Bile Secretion And Gall Bladder Function

Bile is responsible for the principal digestive functions of the liver. The presence of bile in the small intestine is necessary for the digestion and absorption of lipids. The problem of the insolubility of fats in water is solved by the constituents of bile. The bile salts and other organic components of bile are responsible in part for emulsifying fat so that it can be digested by pancreatic lipase. The bile acids also take part in solubilizing the digestion products into micelles. Micellar formation is essential for the optimal absorption of fat digestion products. Bile also serves as a vehicle for the elimination of a variety of substances from the body. These include endogenous products like cholesterol and bile pigments, as well as some drugs and heavy metals.

The liver also carries out many additional nondigestive functions, most of which are treated in chapters relating to the pertinent organ system or in a biochemistry textbook. Because in this text there is no single chapter on the liver in which all of its functions are discussed, the more important ones are briefly summarized here.

The liver plays important roles in carbohydrate, lipid, and protein metabolism. Blood glucose levels are held relatively constant by hormones acting on the liver to regulate glycogenolysis (release of glucose from glycogen stored in the liver) and gluconeogenesis (synthesis of glucose from noncarbohydrate precursors). Hormones also regulate the formation of ketone bodies by fi-oxidation of fatty acids. This process occurs in the liver, and the acetoacetate, acetone, and ^-hydroxybutyrate produced are released into the blood to serve as calorie sources during periods of starvation. The liver is responsible for the synthesis of all nonessential amino acids and for the production of urea from ammonia.

The liver also synthesizes a number of proteins with specific functions. These include all plasma proteins with the exception of the immunoglobulins. Albumins and globulins are responsible for most of the plasma oncotic pressure and for transporting many specialized molecules that are bound to them. The fibrinogens and other proteins are involved in blood clotting. The liver synthesizes very-low-density lipoprotein, which is

Gallbladder Bile Secretion
FIGURE 26 Overview of the biliary system and the enterohepatic circulation of bile acids. Solid arrows indicate active transport processes.

converted into the other lipoproteins. The lipoproteins transport cholesterol and triglycerides throughout the body.

The liver degrades many drugs and toxic products as well as a wide variety of hormones. Some are excreted in the bile. Others are made water soluble by conjugation to substances like glucuronic acid or by chemical transformation, and are then readily excreted by the kidneys.

The liver also serves as a storehouse for a number of substances whose availability to the body may be sporadic. These include iron and vitamins B12, A, and D.

Overview of the Biliary System

Fig. 26 is a schematic illustration of the biliary system and the circulation of bile acids between the intestines and the liver. Bile is continuously produced by the hepatocytes. The principal organic constituents of bile are the bile acids, which are synthesized by the hepatocytes. The secretion of the bile acids carries water and electrolytes into the bile by osmotic filtration. Additional water and electrolytes, primarily NaHCO3, are added by cells lining the ducts. This latter secretory component is stimulated by secretin and is essentially identical to the aqueous component of pancreatic secretion. The secretion of bile increases pressure in the hepatic ducts, causing the gall bladder to fill. Within the gall bladder, the bile is stored and concentrated by the absorption of water and electrolytes. When a meal is eaten, the gall bladder is stimulated to contract by CCK and vagal nerve stimulation. Within the lumen of the intestine, bile participates in the emulsification, hydrolysis, and absorption of lipids. Most bile acids are reabsorbed either passively throughout the intestine or by an active process in the ileum. Those that are lost in the feces are replaced by resynthesis in the hepatocytes. The absorbed bile acids are returned to the liver via the portal circulation, where they are actively extracted from the blood by the hepatocytes. Together with newly synthesized bile acids, the returning bile acids are secreted into the bile canaliculi. Canalicular bile is produced in response to the osmotic effects of anions that are secreted by ATP-dependent transporters present in the biliary canaliculus. In humans, almost all bile formation is driven by bile acids and is, therefore, referred to as being bile acid dependent. The portion of bile stimulated by secretin and contributed by the ducts is termed ductular secretion.

