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Abstract

  1. Top of page
  2. Abstract
  3. Molecular Physiology of AQPs
  4. Expression, Cellular Localization, and Physiological Significance of AQPs in the Hepatobiliary System
  5. Pathophysiology of AQP-Mediated Water Transport in the Hepatobiliary System
  6. Concluding Remarks
  7. References

The review focuses on the potential physiological and pathophysiological roles of aquaporins (AQPs), a family of water channel proteins, in the hepatobiliary system. Among 13 aquaporins (AQP0-AQP12) cloned in mammals, seven AQPs have been identified in the liver and biliary tree. Accumulating evidence suggests that AQPs are likely involved in canalicular and ductal bile secretion, gluconeogenesis and microbial infection and may have other novel roles that affect liver function. (Hepatology 2006;43:S75–S81.)

Aquaporins (AQPs) are integral membrane channel proteins that facilitate rapid passive movement of water. They belong to the broad superfamily (i.e., more than 450 members) of the major intrinsic protein (MIP) transmembrane channels, which are found in eubacteria, archaea, fungi, protozoa, plants, and animals.1–6 The term AQPs initially referred to the MIP channels that selectively facilitate water transport across cell membranes, currently it is used in a broader sense to include the MIP channels that, in addition to water, facilitate transmembrane transport of glycerol, urea, and, in special cases, CO2, ammonia, nitrate, Cl, carbamides, purines, pyrimidines, polyols, and arsenite.1, 3, 4, 7–9

AQP1, the first water channel, was discovered in 1989-1991 in human red cells by Peter Agre, who was awarded the 2003 Nobel Prize in Chemistry in recognition of this seminal discovery. To date, 13 AQPs (i.e., AQP 0-12) have been found in mammals, with a large number (i.e., AQP0, AQP1, AQP4, AQP5, AQP8, AQP9, AQP11) being localized to the hepatobiliary system.10–18

The biological significance of mammalian AQPs in kidney, lung, salivary glands, and eye, organs in which water movement is key for normal functions, as well as their potential roles in selected non–fluid-transporting tissues (e.g., epidermis and adipose tissue) is well accepted.1, 3, 5, 6 In contrast, the role of AQPs in hepatobiliary physiology is a topic of only recent interest. However, given that one of the key functions of the hepatobiliary system is bile formation, and that bile consists of more than 98% water, the involvement of AQPs in bile formation seems likely.10–18

Bile formation is initiated by hepatocytes and is modified by secretory and absorptive processes in the epithelial cells lining the lumen of intrahepatic bile ducts (i.e., cholangiocytes) and gallbladder. Hepatocytes secrete osmotically active substances, primarily bile salts and glutathione, into the canaliculus, resulting in the establishment of osmotic gradients that may generate the passive entry of water via a transcellular, presumably AQP-mediated pathway.10–13

Whereas cholangiocytes account for only 3% to 5% of the liver cell population, they nevertheless play a significant role in bile formation, producing as much as 40% of total bile volume. Analogous to hepatocytes, cholangiocytes establish osmotic gradients by the secretion of ions, primarily Cl and HCO3, and by the absorption of solutes, primarily bile salts and glucose, processes that in turn may drive passive transcellular AQP-mediated movement of water.10–12 Final modification of bile in the gallbladder is mainly the result of the active transport of Na+, Cl, and HCO3, and the passive, presumably AQP-mediated transport of water.15 AQPs are also involved in transport of small solutes (e.g., glycerol) across the hepatocyte basolateral plasma membrane16, 17 and may transport water across the membranes of intracellular organelles.18

In this review, we focus on the molecular physiology of AQPs, their expression, distribution, subcellular localization, and potential physiological and pathophysiological significance in the epithelial cells of the hepatobiliary system.

Molecular Physiology of AQPs

  1. Top of page
  2. Abstract
  3. Molecular Physiology of AQPs
  4. Expression, Cellular Localization, and Physiological Significance of AQPs in the Hepatobiliary System
  5. Pathophysiology of AQP-Mediated Water Transport in the Hepatobiliary System
  6. Concluding Remarks
  7. References

Structure of AQPs.

