Hepatocyte water secretion

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. 

Figure 2.2 Secretion of bile acids and biliary components. Bile acids (BA) cross the hepatocyte bound to 3a-hydroxysteroid dehydrogenase and are exported into the canaliculus by the bile-salt export protein (BSEP). Phosphatidylcholine (PC) from the inner leaflet of the apical membrane is flipped to the outer layer and interacts with bile acids secreted by BSEP. BA, PC, together with cholesterol from the membrane form mixed micelles that are not toxic to epithelial membranes of the biliary tree. Aquaporins (AQP) secrete water into bile.

Figure 22-3. Transport and hepatic metabolism of bilirubin. Bilirubin that is produced in phagocytes is transported to liver as an albumin-bilirubin complex. Uptake into the hepatocytes takes place in liver sinusoids. Within the hepatocyte, bilirubin is transported to the endoplasmic reticulum (microsomes) bound to glutathione S-transferase (GST). Bilirubin is made water soluble by addition of one or two glucuronic acid moieties obtained from UPD-glucuronic acid, catalyzed by bilirubin-UDP-glucuronyltransferase. The product, conjugated bilirubin, is transported across the bile canalicular membrane for secretion into the biliary system, with subsequent movement into the intestines.

Bile is a mixture of electrolytes, bile acids, cholesterol, phospholipids and bilirubin. Adults produce between 400 and 800 ml of bile daily. Hepatocytes secrete bile into canaliculi, then into bile ducts, where it is modified by addition of a bicarbonate-rich secretion from ductal epithelial cells. Further modification occurs in the gall bladder, where it is concentrated up to fivefold, through absorption of water and electrolytes. Gallstones, most of which are composed... 

Bile formation occurs by processes that are not hilly defined. It takes place in canaliculi, minute passages lined by specialized modihcations of the hepatocyte membrane, that ultimately unite to form bile ductules. Hepatic bile contains 5% to 15% total solids, the major component of which is bile acids. The increase in biliary water and electrolyte excretion caused by this osmotic effect represents the bile acid-dependent fraction of bile flow. Even with severe depletion of the circulating bile acid pool, as is seen with bile duct diversion, some bile flow continues. The active transport of sodium and of glutathione and bicarbonate is mediated by Na-K-ATPase, which is responsible for the bile acid-independent flow of bile (up to 40% of total flow). Hormones such as secretin increase bile flow by stimulating secretion of sodium, bicarbonate, and chloride. Hormone-dependent flow accounts for 20% to 25% of the total. 

The bile acids are 24-carbon steroid derivatives. The two primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the hepatocytes from cholesterol by hy-droxylation, reduction, and side chain oxidation. They are conjugated by amide linkage to glycine or taurine before they are secreted into the bile (see cholesterol metabolism. Chapter 19). The mechanism of secretion of bile acids across the canalicular membrane is poorly understood. Bile acids are present as anions at the pH of the bile, and above a certain concentration (critical micellar concentration) they form polyanionic molecular aggregates, or micelles (Chapter 11). The critical micellar concentration for each bile acid and the size of the aggregates are affected by the concentration of Na+ and other electrolytes and of cholesterol and lecithin. Thus, bile consists of mixed micelles of conjugated bile acids, cholesterol, and lecithin. While the excretion of osmotically active bile acids is a primary determinant of water and solute transport across the canalicular membrane, in the canaliculi they contribute relatively little to osmotic activity because their anions aggregate to form micelles. 

Each day hepatocytes secrete about 1L of bile, consisting mostly of water, ions, bile salts (important for the absorption of lipids), cholesterol, and bile pigments. Bile formation by hepatocytes requires the active secretion of inorganic and organic solutes into the canalicular lumen, followed by the movement of water. Other solutes can be carried with this movement of water through the tight junctions between hepatocytes. 

Although the liver is commonly identified with its primary role of drug metabolism, one of the main functions of the liver is the formation of bile. BUe forms in the canaliculus between adjacent hepatocytes following active secretion bUe acids and other components (phospholipids, bilirubin, cholesterol) across the canalicular membrane. These components are either synthesized by the liver or transported into the hepatocyte across the sinusoidal membrane. Bile acid secretion stimulates osmotic water flow across the canalicular membrane. The resulting bile drains into branches of intrahepatic bile ductules that converge to the common hepatic bUe duct. In humans, 500 to 600 ml of bile is produced daily. 

In hepatocytes cultured in the presence of oleic acid, incorporation of pH]-water into secreted lipids and TG was lower than incorporation into synthesized lipids with the 3-thia fatty acids. ° A similar phenomenon was observed with pH]-glycerol as the radioactive precursor. This suggests that some of the hypotriglyceridemic effects of 3-thia fatty acids may arise from a reduction in biosynthesis and/or secretion of TG. 

---