Inhibition of cholesterol absorption or synthesis

Plant sterols (such as ^-sitosterol, which differs from cholesterol in the structure of the side-chain) and stanols (which differ from sterols in having a saturated B-ring; see Figure 4.13) inhibit the absorption of cholesterol from the small intestine. As discussed in section 4.3.2.1, in addition to about 500 mg of dietary cholesterol, about 2 g of cholesterol is secreted each day in the bile. Almost all of this is normally reabsorbed; any inhibition of cholesterol absorption is therefore likely to have a more marked hypocholesterolaemic effect than might be expected simply by considering the dietary intake. A number of products, such as margarine, yoghurts and cream, that contain plant sterols and/or stanol esters have been marketed.

The rate-limiting step of cholesterol synthesis is the reduction of hydroxy-

CH,OH

HMG CoA reductase CH2

COOH

hydroxymethylglutaryl CoA

CH2 COOH

mevalonate

ubiquinone
cholesterol

in plants only

HoC

Figure 7.1 9 Compounds synthesized from mevalonate that inhibit cholesterol synthesis by inhibition of hydroxymethylglutaryl CoA (HMG CoA) reductase.

methylglutaryl CoA to mevalonic acid, catalysed by hydroxymethylglutaryl (HMG) CoA reductase. Cholesterol acts to repress synthesis of HMG CoA reductase, and so do a number of other compounds derived from mevalonic acid, as shown in Figure 7.19. Such compounds include:

  • Plant sterols and stanols (see Figure 4.13), which are absorbed to a limited extent.
  • The tocotrienol vitamers of vitamin E, which have an unsaturated side-chain. This means that the tocotrienols, although they have low vitamin activity (sections 11.4.1 and 11.4.3.1), may have a quite different protective effect with respect to atherosclerosis.
  • Squalene, which is the last non-cyclic intermediate in cholesterol synthesis. Almost uniquely among foods, olive oil is rich in squalene. Studies of the effects of fatty acids on plasma cholesterol in the 1950s and 1960s showed a cholesterol-raising effect of saturated fatty acids, and a cholesterol-lowering action of polyunsaturated fatty acids (see Figure 7.10), with monounsaturated fatty acids being neutral. In most of these studies the source of monounsaturated fatty acids was rape-seed (canola) oil. However, studies in the 1980s and 1990s using olive oil as the source of monounsaturated fatty acids showed a cholesterol-lowering effect. It is not clear whether this was due to the presence of oleic acid (C18:1 W9) or whether the high squalene content of olive oil was responsible.
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