented functions of HDLs that may explain the ability of these lipoproteins to protect against atherosclerosis. The best recognized of these is the ability of HDLs to promote the efflux of cholesterol from cells in a process that minimizes the accumulation of foam cells in the artery wall. HDLs also function as anti-oxidants and as anti-inflammatory agents. They are anti-apoptotic, anti-thrombotic and have the ability to promote the repair of damaged endothelium. So any condition that reduces the HDL concentration has the capacity to greatly increase susceptibility to the development of atherosclerosis. In 2008 the major cause of a low level of HDLs is abdominal obesity, a condition that is increasing worldwide at an alarming rate. People with abdominal obesity typically have a dyslipidemia characterized by an elevated concentration of plasma triglycerides, an LDL fraction in which the particles are smaller and denser than normal and a low concentration of HDL cholesterol. Abdominally obese people are also frequently insulin resistant with evidence of being in a pro-inflammatory state. The low HDL concentration in people with abdominal obesity is the consequence of an increased rate of HDL catabolism, possibly secondary to triglyceride enrichment of the particles resulting from an enhanced activity of the cholesteryl ester transfer protein (CETP). CETP promotes the transfer of cholesteryl esters from HDLs to triglyceride-rich lipoproteins in exchange for triglycerides to generate HDLs that are depleted of cholesteryl esters and enriched in triglycerides. This triglyceride enrichment provides HDLs with the preferred substrate for the enzyme hepatic lipase. Subsequent hydrolysis of the newly acquired HDL triglyceride by hepatic lipase leads to a reduction in volume of the particle core, a consequent decrease in particle size and a dissociation of lipid-free/lipid-poor apolipoprotein (apo) AI from the HDL particle surface. Given that free fatty acids enhance the CETP-mediated remodelling of HDLs, this dissociation of lipid-poor apo AI from HDLs (and its subsequent loss in urine) may be exaggerated in subjects with abdominal obesity in whom an increased concentration of free fatty acids is common. There are several potentially pro-atherogenic forces operating in people with abdominal obesity. An increase in the concentration of the remnants of triglyceride-rich lipoproteins has the capacity to deposit cholesterol in macrophages, converting them into foam cells. There is also an increase in the concentration of small, dense LDLs, particles that are especially susceptible to oxidation and therefore subject to an enhanced uptake by macrophages. Subjects with abdominal obesity frequently manifest a pro-inflammatory state. While this may be no more than a marker of underlying atherosclerosis, inflammatory mediators such as the endothelial cell adhesion proteins and a range of chemokines may also contribute to the process. Under normal conditions pro-atherogenic forces such as these are opposed by HDLs. In people with abdominal obesity, however, the HDL concentration is low and there is a reduced capacity to counter the cholesterol accumulation in macrophages, a decreased ability to prevent the oxidation of small dense LDLs and a reduced inhibition of the pro-atherogenic expression of endothelial cell adhesion proteins and chemokines. This loss of the protection normally provided by HDLs therefore has the capacity to amplify the already powerful pro-atherogenic forces that exist in people with abdominal obesity. One barrier to considering HDLs as a therapeutic target in people with abdominal obesity is the absence of truly effective HDL-raising strategies. Lifestyle measures such as weight reduction, increased physical activity and cessation of smoking have the capacity to increase HDL levels by 20% or more. However, compliance with lifestyle modification tends to be poor and pharmacological approaches are required. Of currently available agents, statins and fibrates may raise the level of HDL cholesterol by about 10%. Niacin is more effective, raising HDL cholesterol levels by up to 25%, with newer extended release formulations being much better tolerated than the earlier acute release form. Rimonabant, a CB1 blocker that is now available in some countries to promote weight reduction in high-risk people with abdominal obesity, appears to have an HDL-raising effect that is more than expected from the associated weight loss. Such an effect has the potential to amplify the beneficial effects associated with the weight reduction achieved with this class of agent. In future, much greater increases in HDL concentration may be possible with the introduction of agents currently under development, although it must be emphasized that it will be some years before any of these newer agents becomes available for clinical use. In conclusion, a low concentration of HDL cholesterol is a common feature in people with abdominal obesity. There is circumstantial evidence that low HDL levels contribute to the increased risk of atherosclerosis in such people. There is logic to considering HDL-raising therapy as a strategy for reducing the risk of atherosclerosis in high-risk people with abdominal obesity. The development of newer, more effective HDL-raising agents has the potential to translate into substantial risk reduction in subjects with abdominal obesity.

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