Liver bile salts, enterohepatic circulation

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. 

Fig. 32.6. Recycling of bile salts. Bile salts are synthesized in the liver, stored in the gallbladder, secreted into the small intestine, resorbed in the ileum, and returned to the liver via the enterohepatic circulation. Five percent or less of luminal bile acids are excreted in the stool under normal circumstances.

Greater than 95% of the bile salts are resorbed in the ileum and return to the liver via the enterohepatic circulation (via the portal vein see Fig. 34.12). The secondary bile salts may be reconjugated in the liver, but they are not rehydroxylated. The bile salts are recycled by the liver, which secretes them into the bile. This enterohepatic recirculation of bile salts is extremely efficient. Less than 5% of the bile salts entering the gut are excreted in the feces each day. Because the steroid nucleus cannot be degraded in the body, the excretion of bile salts serves as a major route for removal of the steroid nucleus and, thus, of cholesterol from the body. 

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 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.]... 

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. 

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 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... 

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... 

Figure 8.8. Biosynthesis of bile acids and the enterohepatic circulation. Bile acids are synthesized from cholesterol in the liver under feedback regulation of the nuclear orphan receptors famesoid X receptor (FXR) and lignane X receptor (LXR). They are stored in the gallbladder and released through the bile duct into the duodenum, where they aid in the digestion of dietary fats. Intestinal uptake of bile acids takes place alongthe entire length of the small intestine, but active reabsorption is confined to the distal ileum to minimize loss of bile salts in the feces. The portal circulation carries bile acids from the intestine to the liver, where they are actively absorbed by hepatoc5Tesand secreted into bile.

Fig. 5. Transport of bile acids in the enterohepatic circulation. The left and right sides of the figure depict a liver and intestinal cell, respectively. Bile acids (BA) are made from unesterified cholesterol (UC) in the liver. The movement of bile acids in the enterohepatic circulation is vectorial. The major transporters thought to be responsible for the entry and exit of bile acids in liver and intestinal cells are sodium/taurocholate cotransporting polypeptide (ntcp SLClOAl), bile salt export pump (bsep ABCBll), apical/sodium bile acid cotransporter (asbt SLC10A2), and organic solute transporters a/p, (Osta/P).

The hver, which stores half of the body s folate, takes up much of the folate from the portal circulation uptake may be through active transport or receptor-mediated endocy-tosis. Within the liver, FH4 is reconjugated to the polyglutamate form before being used in reactions. A small amount of the folate is partially degraded, and the components enter the urine. A relatively large portion of the folate enters the bile and is subsequently reabsorbed (very similar to the fate of bile salts in the enterohepatic circulation). 

The bile salts are syhthesized in the liver, stored ih the gallbladder, and released into the small intestine, where they emulsify dietary lipids and fat-soluble vitamins. This solubilization promotes the absorption of these dietary compounds through the intestinal mucosa. Bile salts are predominantly reabsorbed through the enterohepatic circulation and returned to the liver, where they exert a negative feedback control on 7a-hydroxylase and, thus, regulate any subsequent conversion of cholesterol (4,7). 

EXAMPLE 12.10 About 20 g of bile salts are secreted by the liver into the duodenum each day. Only a small proportion (less than 2 g) enters the feces because the uptake from the intestine into the bloodstream and transport back to the liver are very efficient. This is called the enterohepatic circulation of bile salts. 

There are three sites where the active transport of bile salts has been described. Two of these, the liver and the ileum, are integral parts of the enterohepatic circulation. The third site is the proximal renal tubule, which can reabsorb bile salts from the glomerular filtrate in those situations where appreciable concentrations of bile salts exist in the peripheral (i.e., nonportal) plasma. In addition to these presumed active transport sites, passive transepithelial movement of bile salts has been described in various regions of the gastrointestinal tract. These passive processes play a recognizable role in the enterohepatic circulation of the total bile salt pool, but the quantitative contribution of these passive processes is not precisely known. A number... 

The enterohepatic circulation of bile salts involves the cycling of fairly large quantities of material. It has been estimated that the human liver secretes some 30 g of bile salts per day. Of these 30 g, approximately 0.8 g per day is newly synthesized material (4). This emphasizes the efficiency of the intestinal reabsorptive processes. The liver also is remarkably efficient in extracting bile salts from portal blood, as evidenced by the fact that the concentration of bile salts in peripheral plasma is a small fraction of that of portal plasma (5-7). Direct determination of taurocholate and glycocholate extraction by the liver in the dog has been measured by O Maille et al. (8) and found to be 92%. 

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