| Lipoproteins provide means for the transport of triacylglycerols (triglycerides) and cholesterol between organs and tissues. Also, together with defective function of cells lining the arteries (endothelium) and inflammation affecting arterial walls, they play a key role in atherosclerosis, a disease of the cardiovascular system which leads to heart attack (myocardial infarctions), strokes, and peripheral vascular disease. Cardiovascular disease is presently the most frequent cause of death in the industrialized world.
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| Fatty acids, triacylglycerol, and cholesterol are constantly transported between tissues
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| STATINS ARE DRUGS WHICH DECREASE PLASMA LDL CONCENTRATION |
Statins such as simvastatin , pravastatin, atorvastatin and rosuvastatin are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme in the pathway of cholesterol synthesis. The inhibition of this enzyme results in a decrease in intracellular cholesterol levels. This, acting through SREBP (Chapter 16), increases the expression of LDL-receptors on the cell membrane. An increase in the number of cellular receptors leads to increased cellular uptake of LDL and, consequently, to a lower plasma cholesterol concentration. The treatment with statins decreases cholesterol concentration by 30-60% (depending on the preparation), and decreases future cardiovascular events by 20-30%. |
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| Lipoprotein metabolism links closely with the organism's energy metabolism. The lipids which are used for energy production are fatty acids. They are synthesized primarily in the liver and intestine but are stored mainly in adipose tissue as glycerol esters, triacylglycerols (synonymously called triglycerides) (Chapter 15). Fatty acids are released from triglycerides for use in the liver and muscle (see Chapter 20). Also,
fat contained in food needs to be transported from the intestine to the liver and then to the peripheral tissues. Although free (nonesterified) fatty acids travel in plasma bound to albumin, triacylglycerols are too large and too hydrophobic to be transported in this manner. Instead, they are packaged together with cholesterol, phospholipids, and proteins (apoproteins), into particles known as lipoproteins. These are secreted into plasma by liver and intestine. The transported fatty acids are removed from lipoproteins at target tissues by stepwise enzymatic hydrolysis of triacylglycerol. Lipoproteins present in plasma constitute a dynamic system: they exchange their lipid and protein components and as a result change their size, shape, and density. During this process the conformation of constituent apolipoproteins also changes: this is particularly important because their conformation determines how they 'fit' into their cellular receptors, and therefore how 'their' lipoproteins are taken up by cells. Apart from triacylglycerols, cholesterol, and other lipids, lipoproteins also transport fat-soluble vitamins such as vitamin A and vitamin E.
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| Cholesterol is an essential component of cells
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| Figure 17.1 Regulation of intracellular cholesterol concentration. Intracellular cholesterol concentration is stringently regulated. Intracellular cholesterol regulates the activity of a key enzyme in its synthesis, HMG-CoA reductase, and also the expression of LDL receptors on the cell membrane. Statins are the drugs that inhibit HMG-CoA reductase. |
| Cholesterol is an essential constituent of cell membranes. It is also a precursor of steroids, including vitamin D, and bile acids. A cell can either synthesize cholesterol or acquire it from the outside. Cholesterol is synthesized from acetyl CoA (see Chapter 16). The rate-limiting step in its synthesis is the reduction of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to
mevalonate by HMG-CoA reductase. The activity of HMG-CoA reductase is inversely related to the intracellular concentration of cholesterol. Cells acquire cholesterol through low-density-lipoprotein (LDL) receptors also known as apoB/E receptors, that mediate lipoprotein uptake into cells. Thus there is a balance between intracellular synthesis of cholesterol and its import from plasma (Fig. 17.1).
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