Hepatocyte bile secretion

The bile canaliculus is formed as a bile capillary by means of a groove-like canal in the intercellular space, bounded by 2 adjacent liver cells. The bile canaliculi have no walls of their own, but are surrounded by a special zone of the cell membrane (so-calledpericanalicular ectoplasm). Their diameter amounts to 0.5-1.0 pm. They are interconnected and form an extensive polygonal network. The surface area of the bile capillaries is increased by microvilli, which show great functionally determined variability. The canalicular membrane constitutes 10% of the total plasma membrane in the hepatocytes. Similar to the pericanalicular ectoplasm, the hepatocytes contain contractile microfilaments and other components of the cytoskel-eton. These canaliculi are supplied with carrier proteins and enzymes to control bile secretion. (2,34)... 

These various imaging techniques (s. tab. 8.1) - as well as some nuclear medicine-based methods (see chapter 9) - enable key features of benign and malignant tumours to be recognized, including (7.) vascularity, (2.) internal structure, (2.) hepatocyte functions, (4.) biliary tract, (5.) bile secretion, (d.) calcification, and (7.) Kupffer cell activity. 

The liver functions as an exocrine gland, with each hepatocyte continually secreting a small amount of bile into tiny bile canaliculi located between adjacent pairs of parenchymal cells. These tiny vessels form a continuous network from lobule to lobule... 

Bile produced by hepatocytes is secreted into the bile canaliculi between adjacent hepatic cells. The wall of the canaliculus is formed by the plasma membrane of the hepatocytes, which are held together by tight junctions. Canaliculi arise near central veins and extend to the periphery of the lobules. The direction of bile flow in the canaliculi is centrifugal, whereas that of the blood flow is centripetal. Canaliculi coalesce to form ducts, which are lined by epithelium, and the ducts coalesce to form the right and left hepatic ducts. Outside the liver these ducts form the common hepatic duct. 

Bile acids, which have been taken up by the liver, are transported across the hepatocyte and secreted into the bile canaliculus. Newly synthesized bile acids, in a small amount just sufftcient to balance the fraction lost by fecal excretion, join recycled bile acids for biliary secretion. Intracellular bile acid transport may be mediated by carrier proteins (B24, S42). The detailed mechanism of biliary secretion of bile acids and other organic anions into the bile canaliculus is not yet clear (B24). Possible mechanisms include vectorial vesicular transport, fticilitated diflusion, or an energy-requiring carrier-mediated transport process (B24). 

Hepatocytes show even more complicated pathways of CE metabohsm than macrophages do. As discussed elsewhere (see Chapter 2), they play a key role in sterol metabolism because they possess receptors that can bind and mediate the internalization of chylomicron remnants [99], VLDL remnants [99], LDL [99], and HDL [99,119]. In addition, they sa rete HDL and VLDL into the plasma, and in some species the VLDL can contain appreciable amounts of CE [120]. Hepatocytes also secrete LCAT into the plasma and thus control the formation of CE by this enzyme [121]. Finally, they convert UC into bile acids and secrete both UC and bile acids into the bile. 

Substituents attached to the phenyl ring affect the degree of hepatic uptake and the rate of excretion, as well as urinary elimination of the Tc-IDA complex (Nunn et al. 1983). Approximately 82% of the injected dose of Tc-EHIDA, 88% of Tc-disofenin, and 98% of " Tc-mebrofenin are extracted by the hepatocytes and secreted into bile with a hepatic excretion half-time of 37.3, 19.0, and 17.0 min, respectively (Krishnamurthy and Krishnamurthy 1989 Krishnamurthy and Turner 1990). Clinical comparison of diethyl-IDA (etifenin) and diisopropyl-IDA (disofenin) was also reported (Klingensmith et al. 1981). Tc-DISIDA and Tc-mebrofenin show least hepatic retention and are best suited to delineate hepatic biliary anatomy (Krishnamurthy and Krishnamurthy 1989). 

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... 

Bile secretion is a major function of the liver. Bile is composed of bile salts, bilirubin, GSH, phospholipids, cholesterol, proteins, organic anions, metals, and conjugated xenobiotics (Treinen-Moslen, 2001 Pineiro-Carrero and Pineiro, 2004). Bile salts and bilirubin enter bile canaliculi via active transport through hepatocyte... 

Figure 32-15. Diagrammatic representation of the three major processes (uptake, conjugation, and secretion) involved in the transfer of bilirubin from blood to bile. Certain proteins of hepatocytes, such as ligandin (a family of glutathione S-transferase) and Y protein, bind intracellular bilirubin and may prevent its efflux into the blood stream. The process affected in a number of conditions causing jaundice is also shown.