AQPs are small (25-34 kd), hydrophobic proteins consisting of 6 transmembrane domains with 5 connecting loops (A-E) and with cytoplasmically oriented amino and carboxy termini.1 Connecting loops B (cytoplasmic) and E (extracellular) contain NPA boxes; each of them represents the signature asparagine-proline-alanine motif conserved among family members (Fig. 1A-B). NPA boxes form a single aqueous pathway within a symmetrical structure that resembles an hourglass.1, 19 The water channel itself consists of extracellular and cytoplasmic vestibules connected by an extended narrow pore or selectivity filter with a diameter of 2.8 Å, a width sufficient to allow passage of water molecules in single file in either direction.20, 21 In the plasma membrane, AQPs are assembled as homotetramers that contain 4 single water channels (Fig. 1C).

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Figure 1. Molecular organization of AQPs. (A-B) Topology of a single AQP monomer. Each AQP monomer consists of six transmembrane domains (numbered 1-6) connected by five loops (A-E). Connecting lops B (intracellular) and E (extracellular) contain NPA boxes that form a single aqueous pore by folding into membrane. The arrow shows that water can move through the channel in both directions. (C) Four AQP monomers assembled in the membrane into a tetramer are shown from above. The aqueous pore does not reside in the center of the tetramer. Instead, each tetramer contains four aqueous pores formed by connecting loops B and E of each monomer. Asterisks denote the location of the water pore in each AQP monomer (Modified and reproduced from references 1, 12, with permission of Eurakah.com, and by Nature [www.nature.com]). AQP, aquaporin.

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Transporting Abilities of AQPs.

Mammalian AQPs are divided into 2 main groups (orthodox AQPs and aquaglyceroporins) based on their genomic organization and ability to exclusively transport water (AQP0, AQP1, AQP2, AQP4, AQP5) or both water and small nonionic molecules such as glycerol and urea (AQP3, AQP7, AQP9, AQP10).1–4 Other AQPs (AQP6, AQP8, AQP11, and AQP12) have unique functions and genomic organization (with the exception of AQP6) and remain unclassified.1, 14, 22

AQPs differ in their ability to transport water. For example, AQP0 has a relatively low water permeability (pf = 0.03-0.3 × 10−14 cm3/s/channel), whereas AQP1 and AQP4 have high water permeability (pf 1-16 × 10−14 cm3/s/channel and 15-24 × 10−14 cm3/s/channel, respectively), 50 to 80 times greater than AQP0.20 The functional relevance and molecular basis of the variability in the water-transporting capacities of the individual AQPs remain unclear.

Studies on AQP1 suggest that as water molecules approach the aqueous pore from either direction, they pass through the selective filter not as a continuous unbroken column of molecules; rather they break their intermolecular hydrogen bonds and instead form successively two hydrogen bonds with hydrophilic residues in the constriction region of the pore.19, 21 The presence of a positively charged residue, Arg195, in the aqueous pore prevents the transfer of H+ through the channel, thus providing the unique permeability for only water molecules.23 In total, AQP1 transports approximately 3 × 109 molecules of water per channel per second.20

The movement of water and glycerol through the pore of aquaglyceroporins occurs concertedly, thereby competing for hydrogen bond partners in the channel interior.24

Unclassified AQPs include AQP6, which resides exclusively in the membranes of intracellular vesicles of intercalated cells of the renal collecting duct and is a vacuolar-type AQP not engaged in water transport.8 It exhibits unique selectivity for the nitrate anion (NO3) as a result of a single amino acid substitution (i.e., Asn-60 for Gly-60).25 AQP6 can also transport Cl, glycerol, and urea11, 26 and is genetically clustered with the orthodox AQPs.

AQP8, AQP11, and AQP12 are marked by a divergent evolutionary pathway and unusual genomic organization. AQP8 has ubiquitous tissue expression and a predominant intracellular location.18, 27 When expressed in Xenopus oocytes, both rat and human AQP8 transport water, but mouse AQP8 is also permeable to urea.1 The functional properties of AQP11 and AQP12, which have 20% to 32% identity with other AQPs (highest with AQP8), are still unknown.14, 22

Expression, Cellular Localization, and Physiological Significance of AQPs in the Hepatobiliary System

  1. Top of page
  2. Abstract
  3. Molecular Physiology of AQPs
  4. Expression, Cellular Localization, and Physiological Significance of AQPs in the Hepatobiliary System
  5. Pathophysiology of AQP-Mediated Water Transport in the Hepatobiliary System
  6. Concluding Remarks
  7. References

In the hepatobiliary system, AQPs are found in hepatocytes, cholangiocytes, gallbladder epithelial cells, and blood vessels (Fig. 2).

