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Intrahepatic Cholestasis
Molecular Physiology of Bile Formation and Secretion
Bile is ubiquitous to almost all known vertebrate species. It is a complex aqueous but lipid rich solution composed of water, electrolytes, and a number of organic molecules including bile acids, cholesterol, bile pigments (eg, bilirubin), and phospholipids. Bile is produced by the liver and flows through the biliary tract into the small intestine where bile acids are absorbed to be resecreted by the liver. Bile has a number of important functions: (1) it supplies bile salts that are essential for emulsification and micelle formation required for dietary fat absorption in the intestine; (2) it provides bicarbonate for neutralizing gastric acid; and (3) it serves as a means of elimination of cholesterol and highly protein-bound organic molecules, heavy metals, and lipophilic drug metabolites that are not readily filtered by the kidneys.
The function, secretion, and enterohepatic circulation of bile has been studied since ancient times. The word bile is derived from the Latin word bilis combining bi (meaning double) and lis (meaning contention) that referred to two of the four fundamental humors, yellow and black bile, imbalances of which were considered the basis of disease. Current understanding of this fundamental body “humor” extends to the intricate structurally and genetically defined canalicular transporters and metabolic regulators that have elucidated the physiologic mechanisms of hepatocyte polarity as well as the pathologic basis of cholestatic disorders, potentially paving the way for novel therapeutic options.
Transporter Proteins
Hepatic bile flow may be considered in two phases: secretion of bile by hepatocytes and modification of bile by bile duct epithelium. Bile formation by hepatocytes involves the active transport of bile salts, phospholipids, cholesterol, and other organic solutes from the sinusoidal blood into the biliary canaliculi. This vectorial movement of organic solutes occurs against a concentration gradient and is mediated by active transporters ( Fig. 29A.1 ). Structural, functional, and genetic characterization of many of these transporters has led to a major advance in the understanding of not only bile physiology but of several forms of inherited and drug-induced cholestatic diseases. Hepatocyte polarity is established by the differing functions of these transporters and their targeting and localization on either the sinusoidal (basolateral) or canalicular (apical) membrane of hepatocytes, separated by the tight junctions with adjoining hepatocytes ( Fig. 29A.2 ).
In health, these tight junctions are impermeable to organic anions, and have limited permeability to organic cations. The tight junctions both define and limit the canalicular space between the apical membranes of two adjoining hepatocytes. Given the hexagonal shape of hepatocytes, the canaliculi of adjacent hepatocytes interconnect to form a mesh-like three-dimensional network with a “chicken-wire” appearance ( Fig. 29A.3 ). Within the functional lobular unit of the liver, canalicular bile flows toward the portal tracts, countercurrent to sinusoidal blood flow across the cords of hepatocytes, which flows toward terminal hepatic venules. In cholestatic disease, tight junctions become more permeable to organic anions, allowing them to pass along their concentration gradient from bile to the space of Disse. A physiologic organization of hepatocytes that is best considered in this view of the bile secretory unit is that of hepatocyte zonation. It refers to differing metabolic roles and capacities of periportal (zone 1) and pericentral (zone 3) hepatocytes. In rodent studies, hepatocytes differ in their capacity to eliminate bile salts and organic anions, examples of which are described in the discussion of individual transporters.
Basolateral (Sinusoidal) Membrane Transporters
Hepatic uptake of organic solutes from the substrate rich portal blood is facilitated by transport systems located on the basolateral membrane. These can be divided into sodium (Na + )-dependent and Na + -independent transport systems. Central to Na + -dependent systems is the ATP-dependent sodium/potassium (K + ) pump (Na + /K + -ATPase), which is localized at the sinusoidal membrane and continually expels intracellular Na + in exchange for K + . This Na + /K + -ATPase maintains an inwardly directed Na + gradient, and in conjunction with outward K + movement through a K + channel, maintains an intracellular negative electrical gradient. The Na + -dependent transporter responsible for the majority of bile salt uptake is a Na + /taurocholate cotransporting polypeptide (NTCP encoded by SLC10A1 ). a
a The nomenclature of transporters has evolved, and the latest nomenclature is referenced in this chapter. Human proteins are written in capital letters, whereas the corresponding genes are listed in italicized capital letters.
