Bile is a physiological aqueous solution produced and secreted by the liver. It consists mainly of bile salts, phospholipids, cholesterol, conjugated bilirubin, electrolytes, and water . Bile travels through the liver in a series of ducts, eventually exiting through the common hepatic duct. Bile flows through this duct into the gallbladder, where it is concentrated and stored. When stimulated by the hormone cholecystokinin (CCK), the gallbladder contracts, pushing bile through the cystic duct and into the common bile duct. Simultaneously, the sphincter of Oddi relaxes, permitting bile to enter the duodenal lumen. The hormone secretin also plays an important role in the flow of bile into the small intestine. By stimulating biliary and pancreatic ductular cells to secrete bicarbonate and water in response to the presence of acid in the duodenum, secretin effectively expands the volume of bile entering the duodenum. In the small intestine, bile acids facilitate lipid digestion and absorption. Only approximately 5% of these bile acids are eventually excreted. The majority of bile acids are efficiently reabsorbed from the ileum, secreted into the portal venous system, and returned to the liver in a process known as enterohepatic recirculation .
Bile is produced by hepatocytes and it is then modified by the cholangiocytes lining the bile ducts. The production and secretion of bile require active transport systems within hepatocytes and cholangiocytes in addition to a structurally and functionally intact biliary tree. Initially, hepatocytes produce bile by secreting conjugated bilirubin, bile salts, cholesterol, phospholipids, proteins, ions, and water into their canaliculi (thin tubules between adjacent hepatocytes that eventually join to form bile ducts) . The canalicular membrane of the hepatocyte is the main bile secretory apparatus that contains the intracellular organelles, the cytoskeleton of the hepatocyte, and carrier proteins. The carrier proteins in the canalicular membrane transport bile acid and ions. Transporter proteins found within the canalicular membrane use energy to secrete molecules into bile against concentration gradients. Through this active transport, osmotic and electrochemical gradients are formed. When conjugated bile salts enter the canaliculus, water follows by osmosis. The electrochemical gradient allows for the passive diffusion of inorganic ions such as sodium. The most significant promoter of bile formation is the passage of conjugated bile salts into the biliary canaliculus. The total bile flow in a day is approximately 600 ml, of which 75% is derived from hepatocytes, and 25% is from cholangiocytes. Approximately half of the hepatocyte component of bile flow (about 225 ml per day) is bile salt-dependent, and the remaining half bile salt independent. Osmotically active solutes such as glutathione and bicarbonate promote bile salt independent bile flow .
Canaliculi empty bile into ductules or cholangioles or canals of Hering. The ductules connect with interlobular bile ducts, which are accompanied by branches of the portal vein and hepatic artery forming portal triads. Bile is subsequently modified by ductular epithelial cells as it passes through the biliary tree. These cells, known as cholangiocytes, dilute, and alkalinize the bile through hormone-regulated absorptive and secretory processes. The cholangiocytes have receptors that modulate the bicarbonate-rich ductular bile flow, which is regulated by hormones. These receptors include receptors for secretin, somatostatin, cystic fibrosis transmembrane conductance regulator (CFTR), and chloride-bicarbonate exchanger. For example, when secretin stimulates receptors in the cholangiocyte, a cascade is initiated, which activates the CFTR chloride channel and allows the exchange of bicarbonate for chloride. In contrast, somatostatin inhibits the cAMP synthesis within the cholangiocytes, causing the opposite effect. While bombesin, vasoactive intestinal polypeptide, acetylcholine, and secretin enhance bile flow, somatostatin, gastrin, insulin, and endothelin inhibit the flow .
Cholesterol catabolism by hepatocytes results in the synthesis of the two major primary bile acids, cholic acid and chenodeoxycholic acid. This process involves multiple steps, with cholesterol 7alpha-hydroxylase acting as the rate-limiting enzyme. Primary bile acids undergo dehydroxylation by bacteria in the small intestine, forming the secondary bile acids deoxycholic acid and lithocholic acid, respectively. Both primary and secondary bile acids are conjugated by the liver with an amino acid, either glycine or taurine. Conjugated bile acids are known as bile salts. Bile salts inhibit cholesterol 7alpha-hydroxylase, decreasing the synthesis of bile acids. Despite the increased water solubility of bile salts, they are amphipathic molecules overall . This critical property allows them to effectively emulsify lipids and form micelles with the products of lipid digestion. The bile acid pool is maintained mainly via the enterohepatic circulation and, to a small extent (about 5%), by the hepatic synthesis of bile acids, as long as the daily fecal loss of bile acids do not exceed 20% of the pool.
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