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Functions of the Gallbladder

Chantal Housset, Yves Chrétien, Dominique Debray, Nicolas Chignard

10.1002/cphy.c150050

Source: Volume 6, Issue 3, July 2016

Published online: June 2016

Full Article on Wiley Online Library



ABSTRACT

The gallbladder stores and concentrates bile between meals. Gallbladder motor function is regulated by bile acids via the membrane bile acid receptor, TGR5, and by neurohormonal signals linked to digestion, for example, cholecystokinin and FGF15/19 intestinal hormones, which trigger gallbladder emptying and refilling, respectively. The cycle of gallbladder filling and emptying controls the flow of bile into the intestine and thereby the enterohepatic circulation of bile acids. The gallbladder also largely contributes to the regulation of bile composition by unique absorptive and secretory capacities. The gallbladder epithelium secretes bicarbonate and mucins, which both provide cytoprotection against bile acids. The reversal of fluid transport from absorption to secretion occurs together with bicarbonate secretion after feeding, predominantly in response to an adenosine 3′,5′‐cyclic monophosphate (cAMP)‐dependent pathway triggered by neurohormonal factors, such as vasoactive intestinal peptide. Mucin secretion in the gallbladder is stimulated predominantly by calcium‐dependent pathways that are activated by ATP present in bile, and bile acids. The gallbladder epithelium has the capacity to absorb cholesterol and provides a cholecystohepatic shunt pathway for bile acids. Changes in gallbladder motor function not only can contribute to gallstone disease, but also subserve protective functions in multiple pathological settings through the sequestration of bile acids and changes in the bile acid composition. Cholecystectomy increases the enterohepatic recirculation rates of bile acids leading to metabolic effects and an increased risk of nonalcoholic fatty liver disease, cirrhosis, and small‐intestine carcinoid, independently of cholelithiasis. Among subjects with gallstones, cholecystectomy remains a priority in those at risk of gallbladder cancer, while others could benefit from gallbladder‐preserving strategies. © 2016 American Physiological Society. Compr Physiol 6:1549‐1577, 2016.