NTCP is a member of the solute carrier superfamily, and is localized exclusively to the basolateral membrane of all hepatocytes. Because of the high affinity of NTCP for conjugated bile salts, their uptake is very efficient and, in the fasting state, occurs predominantly in periportal hepatocytes, when the portal blood concentration of bile salts is relatively low. However, in the postprandial state, when intestinal and hence portal bile salt concentration increases, pericentral hepatocytes are enlisted in bile salt uptake. The cellular and membrane location, substrates, genetic diseases, and pharmacogenomics of NTCP and other transporters involved in bile secretion and enterohepatic circulation are collated in Table 29A.1 .
Table 29A.1
Human Transporters Associated With Bile Secretion and Enterohepatic Circulation
| Common (Protein or Gene) Name | Cellular and Membrane Localization | Substrates | Diseases or Phenotypes Associated With Genetic Defects | Role of Polymorphisms in Drug Metabolism and Drug-Induced Liver Injury |
|---|---|---|---|---|
| NTCP | Hepatocyte—basolateral | Bile salts | None defined, but isolated case of associated asymptomatic but extreme bile acid elevation in a child | Possible pharmacogenomic effects of polymorphism on rosuvastatin pharmacokinetics. Probably ursodeoxycholic acid. It is inhibited by cholestatic drugs (rifampicin, rifamycin SV, glibenclamide, and cyclosporine A) in vitro. |
| OATP1B1 a | Hepatocyte—basolateral | Bile salts Organic anions Organic cations |
None defined, but downregulation correlates with hyperbilirubinemia in advanced cholestasis | Transport of a number of drugs is affected by polymorphisms (eg, multiple statins, fexofenadine, repaglinide, caspofungin). It is inhibited by clinically relevant concentrations of gemfibrozil in vitro. |
| OATP1B3 a | Hepatocyte—basolateral | Bile salts Organic anions Organic cations |
None defined | None defined, but may have a role in response of endometrial cancer to paclitaxel and carboplatin. |
| OATP1A2 a | Hepatocyte—basolateral | Bile salts Organic anions Organic cations |
None defined | Polymorphisms influence transport of estrone 3-sulfate. The transporter has many drugs as substrates. |
| OCT1 | Hepatocyte—basolateral | Small organic cations (type II) | None defined | Polymorphism is associated with altered pharmacokinetics of metformin, and may be relevant to antiretroviral pharmacokinetics and drug-drug interactions. |
| BSEP | Hepatocyte—apical | Bile salts | PFIC type 2, BRIC type 2, ICP (potential role) |
Polymorphisms are associated with drug induced cholestasis. |
| MDR1 | Hepatocyte—apical Cholangiocyte—apical Enterocyte—apical |
Hydrophobic drugs and toxins (including type II origin cations) | None defined | Polymorphisms are associated with phenotypic variability in the pharmacokinetics of cardiac glycosides, calcineurin inhibitors, antiretroviral drugs, and tricyclic antidepressants. |
| MDR3 | Hepatocyte—apical | Phosphatidylcholine | PFIC type 3 ICP Intrahepatic cholelithiasis Potential association of haplotypes with progression of primary biliary cholangitis |
Mutations are associated with increased risk of drug induced cholestasis. |
| MRP2 | Hepatocyte—apical Cholangiocyte—apical Enterocyte—apical |
Conjugated endogenous and exogenous organic anions | Dubin-Johnson syndrome | Polymorphisms and haplotypes are associated with susceptibility to herbal and drug hepatotoxicity. Polymorphisms are associated with cancer drug resistance. |
| MRP3 | Hepatocyte—basolateral Cholangiocyte—basolateral |
Conjugated endogenous and exogenous organic anions | None defined | Polymorphisms are associated with cancer drug resistance. |
| MRP4 | Hepatocyte—basolateral | Conjugated endogenous and exogenous organic anions Higher affinity for conjugated bile salts than MRP3 |
None defined | Polymorphisms are associated with outcome in childhood acute lymphoblastic anemia and disposition of methotrexate. Polymorphisms may also influence thiopurine sensitivity. |
| AE2 | Hepatocyte—apical Cholangiocyte—apical |
