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Chylomicrons, VLDL and remnants

Lipoprotein lipase defect (not complete absence) or apolipoprotein CII deficiency

This is known as the Fredrickson classification after the American clinician and biochemist, Donald Fredrickson. N, normal; +, mildly raised; ++, moderately raised; + + +, severely raised.

This is known as the Fredrickson classification after the American clinician and biochemist, Donald Fredrickson. N, normal; +, mildly raised; ++, moderately raised; + + +, severely raised. Primary hyperlipoproteinaemias

The most dramatic primary hyperlipidaemias are those known as familial hypercholesterolemia (FH) and Type I hyperlipoproteinaemia (Table 9.2), also known as chylomicronaemia syndrome.

The first of these, FH, is manifest by a consistently raised blood cholesterol concentration, typically 8-10 mmol/l in people heterozygous for the disease (about 1 in 500 people in the UK), but more like 15-20 mmol/l in people who are homozygous (i.e. who have two copies of the gene which causes it). The incidence of coronary heart disease in such people is very high unless they are adequately treated to lower the cholesterol concentration. This is another reason for believing that there is a direct cause-and-effect link between elevated blood cholesterol concentration and atherosclerosis. The defect in FH is in the amino acid sequence of the LDL receptor. Many genetic defects have been described: some lead to LDL receptors that cannot bind LDL particles normally, others prevent expression of the receptor on the cell surface. The net result is that LDL particles remain in the circulation. Recently, it has been realised that defects in the sequence of apolipoprotein B may produce a very similar syndrome. Because lipoprotein cholesterol is not being taken up into cells, the pathway of cholesterol synthesis is not repressed, and this adds to the problem.

Treatment of FH may involve a low-cholesterol diet, and substances (resins) which bind cholesterol and bile salts in the intestine, preventing their reabsorption (see Box 9.4). However, the preferred form of treatment now is the use of drugs (the statins) which inhibit the pathway of cholesterol synthesis at the enzyme HMG-CoA reductase. The effect of this is not just to reduce cholesterol synthesis. Because cellular cholesterol content is reduced, the synthesis of LDL receptors is up-regulated by the SCAP-SREBP2 system (see Fig. 2.6 and Box 9.3). Increased expression of LDL receptors, especially in the liver, means that LDL particles are removed from the blood and so the blood cholesterol concentration falls.

Type I hyperlipoproteinaemia is a very rare condition, also inherited, in which chylomicrons accumulate in the plasma, giving it a creamy appearance. The major abnormality, unlike FH, is therefore accumulation of triacylglycerol rather than cholesterol. The plasma triacylglycerol concentration may reach 50 or even 100 mmol/l. Interestingly, people with this condition seem not to be at increased risk of coronary heart disease. (This is disputed by some, but the risk is certainly not as high as in FH.) They are at risk of inflammation of the pancreas (pancreatitis). This can be very serious: if the pancreatic juices, with their potent digestive enzymes, leak into the abdominal cavity, the results can be life-threatening. So the disease must be treated, but this can be done very effectively by means of a low-fat diet. Without dietary fat, chylomicrons do not accumulate. The defect in Type I hyperlipoproteinaemia is usually in the enzyme lipoprotein lipase: sufferers are deficient in this enzyme. The condition is only noticed in people who are homozygous for the defect: heterozygotes have sufficient lipoprotein lipase activity to remove chylomicrons relatively normally. In a few cases, the lipoprotein lipase is normal, but the sufferers lack apolipoprotein CII, the essential co-factor for lipoprotein lipase activity.

Type III hyperlipoproteinaemia is another condition with a genetic basis. The particles that accumulate are remnants of VLDL and chylomicrons. We all carry two copies of the gene for apolipoprotein E (apoE) (as we do of all genes except for those on the sex chromosomes). There are two common genetic variations in the apoE gene, leading to either a cysteine or an arginine at position 112, and the same at position 158. This leads to three common forms of apoE: cysteine at both positions (known as apoE2), cystine at 122, arginine at 158 (apoE3) and arginine at both positions (apoE4). (ApoE1 was identified at one time but then recognised to represent the presence of a carbohydrate group, sialic acid: thus it is not a sequence variant. There are also other mutations in apoE at different positions that give similar electrophoretic mobilities to the variants described above.) ApoE is involved in the binding of remnant particles to the LDL receptor. ApoE2 binds much less well than the other forms, and people who have two copies of apoE2 therefore have a defect in removal of remnant particles from their plasma. About 1 in 10 000 people have Type III hyperlipoproteinaemia, although about 1 in 100 people are homozygous for apoE2. The disease becomes manifest when some other condition is present, such as obesity, diabetes or hypothyroidism, or when other genetic variations are present that in themselves might not result in disease. Accordingly, type III hyperlipoproteinaemia is inherited in a polygenic fashion, rather than the monogenic inheritance pattern of Type I hyperlipoproteinaemia or familial hypercholesterolaemia. Secondary hyperlipoproteinaemias

Secondary hyperlipidaemias arise because of diet, bodily factors (e.g. obesity) or other diseases (e.g. diabetes). Here, we will look briefly only at the first of these. The effects of obesity and diabetes will be covered in the next two chapters.

