Bile salts reabsorption

The reabsorption of bile is impeded by oral administration of positively charged polymers, such as cholestyramine, that bind negatively charged bile salts and are not themselves absorbed. Cholesterol synthesis can be effectively blocked by a class of compounds called statins (e.g., lovastatin, which is also called mevacor Figure 26.22). These compounds are potent competitive inhibitors (AT j < 1 nM) of HMG-CoA reductase, the essential control point in the biosynthetic pathway. Plasma cholesterol levels decrease by 50% in many patients given both lovastatin and inhibitors of bile-salt reabsorption. Lovastatin and other inhibitors of HMG-CoA reductase are widely used to lower the plasma cholesterol level in people who have atherosclerosis, which is the leading cause of death in industrialized societies. 

Depending upon their severity, liver diseases may impair bile salt reabsorption, interfere with bile salt conjugation, or both. Detailed discussion of the changes in bile salt concentration in feces, urine, and bile is not necessary it suffices to remark that the concentration of biliary bile salts in serum depends on the rate of production and on intestinal and hepatic reabsorption. The ability of the liver cells to reabsorb bile salts is believed to be the most critical factor therefore, measurements of the bile salt levels in serum can be helpful for diagnosing certain liver diseases. The concentration of primary bile salts in the serum is significant, whereas that of secondary bile salts is too low to influence distribution changes markedly. 

Its target genes regulate the secretion of bile acids and phospholipids into bile (bile salt efflux pump, MDR2 and 3), the intestinal reabsorption of bile add (ileal bile... 

Among the different roles previously described, the liver exerts an excretory function, being involved in the formation of bile, which drains into the small intestine. Bile salts in the bile play an important role as emulsifying agents for the reabsorption of lipids and fatty acids from the intestine. Hepatic and obstructive biliary diseases lead to abnormal metabolism of bile acids (BAs). 

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.]... 

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. 

Biochemically, a change in structure relating to the mucopolysaccharides (neuraminic add ) and monohydroxy bile acids probably accounts for the formation of biliary thrombi. Some of the under-hydroxylated bile salts appear in crystalline form the bile becomes increasingly viscous and its flow is impeded. This defect in the excretion of bile salts culminates in dysfunctions in the secretion of bilirubin, which is why bilirubin is regurgitated into the blood. The bile which accmnulates in the bile ducts ultimately becomes mucous and white because of the reabsorption of bile pigments by the epitheha of the small bile ducts. 

Bile salts are required for supporting the activity of pancreatic lipase as well as for maintaining the polar products of fat hydrolysis in solution. While in the lumen of the small intestine, a fraction of the bile salts is modified by the bacteria present If the taurine or glycine rnoictics are removed by microbial enzymes, they are replaced in the liver after reabsorption of the bile salts in the distal ileum. 

Cholestyramine A synthetic, strongly basic anion exchange resin that will strongly bind bile salts when taken orally and prevent their reabsorption in the intestinal tract. 

Cholestyramine and colestipol are resins that complex bile salts, preventing their reabsorption from the GI tract —>4 feedback inhibition of 7 alpha hydroxylase —>T synthesis of new bile salts —liver cholesterol — T LDL receptors —plasma LDL. 

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.

Does niacin have an effect on the synthesis or reabsorption of bile salts ... 

These drugs bind bile salts (which are cholesterol-based) in the small intestine, preventing their reabsorption. This disruption of the enterohepatic recycling of bile salts forces the liver to use exogenous cholesterol stores for the synthesis of new bile salts. This results in a cascade effect the decrease in hepatic cholesterol triggers an increase in LDL receptor expression, which results in removal of increased amounts of LDL from the blood (see Figure). 

People who have elevated levels of LDL in their serum can be treated in a number of ways. These include restriction of dietary intake of cholesterol, ingestion of positively charged resin polymers that inhibit intestinal reabsorption of bile salts, and administration of lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase. 

One idea for treating hypercholesterolemia is to decrease the reabsorption of bile salts from the intestinal contents by ingesting anion-exchange resin that retains the bile salts in the intestinal lumen (Sec. 12.2). The liver, however, responds by synthesizing more cholesterol so the treatment is not as effective as might have been anticipated. 