Chloride/Bicarbonate | Allelic variation may influence the progression of primary biliary cholangitis under ursodeoxycholic acid treatment | None known. |
| ATP7B | Hepatic—intracellular | Copper | Wilson disease | May contribute to cisplatin resistance in ovarian cancer in vitro. |
| ABCA1 | Hepatocyte—basolateral Enterocyte—basolateral |
Cholesterol | High-density lipoprotein deficiency (Tangier disease) | Candidate target for pharmacologic upregulation to increase HDL levels, but has no defined effect on drug metabolism. |
| ABCG5/ABCG8 | Cholangiocyte—apical Enterocyte—apical |
Plant sterols | Sitosterolemia | They are the drug targets of ezetimibe, but have no defined effect on drug metabolism. |
| Aquaporins b | Hepatocyte—apical and basolateral Cholangiocyte—apical and basolateral |
Water In some cases small uncharged molecules, ammonia, urea |
None defined | None known, but defective expression and canalicular membrane permeability are described in animal models of bile duct ligation, estrogen and lipopolysaccharide-induced cholestasis. |
| CFTR | Cholangiocyte—apical | Chloride | Cystic fibrosis | The mechanism of enhanced clearance of some drugs in cystic fibrosis is unclear, but may be related to variability in both drug metabolism and transporter activity. |
| ASBT | Cholangiocyte—apical Enterocyte—apical |
Bile salts | Diminished intestinal bile acid absorption (bile salt diarrhea) | None defined |
| OSTalpha/beta | Enterocyte—basolateral | Bile salts | None defined | None defined |
This table is a collation of the cellular localization of transporters associated with bile secretion and enterohepatic circulation in humans, and the disease states or clinical phenotypes associated with their genetic defects when known. The roles of these transporters in drug disposition or relationship to drug-induced liver injury are highlighted. Transporter protein function and membrane localization are both influenced by polymorphisms, and regulation of function occurs at both the transcriptional and posttranscriptional stages.
ABCA1, ATP-binding cassette transporter; ASBT, apical sodium-dependent bile acid transporter; BRIC, benign recurring intrahepatic cholestasis; BSEP , bile salt export pump; CFTR , cystic fibrosis transmembrane conductance regulator; HDL , high-density lipoproteins; ICP, intrahepatic cholestasis of pregnancy; MDR, multidrug resistance; MRP , multidrug resistance–associated protein; NTCP, sodium/taurocholate cotransporting polypeptide; OATP , organic anion transporting polypeptide; OCT, organic cation transporter; PFIC, progressive familial intrahepatic cholestasis.
a The OATP transporters have overlapping drugs as substrates.
The remaining fraction of bile salts and other organic anions are taken up by Na + -independent transport. Although many organic anion transporter polypeptides (OATP; SLC21A ) have wide tissue diversity and broad substrate specificity, some have high substrate specificity and exhibit unique cellular expression in distinct organs. Substrate preferences of OATP transporters in human hepatocytes generally overlap, and include conjugated and unconjugated bile salts, organic anions and cations, and numerous drugs (eg, statins, cardiac glycosides, and anticancer agents). OATP1B1; SLC21A6 (also known as OATP2 or OATP-C) is probably the predominant basolateral Na + -independent bile salt uptake and bilirubin transporter in the human liver. It is hepatocyte specific, as is OATP1B3; SLC21A8 (OATP8), a unique transporter of digoxin along with other overlapping substrates. OATP1A2; SLC21A3 (OATP-A), transports a wide range of amphipathic organic anions as well as large organic cations. Polymorphisms of these transporter genes affect their in vitro activity and have been implicated in altered pharmacokinetics of a number of drugs; for example, increased plasma levels of pravastatin with T521C polymorphism of OATP1B1. This is most relevant for drugs with a narrow therapeutic window such as anticancer drugs, and plays a role in drug-drug interactions at the level of hepatocyte uptake.
