How is bile secretion regulated

The gastrointestinal hormones secretin, cholecystokinin CCK , sulfated gastrin, and glucagon increase bile volume and inorganic ion excretion into bile, but none of them influence bile salt secretion.

The action of secretin is clearly physiologic. Nonsulfated gastrin and pentagastrin are not choleretics. The choleretic property of CCK derivatives is dependent upon the presence of sulfated tyrosine at position 7. Catecholamines increase bile flow by a mechanism that involves beta receptors, but the precise mechanism is unknown.

The role of the parasympathetic nervous system is not clear. There is no evidence that hepatic secretion of bile salts is under neural control. The tone of the gallbladder and sphincter of Oddi regulates the amount of bile that actually enters the duodenum. CCK is the only known physiologic cholecystokinetic gastrointestinal hormone. It contracts the gallbladder and relaxes the sphincter of Oddi by direct action on the muscle of these structures.

The parasympathetic nervous system probably participates in regulation of gallbladder muscle tone. This is a preview of subscription content, access via your institution. Rent this article via DeepDyve. Sperber, I. Google Scholar. Presig, R. Wheeler, H. Forker, E. Barnhart, J. Nahrwold, D. Forum 22 , Sutherland, S. Alexander, W. Kuntz, A. Philadelphia, Lea and Febiger, , p. Tanturi, C. Harty, R. Gastroenterology 64 , Kaminski, D.

The sodium-potassium ATPase on the basolateral membrane of the hepatocyte maintains sodium and potassium gradients. Because three sodium ions are expelled from the cell in return for receiving two potassium ions, an electrochemical gradient is formed [1]. The relative negative charge inside the hepatocyte favors the uptake of positively charged ions, while the sodium gradient fuels the sodium-dependent taurocholate cotransporter protein. This transporter allows for the uptake of conjugated bile acids.

In contrast, the organic anion transporter protein does not require sodium to import organic anions. There are several other transporters found on the basolateral surface of the hepatocyte, including the sodium-taurocholate co-transporting protein, ion exchangers that regulate pH, such as the sodium-hydrogen exchanger and the sodium-bicarbonate cotransporter, organic anion and cation transporter, and non-esterified fatty acid transporters.

The transporter proteins found in the canalicular membrane are primarily members of the ATP-binding cassette protein family [9]. These proteins use active transport to secrete molecules and enzymes into the bile. The canalicular membrane transporters help secrete molecules into bile against concentration gradients, and also enzymes such as alkaline phosphatase. Contractile microfilaments facilitate the secretion of bile through the canaliculi. In normal development, the synthesis of bile acids first occurs during weeks 5 to 9 of gestation, with bile secretion occurring at 12 weeks of gestation, and surging after 17 weeks gestation [10] [11].

After birth, the composition of bile acids further changes; in the neonatal period, the ratio of cholic to chenodeoxycholic acid is approximately 2. Abnormal development of the biliary tree can cause congenital liver disease.

These primary cholangiopathies include ductopenic syndromes, ductal plate malformation syndromes, polycystic liver diseases, and fibro-polycystic liver diseases [12]. Bilirubin, the major pigment of bile, is an end product of heme catabolism that travels to the liver bound to albumin. Once inside the liver, the enzyme uridine diphosphate glucuronyltransferase UDPGT conjugates bilirubin to form bilirubin glucuronide.

The water-soluble conjugated bilirubin is then secreted into bile, providing its characteristic yellow color [1]. Rectum: Urobilin and stercobilin compounds oxidized from urobilinogen are responsible for dark fecal pigment. Through the process of emulsification, bile acids break down large lipid droplets into smaller ones, increasing the surface area for digestive enzymes.

Emulsification is possible due to the amphipathic property of bile salts [1]. The hydrophilic portion of the bile salts surrounds the lipid, forcing the lipid to disperse as the negative charges repel each other.

Bile salts also allow the products of lipid digestion to be transported as micelles. The core of the micelle contains monoglycerides, lysolecithin, fatty acids, and the hydrophobic portion of the bile salt. The hydrophilic portion of the bile salt surrounds the lipid core, increasing solubility. Without bile salts, the fat-soluble vitamins A, D, E, K cannot be absorbed.

Cholesterol is eliminated through its conversion into bile acids, allowing the body to maintain cholesterol homeostasis.

Bile acid sequestrants, medications intended to lower cholesterol, function by binding bile acids in the small intestine, and increasing their excretion in the stool. Bilirubin is also eliminated through its secretion into bile, where it eventually forms the dark pigment of feces [13]. Large amounts of bile acids are secreted into the intestine every day, but only relatively small quantities are lost from the body.