Organic Constituents of Bile

Bile is a complex mixture of inorganic and organic components, the physical properties of which account for the ability of bile to solubilize normally insoluble fat digestion products. In fact, bile itself contains molecules that are insoluble in water but that are solubilized in bile because of the interactions of its various organic constituents.

Bile Acids

Bile acids account for about 50% of the organic components of bile. They are synthesized in the liver from cholesterol and contain the steroid nucleus with a branched side chain of three to nine carbon atoms

Bile Acids
FIGURE 27 Principal organic constituents of bile. The two primary bile acids may be converted to secondary bile acids in the intestine. Each of the four bile acids may be conjugated to either glycine or taurine to form bile salts. The R-groups of lecithin represent fatty acids.

ending in a carboxyl group (Fig. 27). Chemically, therefore, they are carboxylic acids. Four bile acids are present in bile; there are also trace amounts of others that are chemical modifications of the four. The liver synthesizes two bile acids, cholic and chenodeoxycholic acid. These are the primary bile acids. Within the lumen of the gut, a fraction of each is dehydroxylated by bacteria to form deoxycholic and lithocholic acids (Fig. 27). These are called secondary bile acids. All four are returned to the liver in the portal blood and secreted into bile. The relative amounts of the bile acids in bile are approximately four cholic to two chenodeoxy-cholic to one deoxycholic to only small amounts of lithocholic.

The solubility of the bile acids depends on the number of hydroxyl groups present and the state of the terminal carboxyl group. Cholic acid, with three hydro-xyl groups, is the most soluble, whereas lithocholic, a monohydroxy acid, is the least soluble. The pKs of the bile acids are near the pH of duodenal contents so there are relatively equal amounts in the protonated (insoluble) form and the ion (soluble). The liver, however, conjugates the bile acids to the amino acids glycine or taurine with pKs of 3.7 and 1.5, respectively. Thus, at the pH of intestinal contents the bile acids are largely ionized and water soluble. These conjugated bile acids exist as salts of various cations, primarily sodium, and are referred to as bile salts (Fig. 27).

The unique properties of the bile salts are due to the fact that they are amphipathic molecules—that is, they have both hydrophilic and hydrophobic portions. The molecules are planar and all of the hydrophilic groups project in the same direction out from the hydrophobic sterol nucleus. The hydrophilic groups are the hydroxyls of the cholesterol nucleus, the peptide bond of the side chain, and either the carbonyl or sulfate group of glycine or taurine (Fig. 28). The bile salts align themselves at air-water or oil-water interfaces with the hydrophilic portions in water. In the lumen of the duodenum, the bile salts arrange themselves around droplets of lipid, keeping them dispersed into a suspension called an emulsion. An emulsion consists of droplets approximately 0.5-1 mm in diameter. In this form, the fat has an increased surface area exposed to the action of pancreatic lipase.

Above a certain concentration, called the critical micellar concentration, bile salts form molecular aggregates called micelles (Fig. 28). Micelles are cylindrical, having the bile salts on the outside with their hydro-philic portions oriented outward. The inside of the micelle is made up of various molecules that are insoluble in water. Micelles, 40-70 A in diameter, are in true solution; hence, the bile salts serve to solubilize

Lecithin Cholesterol And Bile Salts

FIGURE 28 Structures of components of micelles and micelles themselves. (A) Representations of bile salt, lecithin, and cholesterol molecules, illustrating the separation of polar and nonpolar surfaces. (B) Cross section of a micelle, showing the arrangement of these molecules plus the principal products of fat digestion. Micelles are cylindrical disks whose outer curved surfaces are composed of bile salts.

FIGURE 28 Structures of components of micelles and micelles themselves. (A) Representations of bile salt, lecithin, and cholesterol molecules, illustrating the separation of polar and nonpolar surfaces. (B) Cross section of a micelle, showing the arrangement of these molecules plus the principal products of fat digestion. Micelles are cylindrical disks whose outer curved surfaces are composed of bile salts.

these other molecules. Within bile itself, the bile salts are always present in amounts above the critical micellar concentration, and the micelles also contain phospholipids and cholesterol. The osmolarity of bile drawn from the cystic duct is always near 300 mOsm. However, the cation concentration, primarily Na + , may be as high as 300 mmol/L. The apparent discrepancy is resolved by the fact that a single micelle osmotically inactivates many molecules and sequesters a significant number of the inorganic cations. Within the lumen of the proximal small bowel, micelles contain fatty acids, monoglycer-ides, and fat-soluble vitamins in addition to the bile salts, cholesterol, and phospholipids.