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Figure 1. Figure 1. Embryology of the gallbladder. (A) In the early embryo, liver specification occurs in the posteroventral foregut endoderm (future duodenum) interfacing the septum transversum mesoderm. Endodermal proliferation is then triggered and results in the formation of the hepatic diverticulum. (B) The liver develops from the cranial portion (pars hepatica) of the hepatic diverticulum, while the extrahepatic biliary tract develops from the caudal portion (pars cystica) of the hepatic diverticulum. PDX1‐positive/SOX17‐positive cells in the caudal portion undergo lineage segregation into a PDX1‐positive/SOX17‐negative pancreatic domain, which gives rise to ventral pancreas, and a PDX1‐negative/SOX17‐positive biliary domain, which develops into the gallbladder and extrahepatic bile ducts. The duodenum then rotates to the right. (C) Subsequently, the attachment of the developing common bile duct and pancreatic duct is displaced to its definitive position on the dorsal side of the duodenum, while the dorsal and ventral pancreas merge.
Figure 2. Figure 2. Anatomy of the gallbladder. (A) Frontal view (upper panel) and inferior view (lower panel) of the human liver showing the gallbladder fossa, in which the gallbladder is in direct contact with the liver surface. (B) Representation of the gallbladder and extra‐hepatic biliary tract. The major papilla is formed by the choledochoduodenal and pancreaticoduodenal junctions, in the second portion of the duodenum.
Figure 3. Figure 3. Structure of the gallbladder wall. (A) Standard histological microphotographs of human gallbladder tissue showing the three, that is, mucosal, muscular and serosal, layers of the gallbladder wall (left panel), and the mucosal folds, at low (right upper panel) and high magnification (right lower panel). (B) Transmission electron microscopic view of human gallbladder epithelium, showing columnar, clear (C) or dark (D) cells containing mucus secretory granules in their apical zones (m; large arrows point to electron dense cores), basolateral digitations (d), and basement membrane (bm) (Bar = 2 μm). (C) Scanning electron microscopic views of human gallbladder epithelial suface, showing the numerous apical microvilli of each cell apex finely coated with glycocalyx, producing a blurry effect of their tips (left panel, bar = 1 μm); the crater‐like appearance (open arrows) and mucus clumps (small arrow) on cell apices, following the mucus secretory process (right panel, bar = 10 μm). B and C were reprinted from (177), with permission from Wiley publisher © 1997 Wiley‐Liss, Inc.
Figure 4. Figure 4. Profile of gallbladder emptying. Representative example of gallbladder emptying in a normal volunteer in whom ultrasound measurements of gallbladder volume were made at 1‐min intervals. Reproduced with permission from (92).
Figure 5. Figure 5. Neurogenic regulation of gallbladder motor function. Vagal nerve terminals provide cholinergic preganglionic input to gallbladder neurons. Stimulated gallbladder neurons release acetylcholine (ACh) and tachykinins (TK), which cause smooth muscle contraction via M3 muscarinic and NK2 neurokinin receptors, respectively. CCK acts presynaptically to increase acetylcholine release from vagal terminals onto gallbladder neurons, and likely, also directly on CCK1 high‐affinity receptors present on smooth muscle cells to stimulate contraction. Norepinephrin acts presynaptically on α2‐adrenoreceptors, to decrease acetylcholine release from vagal terminals and inhibit contraction. Subsets of gallbladder neurons also release inhibitory transmitters such as VIP or nitric oxide (NO). Adapted, with permission, from (188).
Figure 6. Figure 6. Hormonal regulation of gallbladder motor function. In the fasting state, motilin is secreted at the end of phase II of the migrating myoelectric complex and induces weak gallbladder contraction. After ingestion of a meal, CCK is secreted and induces gallbladder emptying. Bile acids are expelled in the small intestine where they facilitate the absorption of fat. In the duodenum, acidification stimulates the production of VIP, which promotes gallbladder relaxation. In the terminal ileum, bile acids enter enterocytes and stimulate via FXR the production of FGF15/19, which signals back to the gallbladder to induce refilling before the next meal. In the gallbladder itself, bile acids act via TGR5 to promote gallbladder relaxation. Thereby, the gallbladder may adapt its volume to increasing concentrations of bile acids during fasting. Adapted and modified, with permission, from (35,190).