Venous blood from the ileum goes straight into the portal vein, and hence through the sinusoids of the liver. Hepatocytes extract bile acids very efficiently from sinusoidal blood, and little escapes the healthy liver into systemic circulation. Bile acids are then transported across the hepatocytes to be resecreted into canaliculi. The net effect of this enterohepatic recirculation is that each bile salt molecule is reused about 20 times, often two or three times during a single digestive phase.

It should be noted that liver disease can dramatically alter this pattern of recirculation - for instance, sick hepatocytes have decreased ability to extract bile acids from portal blood and damage to the canalicular system can result in escape of bile acids into the systemic circulation. Assay of systemic levels of bile acids is used clinically as a sensitive indicator of hepatic disease.

The flow of bile is lowest during fasting, and a majority of that is diverted into the gallbladder for concentration. Bile acids also have an indirect effect on luminal bacteria, mediated by the nuclear receptor FXR; the mechanism of this effect has not been clarified. Taken from reference Intraluminal deficiency of bile acids. A conjugated bile acid deficiency occurs when the enterohepatic circulation is obstructed, diverted, or when intestinal conservation of bile acids is impaired because of ileal dysfunction.

In patients with a short bowel syndrome, severe bile acid malabsorption occurs because most patients with this condition have lost their ileum. The therapy currently practiced is to enrich dietary triglyceride in medium chain triglyceride, as medium chain fatty acids are water soluble and do not require micellar solubilization for absorption.

Moreover they are absorbed extremely rapidly as they are absorbed both transcellularly and paracellularly. Fat soluble vitamins are given parenterally. Patients with short bowel syndrome have both a loss of intestinal absorptive surface as well as defective micellar solubilization. The feeding of conjugated bile acids can correct the defect in fat digestion. A conjugated bile acid analogue, cholylsarcosine, was synthesized, found the physicochemical properties of the natural conjugates of cholic acid 41 and shown to be resistant to bacterial degradation deconjugation and dehydroxylation in animals 42 and man.

Pharmaceutical companies have shown little interest in cholylsarcosine because there is no patent protection and the perceived market is small. Cholylsarcosine can cause gastric irritation, but if an enteric coating is used, the compound must be rapidly released in the duodenum, as this is a major site of fat absorption, and small intestinal transit is often very rapid in patients with short bowel syndrome. Such a formulation of cholylsarcosine has been reported.

In health, daily bile acid secretion when measured by an indicator dilution technique is mmoles day. The ability to secrete more bile acid than is synthesized results from a recycling bile acid pool. Development of a bile acid pool results from efficient intestinal conservation mediated by in large part by the ileal conjugated bile acid transport system. Schematic views of the enterohepatic circulation of bile acids are shown in Figures 2 and Figure 3.

Schematic illustration of the enterohepatic circulation of bile acids. Conjugated bile acid absorption mediated by OATP3 may also occur throughout the small intestine, but the magnitude of this flux in man is not known. Schematic depiction of the enterohepatic circulation and metabolism of bile acids. Normally, bile acids are efficiently conjugated amidated with glycine or taurine, and cholehepatic shunting is small.

The ileal apical bile acid transporter is present on the apical membrane of cholangiocytes, so a modest amount of cholehepatic cycling of conjugated bile acids does occur. Bile acid synthesis is balanced by fecal loss. The enterohepatic circulation is regulated at two sites.

The first is regulation of biosynthesis from cholesterol, which is mediated in negative feedback manner by several mechanisms. First, bile acids in the hepatocyte activate a heterodimeric nuclear receptor RXR-FXR whose activation induce the synthesis of a protein named shp. Binding of shp down regulates bile acid biosynthesis. Second, there is a shp independent pathway for down regulation, activated by inflammatory cytokines. Bile acid uptake across the apical membrane of the ileal enterocyte is mediated by a sodium dependent conjugated bile acid cotransporter [apical sodium dependent bile acid transporter ASBT that has been found in every vertebrate in which it is sought.

Paracellular absorption of bile acids is believed to be negligible as the bile salt molecule is too large to pass via the tight junctions between small intestinal epithelial cells. Whether subjects with increased intestinal permeability absorb bile acids via a paracellular route is not known.

Were this to occur, the intraluminal concentration of bile acids might fall, leading to bacterial proliferation. Were bacterial proliferation to damage the paracellular junctions, a vicious cycle might ensue. A bile acid binding protein in the ileal enterocyte plays an as yet undefined role in promoting vectorial transport. Exit from the ileal enterocyte is mediated by a heterodimeric bile salt transporter composed of two sub-units OSTalpha and OSTbeta. Schematic illustration of the bile acid transport by the ileal enterocyte.

