Plasma LDL

Rate-limiting enzyme in cholesterol biosynthesis inhibition by statins results in reduction of plasma LDL-cholesterol levels. 

Spady DK, Woollett LA, Dietschy JM Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids. Annu RevNutr 1993 13 355. 

Studies conducted by Barenghi eta.1. (1990) and Lodge etal. (1993) independently have demonstrated the facile, multicomponent analysis of a wide range of PUFA-derived peroxidation products (e.g. conjugated dienes, epoxides and oxysterols) in samples of oxidized LDL by high-field H-NMR spectroscopy. Figure 1.9 shows the applications of this technique to the detection of cholesterol oxidation products (7-ketocholesterol and the 5a, 6a and 5/3,60-epoxides) in isolated samples of plasma LDL pretreated with added coppcr(Il) or an admixture of this metal ion with H2O2, an experiment conducted in the authors laboratories. 

LDL extracted from human or animal atherosclerotic lesions has been shown to be taken up much fester than plasma LDL by macrophages by means of their scavenger receptors. 

Familial hypercholesterolaemia is characterized by a significant elevation in plasma LDL concentration. The basic metabolic defect appears to be abnormal LDL receptor function, arising from mutations in the LDL receptor gene. Several receptor mutations have been identified and hypercholesterolaemia severity as well as the age of onset of ischaemic heart disease has recently been demonstrated to vary according to the type of LDL receptor gene defect (Moorjani et al., 1993). 

Esterbauer et al. (1991) have demonstrated that /3-carotene becomes an effective antioxidant after the depletion of vitamin E. Our studies of LDL isolated from matched rheumatoid serum and synovial fluid demonstrate a depletion of /8-carotene (Section 2.2.2.2). Oncley et al. (1952) stated that the progressive changes in the absorption spectra of LDL were correlated with the autooxidation of constituent fatty acids, the auto-oxidation being the most likely cause of carotenoid degradation. The observation that /3-carotene levels in synovial fluid LDL are lower than those of matched plasma LDL (Section 2.2.2) is interesting in that /3-carotene functions as the most effective antioxidant under conditions of low fOi (Burton and Traber, 1990). As discussed above (Section 2.1.3), the rheumatoid joint is both hypoxic and acidotic. We have also found that the concentration of vitamin E is markedly diminished in synovial fluid from inflamed joints when compared to matched plasma samples (Fairburn etal., 1992). This difference could not be accounted for by the lower concentrations of lipids and lipoproteins within synovial fluid. The low levels of both vitamin E and /3-carotene in rheumatoid synovial fluid are consistent with the consumption of lipid-soluble antioxidants within the arthritic joint due to their role in terminating the process of lipid peroxidation (Fairburn et al., 1992). 

Niacin reduces plasma LDL cholesterol, lipoprotein (a), triglycerides and raises HDL cholesterol in all types of hyperlipoproteinemia [26]. Although available on the market for more than 40 years, the mechanisms of action of niacin are poorly understood. Putative mechanisms are the activation of adipose tissue LPL, diminished HTGL activity, a reduced hepatic production and release of VLDL, and composi-... 

Modified procedure HDL plasma—plasma depleted with apo B-con-taining lipoproteins by pretreatment with dextran sulfate/Mg2+ HDL reagent (Sigma, procedure 352-3). Plasma LDL-bound antiradical parameters can be calculated as the difference between ACW/ACL/ACL0 for whole plasma and for HDL plasma as well. 

The plasma LDL/VLDL-bound antiradical parameter was calculated as the difference between ACP for whole plasma and for HDL plasma as well. 

Atherosclerotic lesions are thought to arise from transport and retention of plasma LDL through the endothelial cell layer into the extracellular matrix of the subendothelial space. Once in the artery wall, LDL is chemically modified through oxidation and nonenzymatic glycation. Mildly oxidized LDL then recruits monocytes into the artery wall. These monocytes then become transformed into macrophages that accelerate LDL oxidation. 

Familial hypercholesterolemia is characterized by a selective elevation in plasma LDL and deposition of LDL-derived cholesterol in tendons (xanthomas) and arteries (atheromas). 

