Enterohepatic circulation bile acids

M. C. Carey, in Enterohepatic Circulation of Bile Acids and Sterol Metabolism, G. Paumgartner, ed., MTP Press, Lancaster, Boston, 1984. 

Most Bile Acids Return to the Liver in the Enterohepatic Circulation... 

Although products of fat digestion, including cholesterol, are absorbed in the first 100 cm of small intestine, the primary and secondary bile acids are absorbed almost exclusively in the ileum, and 98—99% are returned to the liver via the portal circulation. This is known as the enterohepatic circulation (Figure 26—6). However, lithocholic acid, because of its insolubility, is not reabsorbed to any significant extent. Only a small fraction of the bile salts escapes absorption and is therefore eliminated in the feces. Nonetheless, this represents a major pathway for the elimination of cholesterol. Each day the small pool of bile acids (about 3-5 g) is cycled through the intestine six to ten times and an amount of bile acid equivalent to that lost in the feces is synthesized from cholesterol, so that a pool of bile acids of constant size is maintained. This is accomplished by a system of feedback controls. 

Grundy SM, Ahrens EH, Jr., Salen G. Interruption of the enterohepatic circulation of bile acids in man comparative ef-... 

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... 

The metabolites and metabolic pathway of a new anticonvulsant drug, sodium valproate, in rats were investigated using carbon-14 labeled sodium valproate. Most of the metabolites in urine and bile were a glucuronide conjugate of valproic acid. Free sodium valproate was as little as one-seventh of the total metabolites. In feces, only free sodium valproate was detected, and the possibility of enterohepatic circulation of sodium valproate was presumed. A part of dosed sodium valproate was excreted in expired air in the form of CO2. This degradative reaction took place in liter mitochondria and required CoA and oxygen. It was stimulated by ATP... 

Transport by ASBT is electrogenic with a 2 1 ratio of Na rbile acids and membrane potential may regulate transport function. ASBT is essential for the enterohepatic circulation as shown by ASBT gene knockout mice that developed bile-acid malabsorption with no enterohepatic circulation. This is summarised in Figure 2.4. 

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. 

Assay of bile acids was an essential tool for the early investigation of the enterohepatic circulation, and proved a focus of attention with the belief that serum bile-acid concentrations would provide a sensitive diagnostic test for liver disease. There are three fundamental assay types, based on enzymatic oxidation of a hydroxyl with linked NAD reduction, chromatographic separations and quantitation, encompassing both gas-liquid and high-performance liquid chromatography, and radioimmunoassay assays. 

Secondly, ileal resection disrupts enterohepatic circulation of bile acids due to loss of the ileal sodium-dependent bile acid transporter (ISBT) leading to... 

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... 

Pharmacology Bile acid sequestering resins bind bile acids in the intestine to form an insoluble complex, which is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation, preventing their absorption. 

In this chapter we survey recent findings that describe the metabolic fate of the xenobiotic moieties of mercapturic acid pathway (MAP) metabolites that are excreted from the liver with the bile. We show that the products of the MAP undergo an enterohepatic circulation that is mediated by intestinal enzymes and/or intestinal microflora. 

Seventy-four percent of oral doses of PCMTB-l C were excreted in the bile by conventional rats. Most of this (50 to 70%) has been characterized to be products of the MAP (8). Neither of the mercapturates shown in fig. 3 were secreted in the bile therefore, the mercapturic acids that were excreted with the germfree rat feces had to have been formed either by metabolism of the precursors of the mercapturic acid by the intestinal mucosa, or by the tissues during enterohepatic circulation of these precursors. Comparison of the rates of excretion of oral doses of PCMTB- C given to germfree and conventional rats indicate that there was enterohepatic circulation of the in the germfree rats. Conventional rats excreted more than 80 percent of the dose in the feces within two days while it took at least eight days for the germfree rats to excrete 80 percent of the dose in the feces. 

The lowered concentration of bile acids returning to the liver by the enterohepatic circulation results in derepression of 7-a-hydroxylase, the rate-limiting enzyme for conversion of cholesterol to bile acids. This results in increased use of cholesterol to replace the excreted bile acids and lowering of hepatic cholesterol (mechanism VI in Fig. 23.2). Thus, similar to the statins, the ultimate actions of the bile acid-sequestering resins are up-regulation of transcription of the LDL receptor gene, increased hepatic receptor activity, and lowering of plasma LDL cholesterol (mechanism VII in Fig. 23.2). 

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 enterohepatic circulation. Therapeutic Effect Removes LDL cholesterol from plasma. 

Bile salts secreted into the intestine are efficiently reabsorbed (greater than 95 percent) and reused. The mixture of primary and secondary bile acids and bile salts is absorbed primarily in the ileum. They are actively transported from the intestinal mucosal cells into the portal blood, and are efficiently removed by the liver parenchymal cells. [Note Bile acids are hydrophobic and require a carrier in the portal blood. Albumin carries them in a noncovalent complex, just as it transports fatty acids in blood (see p. 179).] The liver converts both primary and secondary bile acids into bile salts by conjugation with glycine or taurine, and secretes them into the bile. The continuous process of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids, and their subsequent return to the liver as a mixture of bile acids and salts is termed the enterohepatic circulation (see Figure 18.11). Between 15 and 30 g of bile salts are secreted from the liver into the duodenum each day, yet only about 0.5 g is lost daily in the feces. Approximately 0.5 g per day is synthesized from cholesterol in the liver to replace the lost bile acids. Bile acid sequestrants, such as cholestyramine,2 bind bile acids in the gut, prevent their reabsorption, and so promote their excretion. They are used in the treatment of hypercholesterolemia because the removal of bile acids relieves the inhibition on bile acid synthesis in the liver, thereby diverting additional cholesterol into that pathway. [Note Dietary fiber also binds bile acids and increases their excretion.]... 

Enterohepatic circulation of bile salts and bile acids. 

Bile is secreted into the intestine, and more than 95 percent of the bile acids and salts are efficiently reabsorbed. They are actively transported from the intestinal mucosal cells into the portal blood, where they are carried by albumin back to the liver (enterohepatic circulation). In the liver, the primary and secondary bile acids are reconverted to bile salts, and secreted into the bile. 

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