Figure 7. Figure 7. Changes in gallbladder motor function in CFTR‐deficient mice. Cystic fibrosis transmembrane CFTR knockout (KO) mice compared with wild type mice, have enlarged gallbladders (upper panels) and delayed gallbladder emptying, attested by 99mTc‐mebrofenin scintigraphy (lower panels). Hepatocytes take up the tracer and then secrete it in bile; after 45 min, the tracer has been secreted into the duodenum in wild type but not CFTR KO mice. Adapted, with permission, from (46).
Figure 8. Figure 8. Fluid transport in the gallbladder in the fasted and fed state. (A) Net water transport was measured in conscious monkeys, showing a shift from absorption in the fasted animals to secretion after feeding (238). (B) Aspect of gallbladder bile obtained by percutaneous transhepatic drainage from a patient, showing a dark color after an overnight fast (left) and a white opalescent color, 2 h after a meal (right) (95). Reproduced, with permission, from (95,238).
Figure 9. Figure 9. Mechanisms and regulation of fluid and ion transport in the gallbladder epithelium. (A) Model of iso‐osmotic fluid absorption across the gallbladder epithelium. Entry of NaCl at apical membrane is mediated by the Na+/H+ and Cl−/HCO3− exchangers, Na+/H+ exchanger of type 3 (NHE3), and anion exchanger of type 2 (AE2), respectively. Sodium enters the cells down an electrochemical gradient generated by the Na+/K+‐ATPase pump, while a KCl cotransporter mediates chloride exit, at basolateral membrane. Water transport occurs passively probably both by paracellular route and through AQPs, in response to the osmotic driving force created by active NaCl transport. (B) Regulation of fluid and bicarbonate secretion in the gallbladder. Cyclic AMP (cAMP) is produced by adenylyl cyclase (AC) and acts via PKA‐mediated phosphorylation (1) to inhibit NHE3, which causes an arrest in fluid absorption, and (2) to stimulate chloride efflux through cystic fibrosis transmembrane CFTR, which drives fluid and bicarbonate secretion. AC enzymes are activated by Gs protein‐coupled receptors, such as the VPAC1 or the membrane‐bound bile acid receptor, TGR5 and they are inhibited by Gi protein‐coupled receptors, such as the endothelin (ET) receptor of type B (ETB). Chloride efflux through CaCCs is stimulated by Ca2+/calmodulin‐dependent protein kinase II (CaM‐kinase II) in response to Gq protein‐coupled receptors, such as the purinergic receptor P2Y2. Bile acids (BAs) entering the cells via the apical ASBT can (i) activate CaCC by the Ca2+/CaM‐kinase II pathway, (ii) potentiate AC activity by PKC activation, (iii) enhance VPAC1 receptor expression by the nuclear FXR.
Figure 10. Figure 10. Model of EBP50 function in the gallbladder epithelium. ERM‐binding phosphoprotein 50 (EBP50) forms a multiprotein complex with ezrin, PKA, Na+/H+ exchanger of type 3 (NHE3) and cystic fibrosis transmembrane CFTR, in the subapical region of gallbladder epithelial cells. Through this complex, EBP50 anchors NHE3 and CFTR to the apical actin cytoskeleton and facilitates their concomitant negative and positive regulations, respectively, by PKA‐mediated phosphorylation. PDZ, postsynaptic density 95/disc‐large/zona occludens.
Figure 11. Figure 11. Transport of lipophilic molecules in the gallbladder. Bile acid absorption can be mediated by the apical ASBT and to a lesser extent, the OATP‐A in the apical domain of the plasma membrane, and by the organic solute transporter α/β (OSTα/β) and ABCC3 (MRP3) in the basolateral domain. Cholesterol absorption can be mediated by the SR‐BI, NPC1L1, and the megalin/cubilin complex in the apical domain of the plasma membrane, and by ABCA1 in the basolateral domain. Cholesterol efflux through ABCG5/ABCG8 and potentially ABCG2 can counterbalance excessive absorption. Drug efflux is mediated by ABCB1 (MDR1). In addition, ABCG2, ABCC2 (MRP2), and ABCC3 (MRP3) transport a number of xenobiotics and endogenous anionic conjugates.
Figure 12. Figure 12. Regulation of mucin secretion in the gallbladder. The expression of MUC genes, at least MUC5AC is upregulated by an EGFR‐dependent pathway, amplified by LPS, and inflammation via COX‐2‐derived prostaglandin E2 (PGE2). Mucus exocytosis is triggered by ATP via P2Y2 receptor and PKC, by bile acids (BA) via Ca2+/calmodulin‐dependent protein kinase II (CaM‐kinase II), and by cholinergic stimulation. ACh, acetylcholine; ASBT, apical sodium‐dependent bile acid transporter; MAPK, mitogen‐activated protein kinase; TLR4, Toll‐like receptor 4.