Phospholipids

Phospholipids, primarily lecithins (see Fig. 27), are the second most abundant organic component of bile and account for approximately 30-40% of the solids present. Phospholipids are also amphipathic, and the hydrophilic phosphatidylcholine group is oriented outward, whereas the hydrophobic fatty acid carbon chains are buried in the core of the micelle (see Fig. 28). As mentioned previously, the phospholipids themselves are insoluble and are solubilized in micelles. Phospho-lipids, however, are extremely important because they increase the ability of bile salts to form micelles and solubilize cholesterol. Approximately 2 mol of lecithin are solubilized per mole of bile salt.

Cholesterol

Bile is the primary excretory pathway for cholesterol. The insoluble cholesterol makes up roughly 4% of the organic material in bile and is solubilized in the core of the micelle (see Fig. 28). If more cholesterol is present than can be solubilized, crystals of cholesterol form in the bile. These crystals may serve as the nidus for gallstone formation.

Bile Pigments

The fourth significant group of organic compounds found in bile is the bile pigments and it accounts for approximately 2% of the solids. The principal bile pigment is bilirubin, produced from hemoglobin by cells of the reticuloendothelial system. Chemically, the bile pigments are tetrapyrroles, which are derived from porphyrins. Bilirubin is insoluble in water, but within the liver it is made soluble by conjugation to glucuronic acid. It is secreted as the soluble salt bilirubin glucuronide and, therefore, is not found within the micelles.

Secretion of Bile Functional Histology of the Liver

The functional organization of the liver is shown schematically in Fig. 29. The liver is divided into lobules organized around a central vein that receives blood

Central Veins Diagram

FIGURE 29 Schematic diagram of the relationship between blood vessels, hepatocytes, and bile canaliculi in the liver. Each hepatocyte is exposed to blood at one membrane surface and a bile canaliculus at the other.

Branch of ■ Hepatic Artery

FIGURE 29 Schematic diagram of the relationship between blood vessels, hepatocytes, and bile canaliculi in the liver. Each hepatocyte is exposed to blood at one membrane surface and a bile canaliculus at the other.

through separations surrounded by plates of hepato-cytes. The separations are called sinusoids, and they in turn are supplied by blood from both portal vein and the hepatic artery. The plates of hepatocytes are no more than two cells thick, so every hepatocyte is exposed to the blood. Openings between the plates ensure that the blood is exposed to a large surface area. The hepatocytes remove substances from the blood and secrete them into the biliary canaliculi lying between the adjacent hepatocytes. The bile in the canaliculi flows toward the periphery, countercurrent to the flow of blood, and drains into peripheral bile ducts. The countercurrent relationship between bile flow and blood flow within the lobule minimizes the concentration gradients between substances in the blood and bile and contributes to the liver's efficiency in extracting substances from the blood.

Bile Acids and the Enterohepatic Circulation

The total bile acid pool in the human body is approximately 2.5 g and includes the bile acids present in the liver, ducts, gall bladder, bowel, and blood, that is, within the entire enterohepatic circulation (see Fig. 26). The bile acid pool may circulate through the entero-hepatic circulation several times during the digestion of a meal, so that 15-30 g bile acids may enter the duodenum during a 24-hr period.

Bile acids are secreted continuously by the liver. The secreted bile acids include those extracted from the portal blood and those newly synthesized. Approximately 90-95% of bile acids in portal blood are carried bound to plasma proteins. Within the liver, the hepa-tocytes extract the bile acids from the portal blood via a secondary active transport mechanism (Fig. 30). The basolateral (blood side) membrane of the hepatocyte contains a transport protein that binds the bile acid and Na + , transporting them both to the cytoplasm. The (Na + ,K + )-ATPase pumps the Na+ out of the cell, providing the concentration gradient for the entry of the bile acids. This extraction of bile acids from the portal blood is nearly 100% efficient.

