Bile acid pool

The isotope dilution method is relatively easy to perform technically. The procedure has been widely used for measurement of cholesterol catabolism in different conditions (69-74) and of bile salt kinetics in gastrointestinal disorders (75-78). Markedly augmented loss of bile acids in ileopathy makes the procedure less reliable because the administered isotope may disappear totally into feces during the first day, sometimes even during the first enterohepatic circulation of the bile acid pool after administration of the label. Under these conditions, no quantitative figures are obtained, the method being suitable for screening of this disorder. 

After an overnight fast, the bile acid pool is almost totally in the gallbladder. If under these conditions a tracer amount of an isotopic bile acid 

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The primary action of BARs is to bind bile acids in the intestinal lumen, with a concurrent interruption of enterohepatic circulation of bile acids, which decreases the bile acid pool size and stimulates hepatic synthesis of bile acids from cholesterol. Depletion of the hepatic pool of cholesterol results in an increase in cholesterol biosynthesis and an increase in the... 

Trautwein, E. A., Kunath-Rau, A., and Erbersdobler, H. F. (1999). Increased fecal bile acid excretion and changes in the circulating bile acid pool are involved in the hypocholester-olemic and gallstone-preventive actions of psyllium in hamsters. /. Nutr. 129, 896-902. 

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Bile acids within the enterohepatic circulation that undergo absorption in the terminal ileum encounter a relatively low number of species and population of bacteria and return to the liver in portal blood relatively unchanged. However, the approximately 5% of the bile-acid pool that enters the colon provides substrate for the extensive microbial population that deconjugate and oxidise hydroxyl groups leading to formation of the secondary bile acids deoxycholic and lithocholic acids that are the major bile acids in faeces. 

Importantly, knowledge of intestinal bile acid transport and metabolism, coupled with increased understanding of the mechanistic basis of the pro-tumorigenic activity of bile acids against CRC cells in vitro, has recently led to development and testing of bile acid-based treatment and prevention strategies for sporadic and inflammatory bowel-disease-associated CRC. Existing evidence that manipulation of the luminal secondary bile acid pool and/or therapy with ursodeoxycholic acid (UDCA) may have promise for prevention of CRC will be assessed. 

It is well recognised that the faecal bile acid content of random stool samples is highly variable with marked daily variation.Therefore, studies testing the association between luminal bile acid exposure and the presence of colorectal neoplasia have usually measured serum bile acid levels, which demonstrate less variability and are believed to reflect the total bile acid pool more accurately. Serum DCA levels have been shown to be higher in individuals with a colorectal adenoma compared with individuals without a neoplasm. Only one study has assessed future risk of CRC in a prospective study of serum bile-acid levels. The study was hampered by the small sample size (46 CRC cases). There were no significant differences in the absolute concentrations of primary and secondary bile acids or DCA/CA ratio between cases and controls although there was a trend towards increased CRC risk for those with a DCA/ CA ratio in the top third of values (relative risk 3.9 [95% confidence interval 0.9-17.0 = 0.1]). It will be important to test the possible utility of the DCA/ CA ratio as a CRC risk biomarker in larger, adequately powered studies. A recent study has demonstrated increased levels of allo-DCA and allo-LCA metabolites in the stool of CRC patients compared with healthy controls. ... 

Bile acids are recycled via the enterohepatic circulation, with less than 5% of the total bile acid pool entering the colon.Bile adds are reabsorbed by ileum columnar epithelium cells and are transported back to the liver by the portal vein where they are extracted by hepatocytes. Approximately 6-12 enterohepatic circulations occur daily. Free bile acids, like DCA, are partly absorbed into the colon and enter the enterohepatic circulation, where they are... 

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. 

When Reuben et al., measured the hourly secretion rates of phospholipids, bile acids and cholesterol in obese and nonobese individuals with and without cholesterol gallstone disease, they found that the pattern of results was quite different in the obese and the nonobese gallstone carriers. The obese had hypersecretion of cholesterol but normal bile-acid output, while the nonobese had normal cholesterol secretion but a reduced bile-acid output. The authors speculated that the most likely explanation for the high biliary cholesterol secretion rates in the obese was their increased total body cholesterol synthesis. Conversely, nonobese gallstone carriers often have a reduced total bile-acid pool size, and if the enterohepatic cycling frequency of this small bile-acid pool remains unchanged (controversial), it could explain the reduced bile-acid secretion rate seen in the normal weight (nonobese) individuals. 

Bile acid synthesis stimulation. Fiber, administered in ration of male rats at a dose of 5% of the diet, produced a higher total bile acid pool size compared to rats fed cellulose. It also lowered the hydrophobicity of the bile acid pool """. 

PO036 Matheson, H. B. and J. A. Story. Di- PO048 etary psylium hydrocolloid and pectin increase bile acid pool size and change bile acid composition in rats. J Nutr 1994 124(8) 1161-1165. PO049... 

The solubility of cholesterol in bile is determined by the relative proportions of bile acids, lecithin, and cholesterol. Although prolonged ursodiol therapy expands the bile acid pool, this does not appear to be the principal mechanism of action for dissolution of gallstones. Ursodiol decreases the cholesterol content of bile by reducing hepatic cholesterol secretion. Ursodiol also appears to stabilize hepatocyte canalicular membranes, possibly through a reduction in the concentration of other endogenous bile acids or through inhibition of immune-mediated hepatocyte destruction. 

