High-density lipoproteins synthesis

Woo W, Gibbs DL, Hooper PL, et al. 1983. The effect of dietary zinc on high-density lipoprotein synthesis. Nutr Rep Int 27 499-502. 

Navab, M., Imes, S.S., Hama, S.Y., Hough, G.P., Ross, L.A., Bork, R.W., Valente, A.J., Berliner, J.A., Drinkwater, D.C., Laks, H. and Fogelman, A.M. (1991). Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic endothelial cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J. Clin. Invest. 88, 2039-2046. 

A 47-year-old male is seen in the medicine clinic with recently diagnosed mixed hyperlipidemia. An anti hyp er lip idem ic is administered that favorably affects levels of VLDL, low-density lipoprotein (LDL), and high-density lipoprotein (IIDL) and inhibits cholesterol synthesis. This drug is ... 

In adult brain most cholesterol synthesis occurs in astrocytes. Apoprotein E (apoE) is the major apolipopro-tein of the CNS and it is secreted by astrocytes. In astrocyte cultures apoE appears in the media as cholesterol-rich particles of a size similar to peripheral HDL (5-12 nm) (Fig. 2-7). The ATP-dependent transporter ABCA1, expressed by both astrocytes and neurons, promotes the formation of the apoE-stabilized high-density lipoprotein (HDL)-sized particles from astrocytic cholesterol. 

An impressive example for the successful use of domino reactions for the synthesis of pharmacological lead structures was described by Paulsen et al1241 Recently, the difluoro compound 57 has been identified as highly potent inhibitor of the cholesterin-ester-transferprotein (CETP), which is responsible for a transfer of cholesterin from high-density lipoprotein (HDL) to low-density lipoprotein (LDL). This clearly results in an increase of LDL and a decrease of HDL which raise the risk of coronary heart desea-ses. The core structure of 57 is now accessible efficiently by a combination of a Mukaiyama-MichaeL... 

Cholesterol is carried in the bloodstream by hpoproteins such as low density lipoprotein (LDL, or bad cholesterol ) and high density lipoprotein (HDL, good cholesterol ). LDL carries cholesterol from the liver to other parts of the body. LDL attaches to receptors (see Chapter 2) on the cell surface and is taken into the cell interior. It is then degraded and the cholesterol is used as a component for the cell membrane. When there is excessive cholesterol inside the cell, it leads to a reduction in the synthesis of LDL receptors. 

One role of high density lipoprotein (HDL) is to collect unesterified cholesterol from cells, including endothelial cells of the artery walls, and return it to the liver where it can not only inhibit cholesterol synthesis but also provide the precursor for bile acid formation. The process is known as reverse cholesterol transfer and its overall effect is to lower the amount of cholesterol in cells and in the blood. Even an excessive intracellular level of cholesterol can be lowered by this reverse transfer process (Figure 22.10). Unfortunately, the level of HDL in the subendothelial space of the arteries is very low, so that this safety valve is not available and all the cholesterol in this space is taken up by the macrophage to form cholesteryl ester. This is then locked within the macrophage (i.e. not available to HDL) and causes damage and then death of the cells, as described above. 

Figure 22.10 Reverse cholesterol transfer. High density lipoprotein (HDL) collects cholesterol from cells in various tissues/ organs the complex is then transported in the blood to the liver where it binds to a receptor on the hepatocyte, is internalised and the cholesterolis released into the hepatocyte. This increases the concentration in the liver cells which then decreases the synthesis of cholesterol by inhibition of the rate-limiting enzyme in cholesterol synthesis, HMG-CoA synthase. The cholesterol is also secreted into the bile or converted to bile acids which are also secreted into the bile, some of which is lost in the faeces (Chapter A).

Estrogens lower serum cholesterol levels by stimulating the formation of high-density lipoproteins and reducing low-density lipoproteins. Reductions in serum albumin and antithrombin III synthesis can occur in the presence of elevated female sex steroids. 

Alterations in the composition of the plasma lipids caused by estrogens are characterized by an increase in the high-density lipoproteins (HDL), a slight reduction in the low-density lipoproteins (LDL), and a reduction in total plasma cholesterol levels. Plasma triglyceride levels are increased. Estrogens decrease hepatic oxidation of adipose tissue lipid to ketones and increase synthesis of triglycerides. 

