Bile acids, density

Anion exchange resins are basic polymers with a high affinity for anions. Because different anions compete for binding to them, they can be used to sequester anions. Clinically used anion exchange resins such as cholestyramine are used to sequester bile acids in the intestine, thereby preventing their reabsorption. As a consequence, the absorption of exogenous cholesterol is decreased. The accompanying increase in low density lipoprotein (LDL)-receptors leads to the removal of LDL from the blood and, thereby, to a reduction of LDL cholesterol. This effect underlies the use of cholestyramine in the treatment of hyperlipidaemia. 

Shindo et al. [66] treated 19 healthy volunteers with omeprazole 20 mg, cultured gastric and jejunal aspirate, and determined gastric pH and bile acid metabolism. Although motility studies were not performed, it can be assumed that intestinal migrating motor complexes were normal [21] (fig. 4). Bacterial colonization was defined by species density exceeding 105 CFU/0.5 ml, and only reported for those exceeding this limit. 

The answer is a. (Katzung, p 590.) Bile acids are absorbed primarily in the ileum of the small intestine. Cholestyramine binds bile acids, preventing their reabsorption in the jejunum and ileum. Up to 10-fold greater excretion of bile acids occurs with the use of resins. The increased clearance leads to increased cholesterol turnover of bile acids. Low-density lipoprotein receptor upregulation results in increased uptake of LDL. This does not occur in homozygous familial hypercholesterolemia because of lack of functioning 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).

As discussed above, obesity is associated with dyslipidemia, a condition where high levels of low-density lipoprotein cholesterol (LDL-C) is common. Elevated LDL-C is strongly associated with an elevated risk of coronary artery disease and for this reason a number of lipid-lowering therapies that target LDL-C have been developed. These include bile-acid sequestrants (BAS), statins (HMG-CoA reductase inhibitors), cholesterol absorption inhibitors, and fibrates. ... 

Currently available BAS include cholestyramine, colestipol and colesevelam hydrochloride (colestimide). Cholestyramine comprises a long-chain polymer of styrene with divinylbenzene trimethylbenzylammonium groups, whereas colestipol is a long-chain polymer of l-chloro-2,3-epoxypropane with diethylenetriamine. Colesevelam HCl is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and 6-bromo-hexyl-trimethylammonium bromide. Bile-acid binding is enhanced and stabilised in the latter compound by long hydrophobic sidechains, increased density of primary amines, and quaternary amine sidechains. For this reason, colesevelam HCl exhibits increased affinity, specificity and capacity to bind bile acids compared with the other BAS. Colesevelam HCl also binds dihydroxy and trihydroxy bile acids with equal affinity, contrasting with cholestyramine and colestipol that preferentially bind dihydroxy bile acids (CDCA and deoxycholic acid). The latter BAS can lead to an imbalance towards trihydroxy bile acids and a more hydrophilic bile-acid pool. 

Samples of gallbladder bile obtained in this way were analysed for bile acids, phospholipids and cholesterol (from which the cholesterol saturation indices were derived). Biliary bile-acid composition was then measured by HPLC. The vesicles were separated from micelles by sucrose density gradient ultra-centrifugation and the cholesterol microcrystal nucleation time measured as described above. 

Applications of cation and anion resins are varied and include purification of sugar, identification of drugs and biomacromolecules, concentration of uranium, calcium therapy to help increase the amount of calcium in our bones (i.e., increase the bone density), and use as therapeutic agents for the control of bile acid and gastric acidity. In the latter use, a solid polyamide (Colestid) is diluted and taken with orange juice, which facilitates removal of bile acids from the body. This removal helps the body to produce more bile acid from cholesterol, thus effectively reducing the cholesterol level. 

Partial summary of lipoprotein metabolism in humans. I to VII are sites of action of hypolipidemic drugs. I, stimulation of bile acid and/or cholesterol fecal excretion II, stimulation of lipoprotein lipase activity III, inhibition of VLDL production and secretion IV, inhibition of cholesterol biosynthesis V, stimulation of cholesterol secretion into bile fluid VI, stimulation of cholesterol conversion to bile acids VII, increased plasma clearance of LDL due either to increased LDL receptor activity or altered lipoprotein composition. CHOL, cholesterol IDL, intermediate-density lipoprotein. 

Mechanism of Action An antihyperlipoproteinemic that binds with bile acids in the intestine, forming an insoluble complex. Binding results in partial removal of bile acid from enterohepaticcirculat ion. Tiierapeutic Effect Removes low-density lipoproteins (LDL) and cholesterol from plasma. 

Mammalian cells acquire cholesterol either by de novo synthesis from acetyl-coen-zyme A (CoA) or via the low-density lipoprotein (LDL)-receptor-mediated uptake of LDL particles that contain cholesterol esterified with long-chain fatty acids. These LDL cholesterol esters are subsequently hydrolyzed in lysosomes, after which free cholesterol molecules become available for synthesis of membranes, steroid hormones, bile acids, or oxysterols [1]. 

In general, drugs act to reduce the concentration of cholesterol within hepatocytes, causing a compensatory increase in low-density lipoprotein-receptors (LDL-R) on their surface, and increased uptake of cholesterol-rich LDL particles from the bloodstream (see Fig. 25.1). Statins decrease the synthesis of cholesterol and the secretion of VLDL and increase the activity of hepatic LDL-receptors. Bile-acidbinding resins deplete the bile acid and thus the cholesterol pool. Fibrates decrease the secretion of VLDL and increase the activity of lipoprotein lipase, thereby increasing the removal of tri-... 

In the liver, cholesterol has three major fates conversion to bile acids, secretion into the blocKlstream (packaged in lipoproteins), and insertion into the plasma membrane. Conversion of cholesterol to cholic acid, one of the bile acids, requires about 10 enzymes. The rate of bile synthesis is regulated by the first enzyme of the pathway, cholesterol la-hydioxylase, one of the cytochrome P450 enzymes (see the section on Iron in Chapter 10), Cholesterol, mainly in the form of cholesteryl esters, is exported to other organs, after packaging in particles called very-low-density lipoproteins. Synthesis of cholesteryl esters is catalyzed by acyl CoA cho-Jesteroi acy(transferase, a membranc bound enzyme of the ER, Free cholesterol is used in membrane synthesis, where it appears as part of the walls of vesicles in the cytoplasm. These vesicles travel to the plasma membrane, where subsequent fusion results in incorporation of their cholesterol and phospholipids into the plasma membrane. 

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