Although hepatic uptake of large organic cations is mediated by OATP1A2, the uptake of smaller organic cations, also referred to as type I cations, is mediated by the five-member family of organic cation transporters (OCT; SLC22A ). In humans, OCT1 is expressed predominantly in liver, but also in kidneys, and its genetic polymorphism is associated with altered pharmacokinetics of metformin, and may be relevant to antiretroviral drug interactions and pharmacokinetics.
Apical (Canalicular) Membrane Transporters
Hepatocyte bile flow is largely determined by bile salt-dependent flow and bile salt-independent flow, which drive the osmotic diffusion of water and small solutes into bile. Bile salt-dependent flow, as the name implies, is determined by the active transport of bile salts into the canalicular space. Bile salt-independent flow is determined mainly by the active transport of glutathione, and to a lesser extent, of bicarbonate into the canalicular space. Other transporters are responsible for the excretion of cholesterol and phospholipids.
The transporters responsible for bile formation are located on the canalicular membrane of hepatocytes. Their function requires significant energy expenditure in the form of ATP and most transporters belong to the ATP-binding cassette (ABC) transporter superfamily. The first recognized transporter mediated drug resistance in cancer cells by transporting anticancer drugs out of the cells. These transporters are commonly referred to as multidrug resistance (MDR) and multidrug resistance–associated proteins (MRP).
Similar to OATP, these transporters are also found in diverse nonhepatic tissues, and regulate transport in the blood brain barrier, renal tubules, and enterocytes. Those relevant to bile secretion, associated lipid metabolism, and pharmacogenomics are located on the apical or basolateral surfaces of hepatocytes, cholangiocytes, and enterocytes. The ABC superfamily has four important subclusters, labeled A, B, C, and D. The ABCB subcluster includes the bile salt export pump (BSEP) and the MDR proteins, also known as P-glycoproteins. The ABCC subcluster includes the MRP proteins.
Bile Salt Export Pump (ABCB11)
Monovalent bile salts are exported across the canalicular membrane by the bile salt export pump (BSEP), and they represent the transporter’s main endogenous substrate. Consequently, BSEP is a major determinant of bile salt-dependent bile flow. Genetic BSEP mutations are associated with variable presentations of cholestasis including progressive familial intrahepatic cholestasis (PFIC) type 2, benign recurrent intrahepatic cholestasis (BRIC) type 2 ( eSlide 29B.2, eSlide 29B.3 ), and intrahepatic cholestasis of pregnancy. These and other genetic causes of cholestasis are discussed in more detail in Chapter 29B . Polymorphisms can lead to variable degrees of BSEP dysfunction, which may predispose to drug-induced cholestasis.
Multidrug Resistance 1 (ABCB1)
The first recognized hepatic canalicular transporter, multidrug resistance 1 (MDR1) or P-glycoprotein, is found on the apical membrane of hepatocytes and enterocytes. Its substrates include endogenous metabolites and toxins, and lipophilic drugs, including large amphipathic cationic (type II) drugs such as verapamil. Although MDR1 does not transport bile salts, it is upregulated in a number of liver injury models, and therefore may play a hepatoprotective role by exporting hydrophobic toxins into bile. Polymorphisms in MDR1 are associated with phenotypic variability in the pharmacokinetics of cardiac glycosides, calcineurin inhibitors, antiretroviral drugs, and tricyclic antidepressants.
Multidrug Resistance 3 Phospholipid Transporter (ABCB4)
Phospholipids are an important component of mixed micelles in bile. MDR3 acts as a phospholipid flippase, transporting phosphatidylcholine from the inner to the outer lipid layer of the canalicular membrane, where it is extracted by the detergent effect of bile salts to form vesicles or mixed micelles. These micelles are in turn essential for solubilizing cholesterol and other biliary lipids. This represents an important, though not exclusive, mechanism for cholesterol biliary secretion and elimination. In addition, by sequestering bile salts into micelles, phospholipids protect the canalicular membrane from their detergent action. Structural factors of the apical membrane can accentuate this vulnerability. Mutation of the ABCB4 (MDR3) gene is associated with increased bile salt to phospholipid ratio in bile, giving rise to PFIC-3 (see eSlide 29B.4 ). MDR3 mutations are also associated with intrahepatic gallstones, cholestasis of pregnancy, and drug-induced cholestasis. The inability to flip phosphatidylserine underlies PFIC-1 ( eSlide 29B.1 ) and BRIC-1.