The rate of synthesis of new bile acids is inversely correlated with the return of bile acids via the portal blood. Under normal conditions, approximately 600 mg of bile acids are synthesized per day. This amount replaces that lost into the stool every day. Bile acids extracted from the portal blood act to feedback-inhibit the 7-a-hydroxylase, the rate-limiting enzyme for bile acid synthesis from cholesterol. If the enterohepatic circulation is interrupted (e.g., by a biliary fistula draining bile to the outside), the rate of synthesis of bile acids becomes maximal. In humans, this is equal to 3-5 g per day. In patients incapable of reabsorbing bile acids, the maximal rate of synthesis equals the total amount of bile acids secreted by the liver. Although this is greater than the bile acid pool, because of the recirculation of bile acids, it is only a fraction of the 15-30 g normally secreted by the liver per day.

Although bile acids returning to the liver in the portal blood inhibit new bile acid synthesis, they are a potent stimulus of bile secretion and greatly increase the rate of bile production. Such a substance is called a choleretic. The volume of bile produced in response to the osmotic gradient caused by the secretion of bile acids, both returning and newly synthesized, is known as the bile acid-dependent fraction of the overall secretion of bile.

FIGURE 30 Mechanism for the secretion of bile by the hepatocytes. Bile acids (B.A.) are reabsorbed from the blood by a secondary active transport mechanism dependent on the Na+ gradient established by the (Na + , K + )-ATPase. They then enter the bile canaliculus via a facilitated diffusion pathway. Water and electrolytes enter the bile through paracellular pathways along an osmotic gradient. This process is known as osmotic filtration.

FIGURE 30 Mechanism for the secretion of bile by the hepatocytes. Bile acids (B.A.) are reabsorbed from the blood by a secondary active transport mechanism dependent on the Na+ gradient established by the (Na + , K + )-ATPase. They then enter the bile canaliculus via a facilitated diffusion pathway. Water and electrolytes enter the bile through paracellular pathways along an osmotic gradient. This process is known as osmotic filtration.

The process by which returning and newly synthesized bile salts are secreted across the apical membrane of the hepatocyte into the bile canaliculus depends on ATP. Two ATP-dependent transporters have been defined in the canalicular membrane. One has specificity for monovalent bile salts and the second for divalent bile salt conjugates.

Bile acids are absorbed throughout the entire small intestine by passive diffusion and in the terminal ileum by an active transport mechanism. This mechanism requires Na+, and is secondary to the Na+ gradient created by the (Na + ,K+)-ATPase. More than 95% of the secreted bile acids are normally absorbed and returned to the liver. Because bile acids are large molecules, their passive absorption depends on their lipid solubility. When bile acids enter the duodenum they are 100% conjugated, almost totally dissociated and, therefore, lipid insoluble. Because the pK of glycine conjugates is higher than that of taurine conjugates, bile acids conjugated to glycine are likely to be absorbed earlier than those conjugated to taurine. Within the lumen bacteria deconjugate the bile salts, increasing their lipid solubility and increasing their passive absorption approximately ninefold. Bacteria also dehydroxy-late bile acids, which increases passive absorption about fourfold. In humans, approximately 50% of the secreted bile acids are actively absorbed. The active mechanism absorbs primarily conjugated bile acids, although a small amount of unconjugated acids also may be absorbed. The location of the active absorptive mechanism in the terminal ileum ensures the presence of adequate amounts of bile acids for micelle formation until all of the fat digestion products are absorbed. The absorption of fat is usually completed by the end of the jejunum. Some bile acids pass into the colon, where they are further deconjugated and modified by bacteria. Some of these may be absorbed passively. The remainder is excreted in the stool. After extraction from the portal blood by the hepatocytes, both primary and secondary bile acids are reconjugated to glycine or taurine and some secondary bile acids are rehydroxylated.