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Figure 2. Expression of AQPs in the hepatobiliary system. Hepatocytes express AQP0, AQP8, AQP9, and AQP11. Cholangiocytes express AQP0, AQP1, AQP4, AQP5, AQP8, AQP9, and AQP11. The gallbladder epithelial cells express AQP1 and AQP8. Blood vessels in the liver and the gallbladder express AQP1. AQP, aquaporin.

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AQPs in Hepatocytes.

Rat hepatocytes express at least 3 AQPs (AQP0, AQP8, and AQP9) in variable amounts (AQP8 >> AQP9 > AQP0).16, 28–34 AQP0 and AQP8 are mainly localized intracellularly and to a lesser degree on the canalicular plasma membrane,31–33 whereas AQP9 is principally localized on the hepatocyte basolateral plasma membrane.33 AQP0 and AQP8 are expressed to a larger degree in hepatocytes surrounding the central vein, whereas AQP9 is uniformly distributed within the hepatic lobe.33 Recently, a message for AQP11 was also found in liver.14

AQP0 was originally localized to the lens fibers of the eye.3 Rat liver is the only other known organ that expresses AQP0. In the lens, AQP0 constitutes 50% of the total membrane protein in the fiber cells, where it has a structural role as a cell–cell adhesion molecule in addition to functioning as a low-capacity water channel.3 The physiological role of AQP0 in hepatocytes is unknown.

AQP8 is expressed in many organs and tissues; in the rat and mouse, the liver is a major site of AQP8 expression. The subcellular distribution of AQP8 in hepatocytes varies with species. In rat hepatocytes, AQP8 is primarily localized intracellularly, and to a lesser degree on the canalicular plasma membrane.33 In mouse hepatocytes, different groups report different AQP8 localization, that is, widespread expression in intracellular membranes including smooth endoplasmic reticulum, subapical vesicles, and mitochondria,27 or, in contrast, strong localization on the plasma membrane with weak intracellular localization.35

The physiological functions of AQP8 in hepatocytes is under active investigation. Our detailed biochemical, biophysical, and microscopic studies on isolated rat hepatocytes, hepatocyte couplets, and enriched hepatocyte plasma membrane fractions suggest that AQP8 is involved in water permeability across the canalicular plasma membrane, supporting its potential importance in canalicular bile formation. Indeed, we found that under basal (i.e., non-stimulated) conditions, AQP8 is largely localized in intracellular vesicles; on stimulation by choleretic agonists such as dibutyryl cyclic adenosine monophosphate (cAMP) or glucagon, AQP8 redistributes to the canalicular plasma membrane (Fig. 3), thereby increasing the apical cell surface permeability and facilitating osmotic water transport.31, 33, 34, 36, 37 In the hepatocyte apical plasma membrane, AQP8 is localized in the lipid microdomains (“rafts”) enriched in cholesterol and sphingolipids that are thought to promote the assembly of AQPs into specific plasma membrane regions.38 Hepatocyte rafts also contain the Cl/HCO3 exchanger, AE2, and the multidrug resistance–associated protein 2, MRP2, suggesting that in the apical plasma membrane, AQP8 is likely clustered with transporting proteins that establish the osmotic gradients driving passive AQP8-mediated water movement into the canaliculus.38 Because AQP8 lacks a consensus sequence for phosphorylation by protein kinase A, through which cAMP and glucagon realize their effects in hepatocytes, its redistribution to the canalicular plasma membrane likely occurs via mechanisms of phosphatidylinositol-3-kinase–dependent microtubule-associated trafficking of vesicles containing AQP8 and other functionally related proteins (e.g., AE2 and MRP2) that mediate canalicular bile secretion.39

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Figure 3. AQPs in rat hepatocytes. In isolated rat hepatocyte couplets, in the basal (non-stimulated) state, AQP0 and AQP8 were observed within the cells and at the canaliculus; AQP9 was localized mainly at the basolateral plasma membrane. Stimulation of hepatocyte couplets with dibutyryl cAMP (d-cAMP) did not affect AQP0 and AQP9, whereas AQP8 redistributed from an intracellular vesicular compartment to the canalicular plasma membrane. (Modified and reproduced with permission from reference 33). AQP, aquaporin; cAMP, cyclic adenomonophosphate.