Multidrug Resistance 2 (ABCC2)
MRP2 transports a wide range of conjugated endogenous and exogenous organic anions, into bile. It also transports glutathione, which drives bile salt-independent bile flow, into the biliary canaliculus. Endogenous substrates of this transporter include conjugates of bilirubin, glutathione, leukotrienes, heavy metals, and sulfated or glucuronidated divalent bile salts. Exogenous substrates include drug conjugates, antibiotics, and other compounds. MRP2 is also found on the brush-border/basolateral membrane of enterocytes, further impacting drug absorption and disposition. MRP2 polymorphisms and associated haplotypes have been associated with varying degrees of susceptibility to herbal and drug hepatotoxicity. MRP2 is genetically deficient in Dubin-Johnson syndrome ( eSlide 29B.5 ) and is associated with conjugated hyperbilirubinemia.
Hepatic Basolateral ABC-Transporter Proteins
These are inducible transporters, which are only weakly expressed on the basolateral membrane of hepatocytes under normal conditions. Although these transporters do not form bile, they play a hepatoprotective role by exporting organic anions and bile salts into the space of Disse when the canalicular transport of these substrates is overwhelmed. Similar to MRP2, MRP3 has a high affinity for glucuronide and glutathione conjugated metabolites and is upregulated by lipopolysaccharides and cytokines (ie, under conditions of stress). Not surprisingly the two transporters share the same nuclear hormone receptors that activate their transcription. MRP4 has a higher affinity for conjugated bile salts than MRP3, and is the main mechanism preventing the buildup of excess intracellular bile salts.
Electroneutral Anion Exchanger
The chloride/bicarbonate anion exchanger (AE2: SLC4A2 ) on the canalicular membrane of hepatocytes, exports bicarbonate into bile in exchange for chloride. This serves to both regulate intracellular pH, and by virtue of excreting bicarbonate, to drive bile salt-independent bile flow.
Other Hepatocyte Transporters
A number of other transporters, referred to here by their common gene nomenclature, facilitate the biliary excretion of specific substances. ATP7B, an intracellular transporter of copper, is defective in Wilson disease. ABCA1 transports cholesterol and, when defective, results in high–density lipoprotein deficiency. ABCG5 and ABCG8 transport plant sterols and, when defective, cause sitosterolemia.
The transcellular transport of water in response to osmotic gradients is integral to bile formation and depends on the expression of aquaporins or water-carrying channels. Diminished hepatocyte and cholangiocyte membrane aquaporin protein has been described in rodent models of cholestatic disease, although a pathophysiologic role in hepatobiliary disease is not yet defined. The intracellular transport of organic solutes may be achieved by a number of diffusion mechanisms as in the case of hydrophilic conjugated bile acids, or by vesicular transcytosis as in the case of large organic solutes. In addition, transporters require appropriate vesicular transport and dynamic localization within hepatocytes for coordinated function. The disruption of vesicular transport therefore may represent an additional mechanism of cholestasis.
The coordinated action of these transporters is necessary for bile formation. In many cases, they are regulated by their substrates, which are ligands for the nuclear hormone receptors that regulate their transcription. The role of transporters in health and disease provides a molecular basis for cholestatic disease.