The average blood cholesterol concentration varies widely, as we saw earlier, from country to country. This might reflect racial genetic differences, but it does not seem to. Japanese people who have moved to the USA have cholesterol concentrations and rates of coronary heart disease which are as high as, or even higher than, other Americans. Something in the Japanese lifestyle keeps the cholesterol concentration low, and evidence suggests that this is a dietary factor. Dietary factors and the serum cholesterol concentration are discussed in Box 9.5.

As Box 9.5 makes clear, dietary fatty acids play a much more important role in determining the serum cholesterol concentration than does dietary cholesterol. The means by which individual fatty acids affect the plasma cholesterol concentration are not entirely clear, although one mechanism has been elucidated. It appears that saturated fatty acids in the liver affect the distribution of hepatic cholesterol between unesterified and esterified forms. In the presence

Box 9.5 Dietary influences on the serum cholesterol concentration

Dietary cholesterol

Perhaps surprisingly, the amount of cholesterol in the diet is not a major factor affecting the blood cholesterol concentration. The amount of cholesterol we eat is not large in comparison with the body pool: we eat less than 1 g per day whereas the amount of cholesterol in the body is more like 140 g, of which about 8 g is present in the plasma (Box 9.4). Contrast this with glucose, where we eat several 'plasma's-worth' in a single meal (see Section 6.1). And cholesterol is not rapidly absorbed like glucose: it enters the plasma slowly, even more so than triacylglycerol. Further, cholesterol intake leads to cholesterol entering cells, which effectively suppresses cholesterol synthesis. The blood cholesterol concentration is related far more closely to the dietary intake of particular fatty acids, especially the ratio of saturated to polyunsaturated fatty acids.

Dietary fatty acids

The initial evidence for the role of saturated fatty acids in raising serum cholesterol concentrations was epidemiological: the wide differences in average plasma cholesterol concentration between different countries were found to relate to the average consumption of saturated fatty acids. More detailed studies since have shown that this is an over-generalisation. Particular saturated fatty acids are worse 'culprits' than others: stearic acid (18:0) seems to be relatively inert whereas palmitic acid (16:0) and myristic acid (14:0) raise the cholesterol concentration. In contrast, polyunsaturated fatty acids (e.g. linoleic acid, 18:2 n-6) have a cholesterol-lowering effect. There has been debate about the effect of monounsaturated fatty acids (oleic acid, 18:1, found in olive oil, is the most common example in the diet). These were until recently thought to be relatively neutral in terms of cholesterol concentrations, but recent evidence suggests that they also lower blood cholesterol. (The experiments to test this are difficult to design: if an experimenter wants to increase the proportion of monounsaturated fatty acid in the diet, something else has to be left out, and the answer may well depend on what is omitted.)

A change in the fatty acid content of the diet will produce a fairly predictable change in serum cholesterol concentration, and formulae have been derived to predict this, such as:

ASerum cholesterol = 0.026 X (2.16AS - 1.65AP + 6.66AC - 0.53)

where ASerum cholesterol represents the change in serum cholesterol concentration in mmol/l, AS the change in dietary saturated fatty acids (expressed as percentage of energy derived from them), AP the change in dietary poly-

unsaturated fatty acids, and AC the change in dietary cholesterol expressed in 100 mg per day. The factor 0.026 converts from mg/dl to mmol/l. Source: Hegsted et al. (1965).

The important point is that dietary saturated fatty acids have a larger detrimental effect than the beneficial effect of polyunsaturated fatty acids (the factor for AS in the equation is greater than that for AP): hence the advice for many people to change from dairy products such as butter, which contain a high proportion of saturated fatty acids, to spreads based on vegetable oils containing more unsaturated fats.

A few points should be stressed. Firstly, such a change alone may make an insignificant difference to coronary heart disease risk in any one individual, and other lifestyle factors (e.g. smoking, physical activity, body weight) may need to be modified as well to influence risk of coronary heart disease. Secondly, many people are misled into thinking that spreads containing unsaturated fatty acids are less fattening than dairy products: this is, of course, not so.

Margarines are made by hardening unsaturated vegetable oils by the process of hydrogenation - reduction of some of the double bonds. (Remember from Chapter 1 that the more saturated fatty acids have higher melting points.) In this process, some of the double bonds are converted to the transconfiguration rather than the usual cis-. Trans-unsaturated fatty acids seem to behave similarly to saturated fatty acids with respect to cholesterol-raising. Most spread manufacturers, at least in the UK, have now recognised this and largely removed trans-unsaturated fatty acids from their products.

This box concerns effects on the serum cholesterol concentration. The polyunsaturated fatty acids referred to above are predominantly those of the n-6 family. The n-3 polyunsaturated fatty acids, as found in fish oils, have different effects. They are relatively neutral in terms of serum cholesterol, but they are quite potent in lowering serum triacylglycerol concentrations. They also have other beneficial effects in relation to coronary heart disease, such as reducing the tendency of platelets to aggregate.

of saturated fatty acids, there is less conversion of unesterified cholesterol to cholesteryl esters. Since it is the tissue unesterified cholesterol content which down-regulates LDL-receptor expression, this change will lead to decreased expression of hepatic LDL-receptors, and thus an elevation of the plasma LDL concentration.

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