This benign autosomal recessive disorder consists of conjugated hyperbilirubinemia in childhood or during adult life. The hyperbilirubinemia is caused by mutations in the gene encoding MRP-2 (see above), the protein involved in the secretion of conjugated bilirubin into bile. The centrilobular hepatocytes contain an abnormal black pigment that may be derived from epinephrine. 

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 15.2 Transport proteins involved in the intestinal absorption and the renal and hepatic excretion of drugs. In the intestine, drugs are taken up from the luminal side into enterocytes before the subsequent elimination into blood. In hepatocytes, drugs are taken up from the blood over the basolateral membrane and excreted over the canalicular membrane into bile. In the renal epithelium, drugs undergo secretion (drugs are taken up from the blood and excreted into the urine) or reabsorption (drugs are taken up from the urine and are excreted back into blood). Uptake transporters belonging to the SLC transporter superfamily are shown in red and export pumps...

Figure 22.10 Reverse cholesterol transfer. High density lipoprotein (HDL) collects cholesterol from cells in various tissues/ organs the complex is then transported in the blood to the liver where it binds to a receptor on the hepatocyte, is internalised and the cholesterolis released into the hepatocyte. This increases the concentration in the liver cells which then decreases the synthesis of cholesterol by inhibition of the rate-limiting enzyme in cholesterol synthesis, HMG-CoA synthase. The cholesterol is also secreted into the bile or converted to bile acids which are also secreted into the bile, some of which is lost in the faeces (Chapter A).

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.

The phosphatidylcholine in bile is synthesised in the endoplasmic reticulum of the hepatocyte and must be transported to the canalicular membrane. One possibility involves the nonspecific phosphatidylcholine transfer protein but a mouse null for this protein did not show reduced phosphatidylcholine secretion into bile and there was no compensatory increase in other phospholipids transfer proteins. However, the plasma membrane would receive a ready supply of phospholipid by insertion of vesicles, and the MDR3 protein translocates this molecule from the inner leafiet to the outer surface where there is contact with bile acids, as suggested by Smit and colleagues. The role of this transporter is shown in Figure 2.2. 

Figure 2.3 Absorption of bile acids by the cholangiocyte in the cholehepatic shunt. Bile acids are absorbed at the apical membrane of the cholangioc5de by the apical sodium-dependent bile-acid transporter (ASBT) that causes cholehepatic shunting of bile acids back to the hepatocyte. Absorbed bile adds are exported across the basolateral membrane by multi-drug-resistance-associated protein 3 (MRP3), a truncated form of ASBT or by the het-eromeric organic solute (OST) a and p forms. Bile adds cause choleresis that is rich in bicarbonate ions secreted by the chloride/bicarbonate ion exchanger.

Hepatocytes make up 60-70% of the total number of liver cells. They have a well-organized intracellular structure with huge numbers of cell organelles to maintain the high metabolic profile. At the apical side or canalicular membrane the cell is specialized for the secretion of bile components. There are several ATP-dependent transport carriers located on this side of the membrane, which transport bile salts, lipids and xenobiotics into the canaliculus. On the sinusoidal side, the cells specialize in uptake and secretion of a wide variety of components. To increase the surface of the membrane for this exchange with the bloodstream, the sinusoidal domain of the membrane is equipped with irregular microvilli. The microvilli are embedded into the fluid and matrix components of the space of Disse and are in close contact with the sinusoidal blood because of the discontinuous and fenestrated SECs. To facilitate its metabolic functions numerous membrane transport mechanisms and receptors are situated in the membrane. 

The hepatocyte secretes biliary fluid into the bile canaliculi (dark green), tubular intercellular clefts that are sealed off from the blood spaces by tight junctions. Secretory activity in the hepatocytes results in movement of fluid towards the canalicular space (A). The hepatocyte has an abundance of enzymes carrying out metabolic functions. These are localized in part in mitochondria, in part on the membranes of the rough (rER) or smooth (sER) endoplasmic reticulum. 

Fig. 12. The relation between hepatocyte shape ( ), 3H-thymidine uptake ( ) expressed as ratio to hepatocytes cultured on polystyrene dishes coated with 1 pg/ml PVLA solution and hepatic function, bile acid secretion (A), expressed as ratio to bile add secretion of hepatocytes cultured on dishes coated with 1 pg/ml of PVLA solution (Reproduced from New Functionality Materials, Vol. B [Ref. 181] through the courtesy of Elsevier Sdence Publisher B.V.)...

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