Figure 1. Embryology of the gallbladder. (A) In the early embryo, liver specification occurs in the posteroventral foregut endoderm (future duodenum) interfacing the septum transversum mesoderm. Endodermal proliferation is then triggered and results in the formation of the hepatic diverticulum. (B) The liver develops from the cranial portion (pars hepatica) of the hepatic diverticulum, while the extrahepatic biliary tract develops from the caudal portion (pars cystica) of the hepatic diverticulum. PDX1‐positive/SOX17‐positive cells in the caudal portion undergo lineage segregation into a PDX1‐positive/SOX17‐negative pancreatic domain, which gives rise to ventral pancreas, and a PDX1‐negative/SOX17‐positive biliary domain, which develops into the gallbladder and extrahepatic bile ducts. The duodenum then rotates to the right. (C) Subsequently, the attachment of the developing common bile duct and pancreatic duct is displaced to its definitive position on the dorsal side of the duodenum, while the dorsal and ventral pancreas merge.


Figure 2. Anatomy of the gallbladder. (A) Frontal view (upper panel) and inferior view (lower panel) of the human liver showing the gallbladder fossa, in which the gallbladder is in direct contact with the liver surface. (B) Representation of the gallbladder and extra‐hepatic biliary tract. The major papilla is formed by the choledochoduodenal and pancreaticoduodenal junctions, in the second portion of the duodenum.


Figure 3. Structure of the gallbladder wall. (A) Standard histological microphotographs of human gallbladder tissue showing the three, that is, mucosal, muscular and serosal, layers of the gallbladder wall (left panel), and the mucosal folds, at low (right upper panel) and high magnification (right lower panel). (B) Transmission electron microscopic view of human gallbladder epithelium, showing columnar, clear (C) or dark (D) cells containing mucus secretory granules in their apical zones (m; large arrows point to electron dense cores), basolateral digitations (d), and basement membrane (bm) (Bar = 2 μm). (C) Scanning electron microscopic views of human gallbladder epithelial suface, showing the numerous apical microvilli of each cell apex finely coated with glycocalyx, producing a blurry effect of their tips (left panel, bar = 1 μm); the crater‐like appearance (open arrows) and mucus clumps (small arrow) on cell apices, following the mucus secretory process (right panel, bar = 10 μm). B and C were reprinted from (177), with permission from Wiley publisher © 1997 Wiley‐Liss, Inc.


Figure 4. Profile of gallbladder emptying. Representative example of gallbladder emptying in a normal volunteer in whom ultrasound measurements of gallbladder volume were made at 1‐min intervals. Reproduced with permission from (92).


Figure 5. Neurogenic regulation of gallbladder motor function. Vagal nerve terminals provide cholinergic preganglionic input to gallbladder neurons. Stimulated gallbladder neurons release acetylcholine (ACh) and tachykinins (TK), which cause smooth muscle contraction via M3 muscarinic and NK2 neurokinin receptors, respectively. CCK acts presynaptically to increase acetylcholine release from vagal terminals onto gallbladder neurons, and likely, also directly on CCK1 high‐affinity receptors present on smooth muscle cells to stimulate contraction. Norepinephrin acts presynaptically on α2‐adrenoreceptors, to decrease acetylcholine release from vagal terminals and inhibit contraction. Subsets of gallbladder neurons also release inhibitory transmitters such as VIP or nitric oxide (NO). Adapted, with permission, from (188).


Figure 6. Hormonal regulation of gallbladder motor function. In the fasting state, motilin is secreted at the end of phase II of the migrating myoelectric complex and induces weak gallbladder contraction. After ingestion of a meal, CCK is secreted and induces gallbladder emptying. Bile acids are expelled in the small intestine where they facilitate the absorption of fat. In the duodenum, acidification stimulates the production of VIP, which promotes gallbladder relaxation. In the terminal ileum, bile acids enter enterocytes and stimulate via FXR the production of FGF15/19, which signals back to the gallbladder to induce refilling before the next meal. In the gallbladder itself, bile acids act via TGR5 to promote gallbladder relaxation. Thereby, the gallbladder may adapt its volume to increasing concentrations of bile acids during fasting. Adapted and modified, with permission, from (35,190).


Figure 7. Changes in gallbladder motor function in CFTR‐deficient mice. Cystic fibrosis transmembrane CFTR knockout (KO) mice compared with wild type mice, have enlarged gallbladders (upper panels) and delayed gallbladder emptying, attested by 99mTc‐mebrofenin scintigraphy (lower panels). Hepatocytes take up the tracer and then secrete it in bile; after 45 min, the tracer has been secreted into the duodenum in wild type but not CFTR KO mice. Adapted, with permission, from (46).


Figure 8. Fluid transport in the gallbladder in the fasted and fed state. (A) Net water transport was measured in conscious monkeys, showing a shift from absorption in the fasted animals to secretion after feeding (238). (B) Aspect of gallbladder bile obtained by percutaneous transhepatic drainage from a patient, showing a dark color after an overnight fast (left) and a white opalescent color, 2 h after a meal (right) (95). Reproduced, with permission, from (95,238).