Loss of excessive bile acids into the colon produces diarrhea. Bile acids or their degradation products inhibit colonic absorption of sodium and H2O. This results in diarrhea without loss of fat in the stool, if the resynthesis of bile acids can keep up with the loss. In cases of extreme loss, such as after ileal resection, the digestion and absorption of long-chain triglycerides is also impaired and steatorrhea results as well. The steatorrhea can be cured by substituting medium-chain triglycerides for long-chain triglycerides in the diet. Medium-chain triglycerides do not require micelle formation for absorption.

Phospholipids and Cholesterol

Phospholipids and cholesterol are secreted by the hepatocytes into the bile. The exact mechanism of secretion is unknown, but the quantity secreted is directly related to the secretion of bile acids. Within the small intestine, phospholipids and cholesterol secreted with the bile are handled in the same manner as those ingested (see Chapter 35).

Bilirubin

Cells of the reticuloendothelial system degrade hemoglobin from worn-out red blood cells. The porphyrin is converted into the yellow pigment bilir-ubin. The insoluble bilirubin is released into the blood, where it is carried to the liver tightly bound to plasma albumin (Fig. 31).

Hepatocytes extract bilirubin from the blood and conjugate it to glucuronic acid to form water-soluble bilirubin glucuronide. Uptake from the blood is mediated by an active anion transport system different from the one that extracts bile acids. This system, however, is also virtually 100% efficient. Bilirubin glucuronide is secreted into the bile and is partially responsible for its golden color. Because it is water soluble, it does not take part in micelle formation. The failure to clear sufficient bilirubin from the blood in patients with liver damage may result in the yellow appearance of the skin and eyeballs, the condition known as jaundice.

Bilirubin glucuronide is not absorbed from the intestine in appreciable amounts, and it is excreted in the feces. A fraction, however, is deconjugated and reduced to urobilinogen by bacteria of the distal small bowel and intestine. Some urobilinogen is excreted in the feces, but some is also absorbed and transported to the liver via the portal circulation. The liver extracts most of the urobilinogen via an active mechanism and secretes it into the bile. The capacity of the liver to extract urobilinogen is low, so that a measurable fraction passes into the systemic circulation, where it is filtered by the kidneys and excreted in the urine. If the liver becomes damaged, the amount of urobilinogen in the urine may increase severalfold. Urobilinogen is colorless; however, in the urine and feces, it is exposed to oxygen and oxidized to urobilin and stercobilin, respectively. These pigments are partially responsible for the color of the excretory products.

Water and Electrolytes

As bile acids are secreted into the bile canaliculi, water and electrolytes enter the bile by the process of osmotic filtration (see Fig. 30). Canalicular bile is, thus, primarily

Bilirubin Formation Pathway

Feces

FIGURE 31 Bilirubin excretory pathways. Heavy arrows represent active processes.

Intestine

Feces

FIGURE 31 Bilirubin excretory pathways. Heavy arrows represent active processes.

an ultrafiltrate of plasma as far as the concentrations of water and electrolytes are concerned. In some species, there is evidence for the active secretion of Na+ into the bile canaliculi. However, this has not been established in humans. The higher the rate of return of bile acids to the liver, the faster they are secreted and the greater the volume of bile. This component is therefore referred to as the bile acid-dependent fraction.

The contribution of the bile ductules and duct to bile production is identical to that of the pancreatic ducts to pancreatic juice. Secretin stimulates the secretion of HCO— and water from the ductule cells (see Fig. 26). This results in significant increases in bile volume, HCO— concentration, and pH, and a decrease in the concentration of bile salts. The mechanism of HCO— secretion by the ducts of the liver involves active transport and is also similar to the one employed by the pancreas. When stimulated by secretin, the HCO— concentration of the bile may increase two- or threefold over that of the plasma.

Gall Bladder Function

Filling

The liver secretes bile continuously. Because the hepatic end of the system is blind (closed), secretion results in the generation of hydrostatic pressure within the ducts. In humans, the secretory pressure normally ranges between 10 and 20 mm Hg. The maximal secretory pressure, above which bile cannot be produced, has been measured at 23 mm Hg.