When IBAPB is ablated, bile acid absorption still occurs, so the protein is not required for active bile acid absorption. Abbreviations of the protein and gene are given in the insert. Ileal transport in man and the mouse appears to be also regulated in a negative feedback manner — thus bile acid feeding down regulates bile acid transport, and bile acid sequestrant feeding upregulates bile acid transport.

Details of regulation of the ileal apical sodium dependent transporter are being clarified. Bile acids are transported to the liver in portal venous blood are efficiently extracted despite being highly albumin-bound. Uptake is dependent on bile acid structure and is greater for trihydroxy bile acids than di-hydroxy bile acids, and for a given steroid moiety, is greater for conjugated bile acids than unconjugated bile acids.

Fractional extraction of bile acids remains constant despite varying bile acid loads to the liver. Therefore bile acid extraction is said to be «blood flow limited».

Vectorial transport by the hepatocyte involves uptake at the basolateral membrane and active secretion across the canalicular membrane. Basolateral uptake is mediated by both sodium dependent and sodium independent transporters.

Although there are continuing efforts to define the substrate specificity and role of the many sinusoidal membrane uptake proteins, 8 - 11 It is still not clear which transporters other than the sodium dependent transporter are involved in bile acid uptake. Figure 5 illustrates schematically the major transporters involved in vectorial transport of bile acids through the hepatocyte.

Schematic illustration of bile acid transport by the hepatocyte. The substrate specificity of the three canalicular transporters is not yet perfectly defined and varies between species.

ABCG2 is also known as the breast cancer related gene. Normally, the proportion of bile acid sulfates or bile acid glucuronosides glucuronides in bile is quite low. MRP4 promotes the cotransport of conjugated bile acids and reduced glutathione.

MRP3 is thought to be involved in efflux of glucuronosides. Secretion across the canalicular membrane involves predominantly the canalicular bile salt export pump BSEP , which is energized by hydrolysis of ATP. Since its cloning in , 55 BSEP has been studied in considerable detail. About 50 mutations have been identified in infants born with «primary familial intrahepatic cholestasis» type 2. When infants are born with non-functioning BSEP, they develop hepatocyte necrosis and liver fibrosis, leading ultimately to liver failure.

Liver transplantation is required and is life-saving. BSEP transports not only bile acids, but also a variety of drugs, including several statins. The major canalicular transporter for organic anions other than bile acids is MRP2. It transports many drug metabolites and bilirubin glucuronides. In animals, MRP2 mediates canalicular secretion of bile acid sulfates.

However, in man, BSEP appears to mediate the canalicular secretion of sulfated and amidated derivatives of lithocholic acid. A survey of biliary lipid composition in over vertebrates showed that in many vertebrates, only bile acids are present in appreciable proportions, i. Human bile is lipid rich containing a high ratio of phospholipid to bile acid 0.

Man appears to differ from all other animals characterized to date in eliminating cholesterol from the body to a greater extent as cholesterol than by conversion to bile acids. Biliary excretion permits the organism to eliminate substrates that cannot be eliminated via renal excretion. Besides bile acids, biliary excretion involves the excretion of organic molecules and heavy metal cations that are highly protein bound.

Because none of such molecules have an appreciable enterohepatic circulation, their concentration in bile is quite low. The digestive function of bile acids has already been summarized, and bile acid transport into bile by BSEP was discussed above. Biliary phospholipid secretion. The major phospholipid of mammalian bile is phosphatidylcholine PC which is not believed to have any important digestive function.

This is because phospholipids are present in dietary lipids, and in addition, the enterocyte can biosynthesize PC which is a key part of the lipid surface layer of chylomicrons. Phospholipid serves to solubilize cholesterol in bile, as it forms the lipid core of the mixed micelles present in bile that can in turn solubilize cholesterol and other biliary lipids.

To date, the only canalicular protein involved in biliary phospholipid secretion is MDR2. The luminal side of the canalicular membrane must be highly resistant to the solubilizing action of bile acids. Sphingomyelin which is a membrane stabilizer is present in the luminal face of the canalicular membrane but is present in mammalian bile in only trace amounts.

Phosphatidylserine is believed to be flipped back from the luminal face to the cellular face by FIC1. Primary familial intrahepatic cholestasis type I involves mutations in a gene called FIC1.

One view of the protein encoded for by this gene is that it promotes the flipflop of phosphati-dylserine from the biliary face of the canalicular membrane to the cytosolic face.

