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21 October 2011

Targeting reverse cholesterol transport: the future of residual vascular risk reduction?

Jean-Charles FRUCHART

President of the R3i Foundation
Jean-Charles FRUCHART Because of the well-documented inverse relation between the plasma levels of HDL cholesterol (i.e., the plasma levels of cholesterol contained in HDL) and coronary artery disease, measurement of this parameter is part of the routine assessment of lipid profile. A substantial amount of evidence also indicates that HDL-C is one of the most useful indicators of residual vascular risk in patients treated according to current standards of care. One should not forget, however, that HDL-C measurement gives only a very limited and static view of HDL particles, and does not reflect the dynamic processes through which this lipoprotein exerts its anti-atherogenic effects.

It has been shown that HDL particles have antioxidant and anti-inflammatory properties and may play a role in the protection of endothelium but their main protective effect is linked to reverse cholesterol transport. Reverse cholesterol transport is the complex physiological process by which cholesterol is transferred from peripheral cells of atheromatous vessels to HDL particles to be transported to the liver and excreted into the bile.

HDL particles undergo a cycle of maturation throughout the whole process of reverse cholesterol transport.

Nascent HDL particles are lipid-free or lipid-poor particles with a discoid shape, essentially made of ApoA-I and some phospholipids. ApoA-I, the main apolipoprotein of HDL, is formed in the intestine and the liver.

Reverse cholesterol transport starts with cholesterol efflux from peripheral cells. First, intracellular cholesterol is transported by different intracellular carriers to the cell membrane. The ATP-binding cassette A1 (ABCA1), a transporter located on the cell surface, transports cholesterol to ApoA-1, thus forming the pre-b-HDL. A second transporter, ABCG1, intervenes later in the process and transfers more cholesterol from the cells to HDL particles. A plasma enzyme, lecithin:cholesterolacyl transferase (LCAT) transforms this free cholesterol into esterified cholesterol. Cholesteryl esters accumulate in the core of HDL particles, which then adopt the typical spherical shape of big, mature HDL.

As reverse cholesterol transport goes on, cholesteryl esters may be removed from the body by two different pathways. Selective uptake of cholesteryl esters (without ApoA-1) by the liver is mediated by the scavenger receptor class-B, type I (SR-BI), which is a docking receptor for HDL. Once in the liver, cholesteryl esters derived from HDL are eventually excreted either as bile acid or as free cholesterol in the bile.

The other important pathway of reverse cholesterol transport involves the action of plasma cholesteryl ester transfer protein (CETP), which transfers cholesteryl esters from HDL particles to ApoB-containing lipoproteins such as VLDL and LDL particles. Eventually, cholesteryl esters transferred in this way also come back to the liver where they are taken up by the LDL receptors.

Using cultured foam cells, Khera et al. have recently demonstrated that decreased cholesterol efflux capacity of HDL in humans is significantly associated with both subclinical atherosclerosis (assessed by measurement of carotid intima-media thickness) and coronary artery disease, after adjustment for classical risk factors such as age, sex, diabetes, smoking, and LDL-C. Their findings deserve consideration for several reasons. It is a good opportunity for clinicians to remember that, when one considers the protective effect of HDL, HDL cholesterol is only a part of the story. Indeed, the relation of efflux capacity with both subclinical and clinical atherosclerosis was independent of HDL-C and even ApoA-1 levels. Khera and colleagues also showed that HDL-C and ApoA-1 levels are significant determinants of cholesterol efflux capacity but accounted for only 40% of cholesterol efflux capacity in their study. Although these authors focused on cholesterol efflux, which is only a part of reverse cholesterol transport, they clearly demonstrated that HDL function is at least as important as HDL-C levels. Why HDL can become dysfunctional in individual patients is not fully understood, but ApoA-1 oxidation is probably one of the main reasons. In some subjects, HDL function is not impaired but ABCA1 is dysfunctional because of a mutation.

The complexity of reverse cholesterol transport – which is not caught up by measurement of cholesterol efflux from macrophages in vitro – offers several opportunities to develop interventions that might be able to reduce residual vascular risk.

CETP inhibition is a strategy under development. If CETP activity is reduced, there is less accumulation of cholesterol in atherogenic lipoproteins such as VLDL and LDL and a large increase in HDL-C levels. Ongoing trials will tell us if this strategy results in clinical benefits.

In their study, Khera et al. reported an increase in cholesterol efflux capacity in some patients treated with pioglitazone. This was not unexpected, as PPARg agonists like pioglitazone act on lipoprotein lipase, which generates ApoA-1 from chylomicrons.

Besides CETP inhibition, an interesting strategy to reduce residual vascular risk through an action on reverse cholesterol transport would be to use PPARag agonists. These dual agonists have the properties of PPARa and PPARg. It is well established that PPARa agonists act on a number of genes coding for proteins that have positive effects on reverse cholesterol transport (Figure 1). They increase the transport of cholesterol to the cell membrane and increase cholesterol efflux by increasing ABCA1 and ABCG1. They also increase ApoA-1 and ApoA-2 production, and SR-B1 expression in the liver. These effects can be combined with those of PPARg agonists, which increase the production of ApoA-1.

Thus, the dynamic aspects of HDL assembly and function will probably attract more and more attention in the future. However, a comprehensive measure of reverse cholesterol transport and its different components is not yet feasible. Despite its limitations, HDL-C remains a strong inverse predictor of coronary risk and a useful parameter to assess residual vascular risk in clinical practice.