HDLcholesterol plasma triacylglycerol and coronary heart disease

Although an elevated LDL-cholesterol concentration is certainly an important marker for risk of coronary heart disease, it is also true that if people who suffer a heart attack, especially those who do so at a relatively early age, are studied, a large proportion will not have elevated cholesterol concentrations. In terms of total risk in the population, factors other than LDL-cholesterol are more important. One important marker of risk is the combination of reduced HDL-cholesterol and elevated triacylglycerol concentrations.

Unlike LDL-cholesterol, elevated HDL-cholesterol concentrations are associated with decreased risk of coronary heart disease (Fig. 9.6). The converse is that a low HDL-cholesterol concentration is a marker of increased risk.

It was mentioned earlier that, in studies of large numbers of people, an inverse relationship is observed between plasma triacylglycerol and HDL-cho-lesterol concentrations. We have seen already (Section 9.3.2) how the inverse relationship between HDL-cholesterol and plasma triacylglycerol concentrations may be brought about. There are two lines of thought about their relationships with coronary heart disease risk. Firstly, HDL-cholesterol may in itself be associated with protection against coronary heart disease. This may reflect the fact that it is a marker of the ef ficiency of reverse cholesterol transport, the removal of cholesterol from tissues.

Alternatively, low HDL-cholesterol concentrations (and thus increased risk) may be a marker for some defect in the metabolism of the triacylglycerol-rich lipoproteins. One implication of defective metabolism of the triacylglyc-erol-rich lipoproteins is that their remnant particles remain for longer in the circulation whilst they are reduced to a sufficiently small size for receptor-mediated uptake. They also become cholesterol-enriched through the action of CETP. These cholesterol-rich remnants themselves may be taken up to initiate the formation of atherosclerotic lesions.

The idea that remnant particles have atherogenic potential explains neatly why people with lipoprotein lipase deficiency and enormously elevated plasma triacylglycerol concentrations are not at risk of coronary heart disease; if their particles are not metabolised at all, no smaller remnants will be produced. In this view, a 'sluggish' metabolism of the triacylglycerol-rich lipoproteins is worse than none at all. Such a condition may result from a genetic change in the lipoprotein lipase sequence, such that the enzyme is not completely ineffective but is less effective than normal. Alternatively it may reflect an increased concentration of VLDL-triacylglycerol which will prevent efficient clearance of chylomicron-triacylglycerol because of competition for lipoprotein lipase. This may result, in turn, from increased hepatic VLDL synthesis or impaired clearance. These are very much areas of current research.

An alternative view of why the combination of low HDL-cholesterol and elevated triacylglycerol concentrations leads to atherosclerosis is that these changes are also associated with alterations in the nature of LDL particles, in a combination of lipoprotein alterations called the atherogenic lipoprotein phenotype. This is discussed in Box 9.6.

A common theme relevant to the low HDL-cholesterol/elevated triacyl-glycerol combination is that of impaired postprandial lipid metabolism. Giv-

Box 9.6 The atherogenic lipoprotein phenotype

In the text the combination of a low HDL-cholesterol concentration with an elevated triacylglycerol concentration is described. These two are closely related with another change in lipoproteins: the LDL particles in the circulation are smaller and more dense than normal. This combination is often called the atherogenic lipoprotein phenotype. It is more common than simple elevation of the plasma cholesterol concentration, and may therefore be a bigger risk factor in population terms for coronary heart disease.

LDL particles are not all of the same size. In any one individual there is a population of particles with different sizes. As for all lipoprotein particles, the larger particles are less dense. In the atherogenic lipoprotein phenotype, the population of particles is skewed towards the smaller, denser end of the spectrum. The mechanism by which this occurs is outlined in Fig. 9.6.1.

Why does this shift in the density of LDL particles matter? It is proposed that small LDL particles may be particularly likely to leave the circulation by penetrating the endothelial lining, and enter the sub-endothelial space. Here they may be exposed to oxidative stress, and small, dense lipid-depleted particles may be particularly at risk of oxidative damage because in losing their core lipid, they may have lost fat-soluble antioxidant vitamins. These oxidatively damaged particles may then be taken up by macrophage scavenger receptors (see Section 9.2.2.2) to begin the process of foam-cell formation and eventually atherosclerosis.

