Gallbladder bile-acid concentration

In response to a meal, cholecystokinin is released from the intestine and causes relaxation of the sphincter of Oddi and contraction of the gallbladder (see Chapter 48). This allows a concentrated solution of micelles (consisting of bile salts, lecithin, and cholesterol) to enter the intestine. In the intestinal lumen, dietary cholesterol and the products of triglyceride digestion (predominantly free fatty acids and monoglycerides) are incorporated into mixed micelles. Micelles deliver lipolytic products to the mucosal surface. To carry out these functions, a critical micellar bile acid concentration of 2ramoI/L is necessary. 

FIG. 1 Movement of cholesterol (CHOL) and bile acids (BA) between the liver and small intestine. CHOL and BA in the liver are secreted into the gallbladder where they are stored temporarily until a fat-containing meal causes their secretion into the intestinal lumen. BA are absorbed with high efficiency (95%) and are recycled back to the liver via the hepatic portal vein. CHOL is absorbed less efficiently (50-60%) and must be incorporated into lipoproteins (chylomicrons) for transport back to the fiver via the systemic circulation. Accumulation of CHOL in the liver can promote secretion of CHOL into plasma, thus increasing LDL-CHOL concentration. Loss of CHOL and BA in feces represents the primary route of CHOL elimination from the body. 

The process of bile acid formation in the liver, movement to the gallbladder, and then movement to the duodenum is a pathway that can concentrate toxicants in hepatocytes. From the gallbladder where they are stored, bile acids are released into the gut to aid in the digestion of lipophobic substances. Most of the released bile acids are reabsorbed in the intestines and are returned to the liver by the hepatic portal circulation. 

Bile is produced by hepatocytes from several components, including bilirubin and bile acids it is concentrated and stored in the gallbladder. 

Bile salts/acids are synthesized in the liver, stored and concentrated in the gallbladder, and secreted into the intestine where they may undergo deconjugation and reduction by intestinal bacteria to produce secondary bile acids (see Figure 31-1). Once formed in the liver, the bile salts/acids are... 

Fasting serum (peripheral venous) As for gallbladder bile, with up to 50% unconjugated bile acids 1-6 pmol/liter Concentration increased after a meal A9, P9, S34, S37... 

The export of phospholipids and cholesterol can be simultaneous owing to the activity of various members of the ABC superfamily (see Table 18-2). The best-understood example of this phenomenon is in the formation of bile, an aqueous fluid containing phospholipids, cholesterol, and bile acids, which are derived from cholesterol. After export from liver cells, phospholipids, cholesterol, and bile acids form water-soluble micelles in the bile, which is delivered through ducts to the gallbladder, where it is stored and concentrated. In response to a fat-containing meal, bile is released into the small intestine to help emulsify dietary lipids and thus aid in their digestion and absorption into the body. As we shall see later, the alteration of biliary metabolism by drugs can be used to prevent heart attacks. 

The quantities of lithocholate required to produce cirrhosis when/ed to rats (about 625 mg/kg) exceed by approximately 100 times the amounts found in man. The concentration of lithocholate in human gallbladder bile ranges from 0.2 to 5 mg/ml (mean 1.5 mg/ml), while that in human blood serum rarely exceeds 1 //g/ml (1). Rats, however, readily convert lithocholate to other less toxic bile salts, mainly 3a, 6) -dihydroxy-5 -cholanoic acid, in feeding experiments (71). The human liver does not readily convert lithocholate to other compounds to any significant extent (2). It thus may be possible that on a mg/kg basis lithocholate may be more toxic to man than to rats. Rabbits, like man, are unable to convert lithocholate to other compounds (73), and cirrhosis develops in these animals when lithocholate is fed at the 0.25% dietary level (about 0.17 mg/kg/day). An estimate of lithocholate synthesis in a healthy adult would be about 3-4 mg/kg/day. 

In the small intestine, pancreozymin causes the gallbladder to contract, and bile, a micellar solution of bile acids, lecithin, and cholesterol, is secreted into the duodenum. Pancreozymin also causes discharge and continued synthesis of pancreatic lipase which adsorbs to the oil-water interface, liberating 2-monoglycerides and fatty acids (76). Whether bile acids adsorb to the interface and if so how they spatially orient with respect to lipolytic products and lipase is unknown. At concentrations below the CMC, bile acids will adsorb to monolayers of lipolytic products (77), but no information is available on the interaction of bile acid solutions above their CMC with monolayers of lipolytic products. Somehow, the lipolytic products are transferred to the bulk phase, where they form mixed micelles with bile acid molecules (Fig. 14). 

Calcium has been recognized as a constituent of gallstones since the earliest chemical studies (see reference 118). It occurs as calcium carbonate (either calcite or aragonite), calcium phosphate (apatite), calcium bilirubinate, or the salts of bile acids and fatty acids. In normal hepatic bile, the calcium concentration is about 21 mg %. It is about 45 mg % in normal gallbladder bile and about twice that in the gallbladder bile of patients with cholesterol stones (119). The concentration of calcium is said to vary with the concentration of bile salts (3). Apparently, calcium in bile is bound in part to bile salt micelles, and under normal conditions this complex remains stable and soluble (120). However, under appropriate conditions of pH, calcium concentration, and anion concentration, calcium salts may precipitate. 

As described and discussed elsewhere in this volume, the excreted bile enters the gallbladder and after being concentrated is discharged into the duodenum near the pancreatic duct. Mixed with the pancreatic juice and tlie food, the bile is transported down the small intestine. The bile acid conjugates, among other biliary constituents, are partly absorbed from the intestine into the portal vessels and return to the liver to be excreted in the bile again. 

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