Figure 9. Mechanisms and regulation of fluid and ion transport in the gallbladder epithelium. (A) Model of iso‐osmotic fluid absorption across the gallbladder epithelium. Entry of NaCl at apical membrane is mediated by the Na+/H+ and Cl−/HCO3− exchangers, Na+/H+ exchanger of type 3 (NHE3), and anion exchanger of type 2 (AE2), respectively. Sodium enters the cells down an electrochemical gradient generated by the Na+/K+‐ATPase pump, while a KCl cotransporter mediates chloride exit, at basolateral membrane. Water transport occurs passively probably both by paracellular route and through AQPs, in response to the osmotic driving force created by active NaCl transport. (B) Regulation of fluid and bicarbonate secretion in the gallbladder. Cyclic AMP (cAMP) is produced by adenylyl cyclase (AC) and acts via PKA‐mediated phosphorylation (1) to inhibit NHE3, which causes an arrest in fluid absorption, and (2) to stimulate chloride efflux through cystic fibrosis transmembrane CFTR, which drives fluid and bicarbonate secretion. AC enzymes are activated by Gs protein‐coupled receptors, such as the VPAC1 or the membrane‐bound bile acid receptor, TGR5 and they are inhibited by Gi protein‐coupled receptors, such as the endothelin (ET) receptor of type B (ETB). Chloride efflux through CaCCs is stimulated by Ca2+/calmodulin‐dependent protein kinase II (CaM‐kinase II) in response to Gq protein‐coupled receptors, such as the purinergic receptor P2Y2. Bile acids (BAs) entering the cells via the apical ASBT can (i) activate CaCC by the Ca2+/CaM‐kinase II pathway, (ii) potentiate AC activity by PKC activation, (iii) enhance VPAC1 receptor expression by the nuclear FXR.


Figure 10. Model of EBP50 function in the gallbladder epithelium. ERM‐binding phosphoprotein 50 (EBP50) forms a multiprotein complex with ezrin, PKA, Na+/H+ exchanger of type 3 (NHE3) and cystic fibrosis transmembrane CFTR, in the subapical region of gallbladder epithelial cells. Through this complex, EBP50 anchors NHE3 and CFTR to the apical actin cytoskeleton and facilitates their concomitant negative and positive regulations, respectively, by PKA‐mediated phosphorylation. PDZ, postsynaptic density 95/disc‐large/zona occludens.


Figure 11. Transport of lipophilic molecules in the gallbladder. Bile acid absorption can be mediated by the apical ASBT and to a lesser extent, the OATP‐A in the apical domain of the plasma membrane, and by the organic solute transporter α/β (OSTα/β) and ABCC3 (MRP3) in the basolateral domain. Cholesterol absorption can be mediated by the SR‐BI, NPC1L1, and the megalin/cubilin complex in the apical domain of the plasma membrane, and by ABCA1 in the basolateral domain. Cholesterol efflux through ABCG5/ABCG8 and potentially ABCG2 can counterbalance excessive absorption. Drug efflux is mediated by ABCB1 (MDR1). In addition, ABCG2, ABCC2 (MRP2), and ABCC3 (MRP3) transport a number of xenobiotics and endogenous anionic conjugates.


Figure 12. Regulation of mucin secretion in the gallbladder. The expression of MUC genes, at least MUC5AC is upregulated by an EGFR‐dependent pathway, amplified by LPS, and inflammation via COX‐2‐derived prostaglandin E2 (PGE2). Mucus exocytosis is triggered by ATP via P2Y2 receptor and PKC, by bile acids (BA) via Ca2+/calmodulin‐dependent protein kinase II (CaM‐kinase II), and by cholinergic stimulation. ACh, acetylcholine; ASBT, apical sodium‐dependent bile acid transporter; MAPK, mitogen‐activated protein kinase; TLR4, Toll‐like receptor 4.
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Article Title: Functions of the Gallbladder
 

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Chantal Housset, Yves Chrétien, Dominique Debray, Nicolas Chignard. Functions of the Gallbladder. Compr Physiol 2016, 6: 1549-1577. doi: 10.1002/cphy.c150050