Bile Acids
Although bile is isoosmotic relative to plasma, it contains high concentrations of bile acids, also referred to as bile salts, which constitute the major functional component of bile. Human bile acids are a family of molecules that have a steroid nucleus and share a root 24 carbon atom structure, thought to be chenodeoxycholic acid. They are the end products of cholesterol metabolism, and possess amphipathic properties related to hydrophilic (hydroxyl group and carboxylic side chains on the concave side) and hydrophobic (methyl groups on the convex side) moieties on opposite planes of wedge-shaped molecules with a negative end charge. Under physiologic conditions in bile, they are almost completely conjugated with glycine or taurine, which increases their water solubility. In concentrations above the critical micellar concentration, they solubilize lipid layers and wedge themselves between fatty acid molecules to form simple spherical micelles. This accounts for the detergent properties of bile. Bile acids are essential to the formation of both bile and intestinal micelles, which are mixed predominantly with phosphatidylcholine/cholesterol and monoglycerides/partly ionized fatty acids, respectively. These mixed micelles allow for the transport of insoluble cholesterol from the liver to the intestine, and the transport of digested fats within the intestine to enterocytes for absorption.
Bile acids are synthesized from cholesterol metabolism, via two main pathways referred to as the “classical” and “alternative” pathways. In humans, the classical or neutral pathway accounts for 90% of bile acid synthesis, mainly the primary bile acids, cholic acid, and chenodeoxycholic acid. The rate limiting step of this pathway is a microsomal cytochrome P450 enzyme that hydroxylates cholesterol (CYP7A1) and is localized exclusively to the liver. The final step in bile acid synthesis involves conjugation of both newly formed and recycled bile acids, which occurs predominantly in peroxisomes. Bile acid synthesis is self-regulated by negative feedback mediated by the action of bile acids on nuclear factor farnesoid X receptor (FXR) in hepatocytes and fibroblast growth factor 19 (FGF19) from ileal enterocytes.
Bile Acid Functions
In addition to digestive functions, lipid metabolism, and molecular signaling, bile acids have regulatory effects on bile flow, hepatocyte cellular function, and regeneration. In the colon, bile salts promote propulsive motility and in higher concentration induce secretion. An antimicrobial effect in the intestine has been reported and may limit bacterial overgrowth. On a cellular level, bile acids can induce reactive oxygen and nitrogen species, deoxyribonucleic acid (DNA) damage, and apoptosis. Their accumulation within hepatocytes initiates ligand-dependent and/or ligand-independent death-receptor oligomerization and modulates these signaling pathways, resulting in a strong sensitization of hepatocytes to death receptor-mediated apoptosis. The functions of bile acids at various stages of the enterohepatic circulation are described schematically in Fig. 29A.4 .
Bile Acid Signaling
Polymorphisms in FXR are increasingly recognized in association with variation in inflammatory bowel disease, and glucose and fatty acid metabolism. These findings underscore the critical role of bile acid signaling in the regulation of glucose and energy metabolism, and underlie novel therapeutics for associated conditions such as nonalcoholic fatty liver disease. Activation of FXR by obeticholic acid, a semisynthetic bile acid derivative, has shown promise in the treatment of nonalcoholic steatohepatitis. Intestinal FXR agonists may reduce to insulin resistance and obesity, and dual FXR and G protein-coupled receptor TGR5 agonists may attenuate fatty liver disease, circulating lipids and inflammation.
Enterohepatic Circulation of Bile
The enterohepatic circulation is intrinsically linked to bile acid synthesis, with important implications in liver and intestinal pathology and pharmacology. Adult humans produce approximately 600 to 1200 ml of bile per day. In a two-stage process, bile is initially secreted by hepatocytes into the biliary canaliculi. This active transport of bile salts and other organic solutes from the hepatic circulation into the biliary canaliculi occurs against a concentration gradient and results in a 1000-fold concentration within these structures. As bile flows through the biliary system, it is modified by both secretion and/or absorption of water, nutrients, electrolytes, and bicarbonate by ductal epithelial cells. In addition, some of the secreted bile salts are taken up by cholangiocytes and then are delivered back to hepatocytes via the peribiliary plexus for resecretion into bile and this process is referred to as cholehepatic shunting. Although the function of this cholehepatic shunting is not entirely clear, it is thought to provide some feedback function on bile metabolism, and may contribute to the hypercholeresis seen with ursodeoxycholic acid treatment used for cholestatic liver diseases.