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In contrast, studies on wild-type and AQP8 knockout mice have been interpreted as evidence against constitutive or cAMP-regulated AQP8 permeability in hepatocytes. Osmotic water permeability in freshly isolated hepatocytes from wild-type mice was low and did not increase after stimulation with Bt2cAMP and did not decrease in AQP8 deficiency.35 In addition, by immunohistochemistry, AQP8 maintained its predominantly intracellular location in hepatocytes of intact perfused rat liver, which was under active choleresis.11 The difference in AQP8-mediated water transport in the rat and mouse liver requires additional studies. At the same time, the observations in AQP-knockout mice should be interpreted cautiously, given the previously stated redundancy in AQP expression in hepatocytes and the recognition that the phenotype of knockout mice reflects both the down-regulation of the target gene as well as the functional modification of other genes in response to the elimination of the target gene.

Finally, preliminary findings show that at least 2 spliced isoforms of AQP8 are present in hepatocytes and that 1 of them might be involved in canalicular water permeability, whereas the other, which is expressed in mitochondria, might be involved in the homeostatic control of mitochondrial volume.11, 18 It has been suggested that AQP8-mediated water transport into and out of mitochondria may be particularly important for control of mitochondrial volume that occurs during active oxidative phosphorylation and apoptotic signaling.18 However, no experimental evidence demonstrates a specific role for AQP8 in mitochondria or in other intracellular organelles.

AQP9, an aquaglyceroporin permeable to glycerol, urea, and certain small, uncharged solutes with minor water transport capacity, is a liver-specific glycerol channel expressed on the hepatocyte sinusoidal (basolateral) plasma membrane (Fig. 3).16, 28, 30, 33 Expression of AQP9 in rat liver is sex-linked; that is, male rats show higher levels of AQP9 in hepatocytes than do female rats.30 The exact role of AQP9 in hepatocytes is obscure. Potentially, AQP9 may mediate water transport between the sinusoidal blood and the hepatocyte interior, and thus, together with AQP8, contribute to canalicular bile secretion.33 However, because AQP9 is also highly permeable to glycerol and urea, it may provide an entry route for glycerol and an exit route for the urea and a number of other solutes produced within hepatocytes.16, 17 Indeed, in vivo studies have demonstrated that in rats fasted for 96 hours, expression of AQP9 in liver increases 20-fold, suggesting that during starvation, the liver takes up glycerol for gluconeogenesis and does it with the involvement of AQP9.17

Overall, accumulating data support important and diverse functions for AQPs in hepatocytes.

AQPs in Cholangiocytes.

Rat cholangiocytes express more AQPs than any cell type reported to date [seven AQPs from the known thirteen (AQP0, AQP1, AQP4, AQP5, AQP8, AQP9, and AQP11)].10, 12 Among these, two AQPs (AQP1 and AQP4) have been well characterized by molecular, biochemical, and functional studies, whereas 5 others (AQP0, AQP5, AQP8, AQP9, and AQP11) have been detected only at a transcript level. AQP1 is present in both cholangiocyte apical and basolateral plasma membrane domains and in an intracellular vesicle compartment; however, the subcellular location of AQP1 varies depending on physiological conditions (see later discussion).40, 41 In contrast, AQP4 is constitutively expressed exclusively on the cholangiocyte basolateral plasma membrane domain.42 Our data indicate that these AQPs account for the water permeability of both the apical and basolateral cholangiocyte plasma membrane domains, AQP1 facilitating mainly the apical transport of water, and AQP4 modulating its basolateral movement.40–42 Among other data supporting this hypothesis are observations that inhibition of AQP1 expression in cholangiocytes of isolated intrahepatic bile ducts by specific siRNAs significantly reduce water transport across biliary epithelia in response to established osmotic gradients,43 whereas overexpression of AQP4 in mouse cholangiocytes results in an increase in water transport.44

The subcellular localization and physiological relevance of other cholangiocyte AQPs (i.e., AQP0, AQP5, AQP8, AQP9, and AQP11) are unknown. The observed redundancy of AQPs in cholangiocytes may reflect the diversity and complexity of their functional roles in this cell type. However, additional studies are needed to understand this phenomenon.

