LDLs

Cholesterol is biosynthesized in the liver trans ported throughout the body to be used in a va riety of ways and returned to the liver where it serves as the biosynthetic precursor to other steroids But cholesterol is a lipid and isn t soluble in water How can it move through the blood if it doesn t dis solve in if The answer is that it doesn t dissolve but IS instead carried through the blood and tissues as part of a lipoprotein (lipid + protein = lipoprotein) The proteins that carry cholesterol from the liver are called low density lipoproteins or LDLs those that return it to the liver are the high-density lipoproteins or HDLs If too much cholesterol is being transported by LDL or too little by HDL the extra cholesterol builds up on the walls of the arteries caus mg atherosclerosis A thorough physical examination nowadays measures not only total cholesterol con centration but also the distribution between LDL and HDL cholesterol An elevated level of LDL cholesterol IS a risk factor for heart disease LDL cholesterol is bad cholesterol HDLs on the other hand remove excess cholesterol and are protective HDL cholesterol IS good cholesterol... 

The distribution between LDL and HDL choles terol depends mainly on genetic factors but can be... 

Low density lipoprotein (LDL) (Section 26 11) A protein which cames cholesterol from the liver through the blood to the tissues Elevated LDL levels are a nsk factor for heart disease LDL is often called bad cholesterol... 

LDL) present in serum. The effects of saturates, polyunsaturates, and dietary cholesterol on total semm cholesterol have been quantitated (98,99) using the following equations ... 

Fig. 18. Schematic representation of cycling of low density Hpoprotein (LDL) receptors from the plasma membrane to the cell interior.

Defects in the LDL receptor have been particularly well explored as a basis of the disease familial hypercholesterolemia (93,111). A number of defects that collectively impair LDL receptor trafficking, binding, or deUvery underHe this disease where LDL and semm cholesterol rise to levels that mediate early cardiovascular mortaUty. Studies of the population distribution of this defect can determine the source of the original mutation. Thus, in Quebec, about 60% of the individuals suffering from familial hypercholesterolemia have a particular 10-kdobase deletion mutation in the LDL gene (112). This may have arisen from an original founder of the French Canadian settiement in the seventeenth century. 

Corona.iy Hea.rt Disea.se, A theory for atherogenesis (120) has been developed whereby oxidation of low density Hpoprotein (LDL) within the arterial wall is the critical first step. It has been hypothesized that sufficient intake of antioxidants would prevent oxidation of LDL and reduce development of coronary heart disease (122). Interest in determining the role of antioxidants in blocking LDL oxidation has led to the development of in vitro test systems. 

Tea extracts and tea polyphenols inhibit copper- and peroxide-induced oxidation of LDL in vitro (116,123,124). The inhibitory concentration for 50% reduction (IC q) values for inhibition of copper-induced oxidation of LDL by some phenoHc antioxidants are Hsted in Table 7. The IC q for epigaHocatechin gaHate was found to be 0.075 p.mM, which was the most potent of all the phenoHc antioxidants tested (123,124). Similar results have been reported elsewhere (115,116,125,126). 

Table 7. Antioxidant Potency of Vitamins and Phenolics Based on LDL Oxidation In Vitrei...

Vitamin E can also act as an antioxidant (qv) in animals and humans alone or in combination with vitamin C (qv). Both are good free-radical scavengers with the vitamin C acting to preserve the levels of vitamin E (35). Vitamin E in turn can preserve the levels of vitamin A in animals (13). It has been shown that vitamin E reduces the incidence of cardiovascular disease (36—39). This most likely results from the antioxidant property of the vitamin which inhibits the oxidation of low density Hpoproteins (LDLs) (40—42). The formation of the oxidized LDLs is considered important in decreasing the incidence of cardiovascular disease (43). 

Reduction in semm Hpids can contribute significantly to prevention of atherosclerosis. In 1985 a consensus report indicating that for every 1% reduction in semm cholesterol there is a 2% reduction in adverse effects of coronary heart disease was issued (145). Recommended semm cholesterol concentration was 200 mg/dL for individuals under 30 years of age, and individuals having concentration 240 mg/dL and LDL-cholesterol over 160 mg/dL should undertake dietary modification and possibly pharmacotherapy (146). Whereas the initial step in reducing semm cholesterol is through reduction of dietary cholesterol intake, a number of dmgs are available that can affect semm Hpid profile (see Fat substitutes). The pathway to cholesterol synthesis is shown in Figure 2. 

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

Calcium Channel Blockers. Because accumulation of calcium is one of the facets of the mote involved process leading to atherosclerosis, it would foUow that the antihypertensive calcium channel blockers might be effective in preventing atheroma. Both verapamil (Table 1) and nifedipine (Table 3) have been shown to stimulate the low density Upoprotein (LDL) receptor (159). This specific receptor-mediated pathway could theoretically improve Upid metaboUsm in the arterial wall, and thereby prove antiatherogenic. These effects have been proven in animals. 

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

Prazosin, a selective a -adrenoceptor antagonist, exerts its antihypertensive effect by blocking the vasoconstrictor action of adrenergic neurotransmitter, norepinephrine, at a -adrenoceptors in the vasculature (200,227,228). Prazosin lowers blood pressure without producing a marked reflex tachycardia. It causes arteriolar and venular vasodilation, but a significant side effect is fluid retention. Prazosin increases HDL cholesterol, decreases LDL cholesterol, and does not cause glucose intolerance. 

Significant increases in LDL, total cholesterol and LDL F[DL ratio No significant effect on levels of plasma cholesterol, FfDL cholesterol or triglyceride... 

No significant effect on levels of total cholesterol, FfDL or LDL... 

Levels of total cholesterol, LDL and FfDL significantly reduced Levels of LDL significantly reduced... 

Thus, it is apparent that soya, some soya products and linseed oil influence blood lipid levels, particularly cholesterol and LDL cholesterol. While the extent of the reduction appears to largely depend on an individual s initial serum cholesterol level, the maximum reductions observed are of the order of 10-15%. For hyperlipidemic individuals this may not be a marked reduction, but such an effect on the general population may well have a beneficial effect on the overall incidence of cardiovascular disease and atherosclerosis. The possibility that non-phytoestrogenic dietary components may contribute to the hypocholes-terolemic properties cannot, however, be discounted. Indeed, certain types of dietary fibre have been shown to have a hypolipidemic effect via their ability to increase faecal excretion rates. 

Fig. 4.29 (page 126), very large proteins, such as low-density lipoproteins (LDL and VLDL), gelatin, and sea worm chlorocruorin, which are excluded even by G4000SW columns, can be covered by PW columns of large pore size such as the G5000PWxl and G6000PWxl columns. 

FIGURE 4.29 Relation between molecular weight of lipoproteins and elution volume for combination GFC columns. Column 7.5 mm i.d. X 60 cm. Sample Chylomicron, VLDL, LDL, HDLj, HDL3, albumin, and ovalbumin. Elution 0.1 hA Tris—HCI buffer (pH 7.4). Flow rate 1.0 ml/min. 

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