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%. 

This was confirmed in dogs (57) in a study which also demonstrated (for cholic, taurocholic, and glycocholic acids) that reabsorption occurs in the proximal tubule (Fig. 7) and that the reabsorptive process involves active transport. The latter conclusion was based on estimates of the tubular fluid/ ultrafiltrable plasma concentration ratio for taurocholate and an estimate of transtubular electrical potential taken from the literature. In addition, it was shown that the reabsorptive process for bile salts had a maximal rate (saturation kinetics) (Fig. 8). 

Stasis is, by definition, a diminution in the normal rate of bile flow, which appears to be necessary for the removal of potential gallstone nidi. This flow is initially determined primarily by bile salt secretion from the hepatocyte, but secretion by ductular cells and reabsorption of fluid and electrolytes by biliary tract epithelium are also important factors. In species with gallbladders, flow in this organ also depends on its filhng passively and then emptying by muscular contraction. In all cases, flow can be diminished by mechanical obstruction, and most of the early work with stasis mentioned... 

Reabsorption of bile acids is very effective, so that only a small percentage escapes into the cecum. The rest returns via the portal circulation as conjugates [or as unconjugated bile salts if free bile acids were present in the gut lumen (34)] into the liver, thus completing the enterohepatic circulation. Before resecretion, free bile salts are conjugated in the liver with taurine and glycine. 

Colonic reabsorption of secondary bile acids seems to be clearly established. The presence of deoxycholic acid as a normal biliary constituent indicates that it has been absorbed from the colon. Furthermore, the human bile contains a variety of other bacterial transformation products such as lithocholic acid and other cholanic acids, some of which may have been further metabolized by the liver (44-47). In contrast to the case in some other mammalian species, human liver is not able to convert deoxycholic acid back to cholic acid. Colonic perfusion with different labeled bile acids has clearly shown that colonic absorption takes place in man (48). Administration of labeled cholic acid into the lumen of the large bowel during operation for cholecystectomy is followed by the appearance of labeled cholic acid and deoxycholic acid in the T-tube bile, the recovery from the T-tube being about 60% of the dose (49). This clearly shows that cholic acid is converted to deoxycholic acid in the human colon and that both of them are absorbed from the large bowel. Colonic reabsorption has been calculated to amount to 200 mg/ day (49). The colonic absorption of secondary bile salts could be even higher if the physical state of some bile acids were not unfavorable for absorption. Lithocholic acid, for example, is a very nonpolar compound and precipitates in the colonic content in addition, it and other secondary bile acids as well are partially associated with fecal debris and bacteria (41). As a result of poor absorption, the amount of secondary bile acids, other than deoxycholic acid, is usually low in human bile. After a continuous biliary drainage, secondary bile acids disappear from the bile in a few days (49-51). 

This raises a question of whether the mechanism of stimulated bile acid production during interrupted enterohepatic circulation of bile acids is different from that found during the enhanced cholesterol production in obesity. It is reasonable to assume that in obesity the biliary secretion of both bile acids and cholesterol is augmented and that subsequent intestinal reabsorption from the expanded intraluminal pool is increased in absolute figures (probably decreased relatively). Thus the fluxes both of bile acids via the portal blood and of cholesterol via the lymphatics back to the liver are augmented. Despite these two fluxes, from which the former at least is supposed to inhibit bile salt production (and cholesterol synthesis as well), the hepatic synthesis of bile acids is actually increased, suggesting that it is an increased cholesterol synthesis which stimulates bile acid production. 

As already discussed, obesity is associated via augmented cholesterol synthesis with an increased bile acid production. Since obesity as such is a result of excessive consumption of calories, it is logical to infer that overeating stimulates cholesterol synthesis and secondarily bile acid production. An increased number and quantity of daily meals may, however, change under these conditions the metabolism of both cholesterol and bile acids in complicated ways which are not yet completely understood, by augmenting the number of enterohepatic circulations of bile salts. Increased intestinal contents and fecal mass may also interfere with reabsorption of bile acids. 

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