Normal (cholesterol-rich) LDL particles MZ^T»'- riepatic lipise

CholesteryH esters

Hydrolysis of TG

Smaller, denser (lipid depleted) LDL particles

Expanded pool of TG-rich particles (e.g. due to excessive VLDL secretion or impaired LPL action)

Fig. 9.6.1 CETP, cholesteryl ester transfer protein (see Section 9.2.3.2); TG, triacylglycerol.

ing a fatty meal 'stresses' the fat metabolism system and may unmask defects (Fig. 9.7), just as giving oral glucose can be used to test for adequate glucose metabolism (discussed in Chapter 10; see Box 10.2). But eating meals that contain fat is also part of everyday life. Suppose someone has a reduced ability to clear triacylglycerol from the circulation in the period following a meal. This may reflect low activity of lipoprotein lipase, increased competition for clearance from VLDL particles, or many other factors (see Section 9.3.1). The consequence will be a reduced transfer of cholesterol (from the action of lipoprotein lipase on triacylglycerol-rich particles) into HDL particles, and also, through the action of CETP, loss of cholesterol from the HDL pool (these mechanisms were explained in more detail in Section 9.3.2). In addition, the walls of blood vessels will be exposed for longer to the potentially atherogenic remnants of the triacylglycerol-rich lipoproteins. Impaired postprandial lipid metabolism may be more than just a diagnostic test: it may reflect a situation that occurs several times a day, day after day, leading to atherosclerosis. It is, incidentally, a common feature of conditions in which insulin is not as effective as usual (insulin resistance: see Box 10.1), for reasons which are relatively obvious if we think about the normal roles of insulin in coordinating lipid metabolism. These conditions include physical inactivity, obesity and Type II diabetes mellitus, in all of which there is a predisposition to atherosclerosis.

Treatment of this condition may involve modification of the factors that predispose to it, e.g. increasing physical activity and losing of weight. But there is one group of drugs that is particularly effective in reducing elevated triacyl-

Time after meal (min)

Fig. 9.7 Impaired postprandial triacylglycerol metabolism in patients with coronary heart disease. A meal containing a relatively large amount of fat (50 g per m2 body surface area; around 100 g for most people) was given at time 0. Open points show healthy controls (n = 10); solid point show patients who have had a myocardial infarction (at least 5 years before the test) (n = 34). The patients show elevated triacylglycerol (TG) concentrations in the fasting state (time 0) and an exaggerated rise in plasma triacylglycerol concentration after the fat load, showing an impairment of the normal rapid metabolism of dietary triacylglycerol. From Karpe et al. (1992) with permission.

Time after meal (min)

Fig. 9.7 Impaired postprandial triacylglycerol metabolism in patients with coronary heart disease. A meal containing a relatively large amount of fat (50 g per m2 body surface area; around 100 g for most people) was given at time 0. Open points show healthy controls (n = 10); solid point show patients who have had a myocardial infarction (at least 5 years before the test) (n = 34). The patients show elevated triacylglycerol (TG) concentrations in the fasting state (time 0) and an exaggerated rise in plasma triacylglycerol concentration after the fat load, showing an impairment of the normal rapid metabolism of dietary triacylglycerol. From Karpe et al. (1992) with permission.

glycerol concentrations and raising HDL-cholesterol. These are the fibric acid derivatives or fibrates. The fibrates are agonists for the liver nuclear receptor PPARa (see Section 2.1.3.2). By activating this receptor, they increase fatty acid oxidation and reduce triacylglycerol synthesis. Activation of PPARa also affects apolipoprotein synthesis in the liver. Expression of apo-AI and apo-AII increases. Since these are important components of HDL, more HDL particles may be formed and the HDL-cholesterol concentration increases. Expression of apo-CIII is reduced. Since this apolipoprotein may be an inhibitor of lipoprotein lipase (Box 9.1) this will enhance triacylglycerol clearance from the circulation. Activation of PPARa can in addition induce lipoprotein lipase expression. The significance of this is not immediately clear since this would be a hepatic effect (PPARa is expressed mainly in the liver) but the adult liver does not normally express lipoprotein lipase. In animal experiments, it seems that the fibrates do indeed reactivate lipoprotein lipase expression in the liver (it is normally switched off early in life) but the situation is not clear in humans.

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