It is SREBPs which coordinate the expression of HMG CoA reductase and cell surface receptors for LDL. Cholesterol is an essential component of membranes so if delivery of cholesterol to the cell is limited by low concentrations of LDL-cholesterol, the expression of the genes for both the LDL receptor and HMG CoA reductase are up-regulated allowing the cell to extract as much as possible form the circulation and also to synthesize cholesterol, thus there is an inverse relationship between plasma LDL-cholesterol concentration and HMG CoA reductase activity. 

Sniderman, A.D., Zhang, X.J., and Cianflone, K., 2000, Govemace ofthe concentration of plasma LDL a reevaluation of the LDL receptor paragdim, Atherosclerosis 148 215-229. 

This finding has been replicated several times in clinical studies. Let me cite one example. In a careful metabolic study carried out in 1990, Mensink and Katan determined the plasma LDL/HDL ratio when 10% of the energy from oleic acid was replaced in the diet by either the corresponding trans fat or the corresponding saturated fatty acid, stearic acid. The resulting LDL/HDL ratios were 2.02 on the oleic acid diet, 2.34 on the stearic acid diet, and 2.58 on the trans fatty acid diet. This is one more example of the impact of small structural changes in molecules on their biological properties. 

For people who are at risk of cardiovascular disease due to high plasma LDL cholesterol levels, lifestyle changes to control plasma cholesterol levels are the first and best place to start. When efforts to control plasma cholesterol levels by diet and exercise fail, people frequently turn to drugs, some of which are effective in producing substantial lowering of cholesterol levels and realizing associated clinical benefits. 

Heterozygotes for type 11 hypercholesterolemia have one normal and one mutant LDL receptor gene. Thus, they have just half the normal number of functional hepatic LDL receptors. They are, therefore, less than fully effective at eliminating cholesterol from the body. These individuals have substantially elevated plasma LDL cholesterol levels and frequently experience heart attacks in their 40s and 50s. 

The statins have been demonstrated to markedly lower plasma LDL levels (and triglyceride levels to a lesser extent). In fact, statins were approved by the US FDA on the basis of a surrogate endpoint reduction in plasma cholesterol levels. Since we know that increased plasma cholesterol levels are correlated with increased risk of coronary artery disease, it seems logical that reducing plasma cholesterol levels would lead to reduced risk. That turns out to be true in this case. However, see the case of hormone replacement therapy (HRT) for women for a more complex example, discussed below. 

These studies demonstrate that optimal doses of statins reduce the incidence of clinical events in patients with established coronary artery disease, in patients with elevated plasma LDL levels but without existing coronary artery disease, in individuals with normal plasma LDL levels without existing coronary artery disease, and in diabetics, a patient population at high risk of cardiovascular disease. ... 

Ezetimibe (1) is the first in a new class of cholesterol absorption inhibitors that reduce plasma LDL-C levels by direct inhibition of the uptake of free cholesterol from the... 

The lowered concentration of bile acids returning to the liver by the enterohepatic circulation results in derepression of 7-a-hydroxylase, the rate-limiting enzyme for conversion of cholesterol to bile acids. This results in increased use of cholesterol to replace the excreted bile acids and lowering of hepatic cholesterol (mechanism VI in Fig. 23.2). Thus, similar to the statins, the ultimate actions of the bile acid-sequestering resins are up-regulation of transcription of the LDL receptor gene, increased hepatic receptor activity, and lowering of plasma LDL cholesterol (mechanism VII in Fig. 23.2). 

Probucol (Lorelco) is a hypocholesterolemic drug with few side effects that modestly (15-30%) decreases elevated plasma LDL cholesterol levels. The marginal... 

The answer is d. (Hardman, pp 885-886. Katzung, pp 591-592.) Atorvastatin is a structural analogue of an intermediate formed from the action of HMG-CoA reductase. This could result in a modest decrease in plasma cholesterol. Hepatic cholesterol synthesis may decrease significantly however, nonhepatic tissues increase their rate of synthesis as a compensatory mechanism. The other and perhaps more important effect of the HMG-CoA inhibitors is to increase high-affinity LDL receptors. The plasma LDL is lowered by this action because of an increase in the catabolic rate of LDL and hepatic extraction of LDL precursors. 

Aral, Y. et al.. Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration, J. Nutr., 130, 2243, 2000. 

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