During the interdigestive period, the gall bladder is flaccid and the sphincter of Oddi at the opening of the duct into the duodenum is closed. This causes bile to flow into the gall bladder. The capacity of the human gall bladder ranges between 20 and 60 mL. The volume of bile produced by the liver before the gall bladder empties, however, may be several times this amount.

Concentration of the Bile

The gall bladder epithelium concentrates the bile by actively reabsorbing Na + , CP, and HCO—. Water follows down the osmotic gradient created. The active transport mechanism employed varies between species. In some species, NaCl and NaHCO3 are absorbed via a coupled transport system that is not electrogenic. In humans, an electrical potential difference, inside approximately —8 mV, is created, indicating that the system is not coupled, that Na+ may be the only ion actively transported, and that Cl— and HCO— follow passively. Hydrogen ion is also secreted, which neutralizes HCO—, and the resulting CO2 is absorbed across the gall bladder epithelium. In any case, the net result is a decrease in the pH, total amounts of Na + , Cl—, HCO—, and water in the bile and a large increase in the concentration of the organic constituents of bile (Table 2).

Bile remains isosmotic to plasma even though the organic constituents are concentrated greatly. The bile salts, cholesterol, and phospholipids are present in osmotically inactive micelles. Because bile salts are anions, many of the inorganic cations are bound within the micelles and are also osmotically inactive. This

Clinical Note

Gallstones

Approximately 10% of the white population over 29 years of age in the United States is estimated to have gallstones. There are basically two types of gallstones, cholesterol stones and pigment stones, although both have a mixed composition.

Cholesterol stones are 50-75% cholesterol and most contain a pigment center (bilirubin) that probably acted as a nidus for stone formation. During the course of a day, about 50% of bile secreted by nonstone individuals is supersaturated with cholesterol. All bile produced by patients with cholesterol stones is supersaturated with cholesterol. The solubility of cholesterol in bile depends on micelle formation, which in turn depends on the relative amounts of bile salts, lipids, and cholesterol in the bile. In nonobese cholesterol stone patients, the amount of lipids is decreased. In obese patients, the amount of cholesterol is increased. In both groups, the bile acid pool is reduced for some reason to about 50% of normal. Supersaturation results in crystal formation and the growth of the crystals into stones.

Pigment stones are produced when unconju-gated bilirubin precipitates with calcium to form a stone. In normal bile, bilirubin is solubilized by conjugation to glucuronic acid, and approximately only 1% remains unconjugated. Gall bladder bile from patients with pigment stones, however, is saturated with unconjugated bilirubin. The enzyme ^-glucuronidase is responsible for the deconjugation of bilirubin within the gall bladder. The enzyme is released from the wall of the damaged gall bladder, and it is present in high concentrations in a variety of bacteria, including Escherichia coli, which may infect the gall bladder.

The treatment for gallstones is surgical removal of the gall bladder, known as cholecystectomy. Normal digestion and absorption are unaffected in individuals after cholecystectomy. Without the gall bladder, bile is released continuously into the duodenum as it is produced by the liver. Amounts produced are higher than normal during interdigestive periods, because bile salts are not being stored in the gall bladder. They therefore return to the liver continuously to stimulate bile production. The large increases of bile secretion into the duodenum at the beginning of a meal, however, are absent in the cholecys-tectomized patient, and the overall secretion of bile in response to a meal is somewhat reduced. The gall bladder is naturally absent from some species of animals, including the rat and the horse.

also explains the great excess of inorganic cations over inorganic anions in concentrated bile. The mechanism of water absorption across the gall bladder epithelium is similar to that across other tight epithelia (see Chapter 36). The layer of epithelial cells has large lateral intercellular spaces. These are closed by

TABLE 2 Approximate Values for Major Components of Liver and Gall Bladder Bile

Component

Liver Bile

Gall bladder bile

Na+ (mmol/L)

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Responses

  • j
    Where is bile created?
    10 months ago
  • katherine
    Is bile secreted by gall bladder in some amount?
    7 months ago
  • topi
    Where is bile synthesized?
    6 months ago

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