Bile salts enterohepatic circulation

A molecule of bile salt may circulate many times per day through the enterohepatic system. This pnfcess can be interrupted by consumption of a special powdered resin that binds to the bile salts. Neither the resin itself nor the complex of resin and bile salt is absorbed by the iiitestines. Consequently, the complex is excreted in the feces. This resin, cholestyramine, is a synthebe compound used as a drug to lower serum cholesterol levels in the treatment of cardiovascular disease. 

Houten SM, Auwerx J (2004) The enterohepatic nuclear receptors are major regulators of the enterohepatic circulation of bile salts. Ann Med 36 482-491... 

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. 

Bile is produced continuously by the liver bile salts are secreted by the hepatocytes and the water, sodium bicarbonate, and other inorganic salts are added by the cells of the bile ducts within the liver. The bile is then transported by way of the common bile duct to the duodenum. Bile facilitates fat digestion and absorption throughout the length of the small intestine. In the terminal region of the ileum, the final segment of the small intestine, the bile salts are actively reabsorbed into the blood, returned to the liver by way of the hepatic portal system, and resecreted into the bile. This recycling of the bile salts from the small intestine back to the liver is referred to as enterohepatic circulation. 

Small, D. M. Point mutations in the ileal bile salt transporter cause leaks in the enterohepatic circulation leading to severe chronic diarrhea and malabsorption. J. Clin. Invest. 1997,... 

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. 

For some drugs that, for physiological and anatomical reasons, mainly follow a passive absorption mechanism, a satisfactory colonic absorption was demonstrated. Similar absorption rates from the small and large intestine were found for oxprenolol, metoprolol, isosorbide-5-mononitrate, and glibenclamide [9], It has also been known for many years, that some lipophilic vitamins, as well as bile salts and some steroids, that undergo enterohepatic circulation show satisfactory colonic absorption [2],... 

BSEP also known as sister-P-glycoprotein (SPGP) was originally cloned from pig liver (185). BSEP is localized on the canalicular membrane of hepa-tocytes and is responsible for the secretion of bile salts across the canalicular membrane into bile. BSEP appears to be the predominant bile salt efflux system for hepatocytes, and is a critical component in the enterohepatic circulation of bile acids. A number of mutations in the transporter were found to the basis for progressive familial intrahepatic cholestasis type 2 (PFIC2) (186-188). Mutations found in PFIC2 patients include frameshifts, missense mutations, and premature termination codons. Most PFIC2 patients lack immunohistochemically detectable BSEP in their liver. Recently, seven... 

The digestion and absorption of dietary lipid can be completed only in the presence of adequate amounts of bile salts that are synthesized in the liver and pass, via the bile duct, into the duodenum and thence into the jejunum. Reabsorption of the bile salt micelles occurs in the ileum, from which a large proportion return via the blood to the liver. The bile ducts carry bile salts from the liver to the gallbladder, where they are stored excreted (excess) cholesterol is dissolved in the bile salt micelles. Overall, 90 percent of the bile salts involved in absorption of lipid in the jejunum are recycled, in a process called the enterohepatic circulation, and 10 percent are lost in the feces. Replacement of this amount necessitates conversion from cholesterol. Thus, de novo synthesis of cholesterol itself plays an important part in maintaining the supply of bile salts. 

Only relatively small quantities of bile acids are lost from the body approximately 95% of bile acids delivered to the duodenum are absorbed back into blood within the ileum. Venous blood from the Ueum goes straight into the portal vein, and hence through the sinusoids of the liver (enterohepatic circulation). Hepatocytes extract bile acids very efficiently from sinusoidal blood they are re-secreted into canaliculi. The net result of enterohepatic recirculation is that each bUe salt molecule may be reused up to 20 times, and often 2 or 3 times during a single digestive phase (Figure 6.1). 

FIGURE 2.38 Enterohepatic circulation of bile salts. Bile salts from the liver enter the duodenum at the ampulla of Vater, the same opening through which material from the exocrine pancreas is released. Most of the gall bladder is hidden within the lobes of the liver. After varying degrees of utilization and reutilization for lipid absorption, the bile salts reach the distal ileum, where they are reabsorbed and returned to the liver via the portal vein. The portal vein is very important because it also carries water-soluble nutrients absorbed from the diet. 

Bile-acid-binding resin results in an interruption of the enterohepatic circulation of bile salts and in their increased excretion in the feces. This drug therapy can produce a 20-25% decrease in plasma LDL-cholesterol. A side effect of cholestyramine is constipation, but this problem can be relieved by a high fiber diet. 

Bile salts are extensively metabolized to secondary bile acids by intestinal microflora in the gut. Approximately 94% of the bile salts are reabsorbed at special mucosal receptor sites in the distal ileum and reused by the liver by the process of enterohe-patic circulation. In enterohepatic circulation, compounds secreted in bile are reabsorbed in the gastrointestinal tract and returned to the liver. On reaching the liver in the portal blood, almost all of the bile salts are taken up across the sinusoidal membranes of hepatocytes (predominantly in periportal... 

Most dietary riboflavin is taken in as a complex of food protein with the coenzymes FMN and FAD. These coenzymes are released from noncovalent attachment to proteins as a consequence of gastric acidification. Nonspecific action of pyrophosphatase and phosphatase on the coenzyme occurs in the upper gut. The vitamin is primarily absorbed in the proximal small intestine by a saturable transport system that is rapid and proportional to intake before leveling off at doses near 27 mg riboflavin per day. Bile salts appear to facilitate the uptake, and a modest amount of the vitamin circulates via the enterohepatic system. Active transport at lower levels of intake was thought to be sodium ion-dependent and involve phosphorylation, though later work has suggested that uptake is independent of sodium... 

The most successful therapy for cholestasis of pregnancy has been ursodeoxycholic acid (Figure 33-1). Ursodeoxycholic acid is a naturally occurring bile acid, which, when administered, relieves both pruritus and liver function abnormalities. Experimental evidence suggests that it protects hepa-tocytes and cholangiocytes from bile acid-induced cytotoxicity and improves hepatobiliary excretion. Additionally, it decreases bile salt transfer to the fetus and improves the secretory function of placental trophoblast cells. Ursodeoxycholic acid is recycled through the enterohepatic circulation. 

Nearly all bile acids are choleretic agents that is, they increase bile flow when infused intravenously into various animal species. In all vertebrtae species examined, there is a close relationship between bile flow and the hepatic excretion rate of bile acids (B24). Acute interruption of the enterohepatic circulation of bile acids in man by diversion of bile flow causes the rate of bile secretion to decrease by about 50% (TIO). Thus, the excretion of bile acids from the liver is the major determinant of bile water and solute excretion, predominantly because of the osmotic activity of bile acids in bile. Some interesting studies in dogs have been performed with the bile salt taurodehydrocholate (taurine conjugate of 3,7,12-triketo-5fl-cholan-24-oic acid), which, for stereochemical reasons, cannot form micelles and should therefore have greater osmotic activity than other bile acids. At the same... 

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