In summary, the consumption of garlic appears to reduce serum cholesterol in experimental animals in a dose-dependent fashion. This may be due to decreased synthesis or increased excretion of cholesterol through the intestinal tract. It has been reported that garlic consumption increases high-density lipoprotein (HDL) levels, which may help to remove excess cholesterol from arterial tissue. 

Cholesteryl esters that are internalized via the LDL receptor are hydrolyzed to produce cholesterol and an acyl chain. Cholesterol, in (urn, activates the enzyme acyl-CoA cholesterol acyl-transferase (ACAT) which re-esterifies cholesterol. In an apparently futile cycle, the cholesteryl esters are hydrolyzed by cholesteryl ester hydrolase. The cholesterol moiety has several fates it may leave the cell and bind to an acceptor such as high-density lipoprotein (HDL), it may be converted to steroid hormones, or it may be reesterified by ACAT. When the cellular cholesterol concentration falls, the activity of HMG-CoA reductase is increased, as is the number of LDL receptors, which results in an increase of cellular cholesterol, due both to de novo synthesis and to the uptake of cholesterol-rich lipoproteins in the circulation. An increase in cellular cholesterol results in the rapid decline in the mRNA levels for both HMG-CoA reductase and the LDL receptor. This coordinated regulation is brought about by the presence of an eight nucleotide sequence on the genes which code for both proteins this is termed the sterol regulatory element-1. 

Lipoproteins are assembled in two organs, the small intestine and the liver. The lipoproteins assembled in the intestine contain the lipids assimilated from the diet. These lipoproteins, called chylomicrons, leave the enterocyte and enter the bloodstream via the Lymphatic system. The lipoproteins assembled in the liver contain lipids originating from the bloodstream and from de novo synthesis in the liver. The term de novo simply means "newly made from simple components" as opposed to "acquired from the diet" or "recycled from preexisting complex components." These lipoproteins, called very-low-dcnslty lipoproteins (VLDLs), are secreted from the liver into the bloodstream. The liver also synthesizes and secretes other Lipoproteins called high-density Lipoproteins (HDLs), which interact with the chylomicrons and VLDLs in the bloodstream and promote their maturation and function. The data in Table 6-4 show that chylomicrons contain a small proportion of protein, whereas HDLs have a relatively high protein content. Of greater interest is the identity and function of the proteins that constitute these particles. These proteins confer specific properties to lipoprotein particles, as detailed later in this chapter. 

Zinc helps in wound healing and maintaining taste and smell. Zinc stimulates enzymes involved in the production of insulin, sperm, DNA synthesis, and the immune system. Zinc supplements larger than 150 mg can result in decreased high-density lipoprotein (HDL) cholesterol and copper deficiency, and can weaken the immune response. Zinc supplements should not be taken with antibiotics because it inhibits tetracycline (antibiotic) absorption. Wait 2 hours after taking any antibiotic before taking zinc. 

The liver is responsible for synthesis of cholesterol, high-density lipoproteins, and very-low-density lipoproteins. The enzymes lipoprotein lipase and lecithin-cholesterol acyltransferase also are synthesized in this organ. Increased serum triglyceride and FFA concentrations are encountered in patients with hepatic failure, primarily due to the increased lipolysis. The significant insulin resistance that can be seen in cirrhosis causes a shift to lipids as a fuel source. Whereas only 35% of total calories are derived from fat in normal patients after an overnight fast, this can increase to 75% in patients with cirrhosis. Incorporation of late evening snacks in patients with liver cirrhosis may correct abnormal substrate metabolism, increase carbohydrate, and decrease fat oxidation rates. ... 

Niacin is a vitamin that is used in high doses to treat hypercholesterolemia. Niacin acts to decrease VLDL and LDL plasma levels. Its mechanism of action is not clearly nnderstood but probably involves inhibition of VLDL secretion, which in tnm decreases the production of LDL. Niacin inhibits the release of free fatty acids from adipose tissue which leads to a decrease of free fatty acids entering the liver and decreased VLDL synthesis in the liver. This decreases the availability of VLDL for conversion to LDL (containing cholesterol esters). Niacin also increases high-density lipoprotein (HDL) (the good cholesterol ) by an nnknown mechanism. 

HI. Halloran, L. G., Schwartz, C. C., Vlahcevik, Z. R., Nisman, R. M., and Swell, L., Evidence for high-density lipoprotein-free cholesterol as the primaiy precursor for bile acid synthesis in man. Surgery 84, 1-7 (1978). 

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