Conjugated bile salts are normally absorbed in the terminal ileum. Disease of the terminal ileum (eg, Crohn s disease) or surgical resection leads to malabsorption of bile salts, which may cause colonic secretory diarrhea. The bile salt binding resins cholestyramine or colestipol may decrease diarrhea caused by excess fecal bile acids (see Chapter 35 Agents Used in Hyperlipidemia). The usual dose is 4-5 g one to three times daily before meals. Side effects include bloating, flatulence, constipation, and fecal impaction. In patients with diminished circulating bile acid pools, further removal of bile acids may lead to an exacerbation of fat malabsorption. These agents bind a number... 

If bile acid excretion is different, further experiments should be done to determine if bile acid recovery by the intestine or bile acid pool size is changed. The former can initially be assessed by western blot detection of the transporter ASBT. Pool size is... 

Receptor numbers have been increased by the administration of cholestyramine or colestipol, bile acid sequestrants that diminish the bile acid pool, force the liver to convert more cholesterol into bile acids (Dll), lower the intracellular cholesterol in hepatic cells, and thus increase the number of hepatic B-100,E receptors (K25, S27). 

Colestyramine is an oral anion-exchange resin, which binds bile acids in the intestine. Bile acids are formed from cholesterol in the liver, pass into the gut in the bile and are largely reabsorbed at the terminal ileum. The total bile acid pool is only 3-5 g but, because such enterohepatic recycling takes place 5-10 times a day, on average 20-30 g of bile acid are delivered into the intestine every 24 hours. Bile acids bound to colestyramine are lost in the faeces and the depletion of the bile acid pool stimulates conversion of cholesterol to bile acid the result is a... 

Ursodeoxycholic acid can be used to dissolve cholesterol gallstones it supplements the bile acid pool... 

The body s bile acid pool (2-5 g, 5-10 mmol) is held constant by the balance between the rates of synthesis and excretion. This pool is brought into circulation 3-10 times/day by biliary secretion of the bile acids into the intestine at a rate of 12-24 g/day (30-60 mmol/ day). As a general rule, the pool circulates 2(-3) times per meal. Approximately 95% of the intestinal bile acids are reabsorbed. The hourly uptake of bile acids by the liver is in the order of 450 gmol (180 mg). 

Inhibition of the neosynthesis of bile acids from cholesterol leads to a decrease in the bile acid pool. 

Pancreatic enzyme activity may be low at birth, but enzymes such as amylase, lipase, and trypsin develop to adult levels within the first year of life. Premature infants appear to have lower amylase levels than do full-term infants. Low concentrations of pancreatic enzymes may be the reason why newborns have a decreased ability to cleave prodrug esters such as chloramphenicol palmitate. Lipid-soluble drugs may not be well absorbed by neonates because of low lipase concentrations and bile acid pool. ... 

Salen, G., Shefer, S., Chen, F.W., Dayal, B., Batta, A. K. and Tint, G. S. (1985). Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylation at C-12, C-25, and C-26. J. Clin Invest. 76 744-751. 

Bile formation occurs by processes that are not hilly defined. It takes place in canaliculi, minute passages lined by specialized modihcations of the hepatocyte membrane, that ultimately unite to form bile ductules. Hepatic bile contains 5% to 15% total solids, the major component of which is bile acids. The increase in biliary water and electrolyte excretion caused by this osmotic effect represents the bile acid-dependent fraction of bile flow. Even with severe depletion of the circulating bile acid pool, as is seen with bile duct diversion, some bile flow continues. The active transport of sodium and of glutathione and bicarbonate is mediated by Na-K-ATPase, which is responsible for the bile acid-independent flow of bile (up to 40% of total flow). Hormones such as secretin increase bile flow by stimulating secretion of sodium, bicarbonate, and chloride. Hormone-dependent flow accounts for 20% to 25% of the total. 

Enterahepatic Circulation of Bile Acids. The body conserves the bile acid pool through a recirculating system known as the enterohepatic circulation. The anatomical components of the enterohepatic circulation are the Ever, biliary tract, terminal ileum, and portal venous circulation. 

Kinetics of Bile Acid Metabolism. Using an isotope dilution technique, the bile acid pool in normal adults has been found to average from 2 to 4g. Steady state is reached when hepatic synthesis and fecal loss are in balance. In health, the magnitude of each process is 0.3 to 0.8g/day. There are usually 4 to 10 enterohepatic cycles per day. Because of this recycling mechanism, the jejunal concentration of bile acids is maintained at -5 to lOmmol/L during the postprandial state, much higher than the critical micellar concentration of 2mmol/L. Between meals, with decreased entry of bile acids into the intestine, the intraluminal concentration... 

The bile acid pool normally consists of about 2-4 g of conjugated and unconjugated primary and secondary bile acids. Daily loss of bile acids in feces, mostly as lithocholate, is about 0.2-0.4 g. Hepatic synthesis of bile acids equals this amount, so that the size of the bile acid pool is maintained at a constant level. 

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