Defective removal of this phospholipid from the biliary face of the canalicular membrane results canalicular membrane fragility. As a result phosphatidylserine as well as canalicular proteins are released into bile when bile flow is induced by infusing bile acids. It is generally assumed that the PC molecules that enter bile at the canaliculus remain in the mixed micelle and are not absorbed by the biliary ductules.

The validity of this assumption is not known. Knockout of this gene in mice results in the absence of biliary phospholipid and causes the development of a peribiliary fibrosis. The monomeric activity of bile acids is higher in the absence of phospholipids, and the increased monomeric activity of bile acids has been considered the causal agent for biliary ductule injury, Nonetheless, the increase in the monomeric bile acid concentration is modest, if findings in model systems apply to the in vivo situation.

Some work on other organs suggests 71 that the combination of PC and cholesterol in bile may render membranes resistant to bile acids. The phenotype of decreased MDR function in man has been reported to be calculous biliary disease, 72 presumably because of defective micellar solubilization of cholesterol; mutations in MDR have also been reported in cholestasis of pregnancy. Our laboratory reported a group of patients with gallbladder inflammation despite the absence of gallstones, a disease named chronic acalculous cholecystitis.

This observation has not been confirmed. In these patients, the decreased phospholipid could result from rather than cause the mucosal inflammation. There would appear need for additional work to characterize the phenotype of MDR3 deficiency in man.

The MDR2 knockout mouse develops a striking peribiliary fibrosis. This can be treated successfully by administering norursodeoxycholic acid, the C 23 C 24 -nor homologue of UDCA; 76 such a molecule has an isobutanoic acid side chain and thereby differs from UDCA which has an isopentanoic acid side chain. Nor UDCA is secreted intact into bile and reabsorbed in the biliary ductules to undergo cholehepatic shunting in animals 77 and apparently in man.

UDCA has a much weaker effect. Whether nor UDCA will prove to have any clinical value in man is quite uncertain. In contrast to other natural bile acids, it has considerable renal excretion, especially of its ester glucuronide, its major metabolite.

Although the peribiliary fibrosis of the MDR2 knockout mouse resembles primary sclerosing cholangitis, biliary phosphor lipid secretion is quite normal in this disease, so it remains quite uncertain that nor UDCA will have a therapeutic effect in sclerosing cholangitis. Ezetimibe is secreted into bile as a glucuronide that maintains pharmacodynamic activity. As yet, whether such vigorous cholesterol absorption by cholangiocytes that occurs in the dog, is also present in other species is not known.

During gallbladder storage, the proportion of cholesterol in bile falls, indicating that cholesterol is absorbed by the healthy gallbladder. Bile acid therapy: Bile acid therapy is still used infrequently in liver and intestinal disease, with the single exception of ursodiol that is used by most physicians for a variety of uncommon hepatobiliary diseases in which cholestasis occurs. Rationale of bile acid therapy: liver defects.

Rationale of bile acid therapy: liver disease continued and intestinal disease. At present, there are four rationales for bile acid therapy. Bile acid replacement is when bile acids are administered to replace a deficiency state. Such occurs in inborn errors of bile acid biosynthesis or bile acid conjugation, as well as in conditions when there is a deficiency in the small intestine because of ileal dysfunction.

This occurs in short bowel syndrome, as the ileum has usually been resected in such patients. Bile acid deficiency in the small intestine also occurs in cholestatic liver disease, but usually bile acid secretion into the small intestine is sufficient to permit adequate lipid absorption in the adult, and it has been considered dangerous to administer exogenous bile acids other than ursodiol when endogenous bile acids are already.

Bile acid displacement occurs when the composition of the circulating bile acids is changed by exogenous bile acid administration, but there is relatively little change in bile acid secretion. Bile acid displacement is the rationale when ursodiol is used in cholestatic liver diseases.

The mechanism of action of ursodiol is complex and involves replacement of endogenous cytotoxic bile acids [chenodeoxycholic CDCA and DCA by UDCA a non-cytotoxic bile acid; the mechanism is likely to be competition for active ileal transport. UDCA also has anti apoptotic effects, and anti-oxidative injury effects. It may also reduce endoplasmic reticulum «stress» and appears to also have anti-inflammatory effects.

UDCA is also used to lower the cholesterol proportion in bile and thereby induce gallstone dissolution. UDCA is amidated with glycine or taurine in the liver, and the resulting UDCA conjugates, as any natural conjugated bile acid, induce bile acid dependent bile flow.

In cystic fibrosis, ductular bile flow is decreased because of non-functioning of the CFTR chloride channel. Increased canalicular bile flow induced by UDCA administration is thought to benefit children with cystic fibrosis by reducing the likelihood of developing chronic liver disease. A third rationale for bile acid therapy may be termed FXR activation.