Cholesterol uptake

Drugs Drugs that lower the blood levels of cholesterol are frequently used as part of the treatment these include (i) Oral bile acid binding exchange resins. Resins such as cholestyramine are effective because, when taken by mouth, they prevent the reabsorption of bile acids in the lower small intestine, so that they are excreted in the faeces. Since bile acids are formed in the liver from cholesterol, synthesis of more acids requires more cholesterol uptake by the liver from the blood, which occurs via LDL-cholesterol, so that the concentration of the latter is decreased. 

The altered composition of bile increases the capacity for cholesterol uptake. Thus, gallstones can be dissolved in the course of a 1- to 2 y treatment, provided that cholesterol stones are pure and not too large (<15 mm), gall bladder function is normal, liver disease is absent, and patients are of normal body weight. UCDA is more effective (daily dose, 8-10 mg) and better tolerated than is CDCA (15 mg/d frequent diarrhea, elevation of liver enzymes in plasma). Stone formation may recur after cessation of successful therapy. 

Were the antibody versus mole % cholesterol uptakes made at constant hapten concentration ... 

We begin with an account of the main steps in the biosynthesis of cholesterol from acetate, then discuss the transport of cholesterol in the blood, its uptake by cells, the normal regulation of cholesterol synthesis, and its regulation in those with defects in cholesterol uptake or transport. We next consider other cellular components derived from cholesterol, such as bile acids and steroid hormones. Finally, an outline of the biosynthetic pathways to some of the many compounds derived from isoprene units, which share early steps with the pathway to cholesterol, illustrates the extraordinary versatility of isoprenoid condensations in biosynthesis. 

Westergaard, H., and J.M. Dietschy. 1976. The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell. J Clin Invest 58 97. 

The primary function of the pBz receptor is in the regulation of cholesterol uptake and the synthesis of neurosteroids. The latter compounds have an affinity for the GABA-A receptors which provide an indirect coupling between the pBz and the GABA receptors in the brain. 

Vitamin E, like neutral lipids, requires apoB lipoproteins at every stage of its transport (Fig. 27-2). Dietary vitamin E becomes emulsified in micelles produced during the digestive phase of lipid absorption and permeates the intestinal epithelium, similar to fatty acids and cholesterol. Uptake of vitamin E by enterocytes appears to be concentration dependent. Within intestinal cells, vitamin E is packaged into chylomicrons and secreted into lymph. During blood circulation of chylomicrons, some vitamin E may be released to the tissues as a consequence of partial lipolysis of these particles by endothelial cell-anchored lipoprotein lipase. The rest remains associated with chylomicron remnants. Remnant particles are mainly endocy-tosed by the liver and degraded, resulting in the release of fat-soluble vitamins. 

Fig. 13-3 The fate of LDL-receptor complexes in cholesterol uptake into cells.

IDL complexes are formed as triacylglycerols and are further removed from VLDLs. The fate of IDLs is either conversion to LDLs or direct uptake by the liver. Conversion of IDLs to LDLs occurs as more triacylglycerols are removed. The liver takes up IDLs after they have interacted with the LDL receptor to form a complex, which is endocytosed by the cell. For LDL receptors in the liver to recognise IDLs requires the presence of both apo-B-100 and apo-E (the LDL receptor is also called the apo-B-lOO/apo-E receptor). The importance of apo-E in cholesterol uptake by LDL receptors has been demonstrated in transgenic mice lacking functional apo-E genes. These mice develop severe atherosclerotic lesions at 10 weeks of age. 

Cholestyramine or colestipol (resins). These are compounds that bind bile acids the drop in hepatic reabsorption of bile acids releases a feedback inhibition, resulting in a greater amount of cholesterol being converted to bile acids to maintain a steady level in the circulation. Additionally, synthesis of LDL receptors increases to allow for the increased cholesterol uptake for bile acid synthesis the overall effect is a reduction in plasma cholesterol. 

LDL takes place by way of specific ceE surface LDL receptors on the adrenal gland surface that internalize the cholesterol moiety, releasing it as substrate for steroidogenesis however, ail steroidogenic cells are capable of de novo synthesis from acetyl coenzyme A. To ensure a continuous supply of free cholesterol for steroid synthesis, lipoprotein cholesterol uptake is coordinated with intracellular cholesterol synthesis and with the mobilization of intracellular cholesteryl ester pools. When the rate of cholesterol uptake exceeds the rate of steroidogenesis, intracellular cholesterol synthesis is suppressed, and cholesterol in excess of cellular needs is esterified and stored for future use. 

Exposure of cholesterol-starved cells to LDL is followed by massive buildup of intracellular free cholesterol pools. HMG-CoA reductase is suppressed, shutting down cellular cholesterol synthesis [84,85]. ACAT is stimulated as much as 500-fold by a process that apparently is independent of protein synthesis [86]. Subsequently, the number of LDL receptors declines dramatically with a calculated half-life of 15-20 h [29,31]. Since the rate of decline under conditions which block protein synthesis is comparable to the LDL-mediated rate of decline [29,87], down-regulation may be due to suppression of receptor synthesis. Excess eholesterol is esterified and stored in the c)rtoplasm as cholesteryl esters. A steady-state characterized by large cholesteryl ester and free cholesterol pools and by basal levels of both HMG-CoA reductase and LDL receptors is ultimately attained. This regulatory mechanism allows cells to control their rate of cholesterol uptake, synthesis, and storage in response to the available supply of lipoprotein cholesterol. 

While the LDL pathway for control of cholesterol uptake was elucidated using cultured cells, it also appears to be functional in vivo. The pattern of regulation depicted in Fig. 5 has been confirmed in freshly isolated blood leukocytes and lymphocytes [89-92]. In addition, administration of 4-aminopyrazolepyrimidine, a drug which suppresses lipoprotein release from animal liver [93], elevates HMG-CoA reductase levels and cholesterol synthesis in non-hepatic tissues [94,95]. These observations are consistent with the hypothesis that non-hepatic cells exhibit a low rate of cholesterol synthesis because they utilize cholesterol synthesized by the liver and present in the plasma lipoproteins [96],... 

Diseases related to receptor-mediated cholesterol uptake... 

Fig. 8. Rate of LDL-cholesterol uptake in the mucosa along the villus-crypt axis in the rat intestine. The rates of LDL-cholesterol uptake were determined by measuring the tissue clearance of [ C]sucrose-labeled LDL in vivo and then isolating different cell fractions from the mucosa. These clearance values were multiplied by the LDL-cholesterol concentration in plasma and expressed as the nmoles of LDL-cholesterol taken up per h/mg of cell protein (panels A and B) or as the percentage of total mucosal uptake found in each cell fraction (panels C and D). The columns and bars represent means +1 S.E.M.

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