In the fasting state bile is stored in the gallbladder, where lining epithelia add mucin and reabsorb fluids leading to further concentration and increased viscosity. In the postprandial state gallbladder contraction delivers bile to the small intestine, where bile acids and bicarbonate aid in digestion and fat absorption. Bile acids also undergo biotransformation because of the action of microbes, through deconjugation or oxidation of the hydroxyl group in the small intestine, and additionally through dehydroxylation by anaerobic microbes in the colon. However, the efficient absorption of conjugated primary bile salts, especially by active transport in the distal ileum, results in a smaller fraction (10%) of bile salts reaching the colon and undergoing dehydroxylation to secondary bile acids (mainly lithocholic and deoxycholic acid). These are relatively more toxic bile acids, and undergo passive absorption along with the other remaining bile acids in the colon. These physiologic mechanisms contribute to the low fraction of secreted bile acids being lost in feces (1% to 3%), and determine the composition of primary and secondary bile acids in the bile acid pool. Reabsorbed bile salts are delivered by portal flow back to the liver, where efficient hepatic extraction of bile acids by hepatocytes completes the enterohepatic circulation, thus maintaining the bile acid pool.
The total bile salt pool in adult humans is 50 to 60 mmol/kg of body weight (corresponding to 3 to 4 grams). It circulates 6 to 10 times per day and results in daily bile salt secretion of 20 to 40 grams. Despite a high degree of intestinal absorption, 0.5 gram of bile salts are lost through fecal excretion, which corresponds to the daily compensatory hepatic de novo bile salt synthesis.
Cholangiocyte Modification of Bile
In linking the small interlobular bile ducts to the common bile duct, the tributaries of the biliary system join into ducts of increasing size, with an associated increase in the size of the lining cholangiocytes. These cholangiocytes are also heterogeneous in expression of receptors and functions. Similar to hepatocytes, cholangiocytes are polarized epithelial cells and dynamic participants in liver function. They modify bile in response to both enteric and hepatic stimuli, predominantly by secreting bicarbonate and water, and reabsorbing glucose, amino acids, and some bile acids. Meals stimulate duodenal production of secretin, which stimulates intracellular adenosine 3’,5’-cyclic monophosphate (cAMP) of medium and large bile duct cholangiocytes via secretin receptors expressed on their basolateral membrane. This increase in intracellular cAMP level leads to activation of cAMP-dependent chloride secretion by CFTR (cystic fibrosis transmembrane conductance regulator) on the apical membrane into bile. This in turn drives apical bicarbonate transport into bile in exchange for chloride by AE2, similar to biliary bicarbonate secretion in hepatocytes. The resultant cholangiocyte depolarization leads to increased basolateral bicarbonate cotransport with sodium, which compensates for the apical bicarbonate secretion. The vesicular transport of AE2 and aquaporins for insertion and colocalization with CFTR in apical membranes of cholangiocytes also appears to be cAMP responsive. Impaired CFTR mediated hydrochloresis of bile occurs in cystic fibrosis and primary biliary cholangitis Additional apical chloride channels responsive to biliary calcium, sensed by cholangiocyte cilia or stimulated by other secretagogues, provide alternative means of chloride secretion. This highlights an increasingly recognized role of calcium in intercellular signaling and apoptosis and its involvement in biliary diseases.
Bile salts also appear to influence cholangiocyte intracellular pathways mediated by calcium and protein kinases. This influence extends to bile salt targeting of cholangiocyte gene expression, proliferation, secretion, and survival. A limited proportion of certain bile salts are reabsorbed into cholangiocytes, by the apical sodium-dependent bile acid cotransporter (ASBT), which is also regulated in part by biliary bile salt concentrations. Reabsorbed bile acids, mainly taurocholate, are conjugated and transported by a number of basolateral transporters into the periductular capillary plexus and returned directly to hepatocytes, the result being cholehepatic shunting of bile acids. This pathway amplifies the canalicular osmotic effects of bile acids, and may contribute to adaptation in chronic cholestasis because of extrahepatic obstruction.
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