In cholangiocytes, AQP1 is a regulated water channel. Indeed, exposure of isolated cholangiocytes to either secretin (a hormone that regulates cholangiocyte secretion in vivo through the cAMP signaling pathway) or to cAMP alone results in the exocytic insertion of AQP1 normally sequestered in cytoplasmic vesicles into the cholangiocyte apical plasma membrane.40, 41 This process promotes channel-mediated water transport across the biliary epithelial cell barrier in response to osmotic gradients established by secreted osmotically active ions, Cl and HCO3. Under basal (i.e., non-stimulated) conditions, AQP1 is co-localized in intracellular vesicles with the CFTR Cl channel and the Cl/HCO3 exchanger, AE2; after exposure of cholangiocytes to dibutyryl AMP in vitro or after secretin infusion in vivo, these 3 proteins co-redistribute to the cholangiocyte plasma membrane, forming a membrane microdomain transporting complex involved in hormone-induced ductal bile secretion45 (Fig. 4). In contrast, exposure of isolated rat cholangiocytes to secretin does not alter the intracellular distribution of AQP4, suggesting that AQP4 is not a regulated water channel, at least by secretin.42

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Figure 4. A model for the regulation of AQP-mediated water transport in cholangiocytes. (A) In the basal or unstimulated state, AQP1 is colocalized with CFTR and AE2 in intracellular vesicles. In contrast, AQP4 is constitutively expressed on the basolateral plasma membrane domain promoting water movement in either direction, i.e., into the cell or out of the cell. (B) Secretin by increasing intracellular cAMP production induces the exocytic insertion of vesicles containing AQP1, CFTR, and AE2 into the apical plasma membrane, resulting in secretion of Cl, HCO3, and water. Somatostatin inhibits HCO3 and water secretion by blocking intracellular cAMP production and stimulating the endocytic retrieval of the vesicles containing AQP1, CFTR, and AE2. (Modified and reproduced from reference 12, with permission of Eurakah.com). AQP, aquaporin; cAMP, cyclic adenomonophosphate.

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Cholangiocytes not only secrete but also absorb water with the involvement of AQPs. Substantial AQP-mediated water movement from lumen to bath was observed in microperfused rat intrahepatic bile ducts if a net outward osmotic gradient was established by an increase in osmolality of the bathing buffer or as a result of glucose absorption.46, 47

Thus, it seems very plausible that in cholangiocytes, AQPs are involved in ductal bile formation providing transcellular water transport in both directions—into the lumen (secretion) or out of the lumen (absorption) of intrahepatic bile ducts. However, this scenario represents a working hypothesis, and its ultimate validation requires ongoing experimentation, especially in the light of reported observations that deletion of AQP1 does not affect bile formation in mice.48, 49

AQPs in the Gallbladder Epithelia.

The epithelial cells of human and mouse gallbladder express 2 AQPs (AQP1 and AQP8).3, 15 Messenger RNA for AQP8 was also found in calf, rabbit, and guinea pig gallbladders.19 In the epithelial cells of the neck of the human gallbladder, AQP1 is localized on both the apical and basolateral plasma membranes.3 In the epithelial cells of the neck and corpus of mouse gallbladder, AQP1 is also localized on the apical and basolateral plasma membranes and in subapical vesicles, whereas AQP8 is localized primarily apically and intracellularly to a lesser extent.15

The physiological role of AQPs in mammalian gallbladder epithelia is unclear but may relate to the determination of the final composition of bile. Gallbladder epithelia are primarily absorptive epithelia, which express a number of exchangers and channels (i.e., NHE1 and NHE3 Na+/H+ exchangers, Cl and K+ channels, AQPs) that are likely involved in the concentration of bile by transporting primarily Na+, Cl, and water from the gallbladder lumen. In addition, under specific conditions (e.g., when transport of Na+ and Cl is inhibited by vasoactive intestinal peptide, serotonin, or secretin), gallbladder epithelia may secrete HCO3 followed by passive movement of water into the gallbladder lumen. The presence of 2 distinct AQPs (AQP1 and AQP8) on both the apical and basolateral plasma membranes of the gallbladder epithelial cells suggests that they may be involved in both water absorption and secretion.15 However, this hypothesis requires additional experimental testing.

AQPs in the Hepatic Blood Vessels.

AQP1 is highly expressed in the peribiliary vascular plexus, a mesh-like arrangement of blood vessels that surround the intrahepatic bile ducts, and in the blood vessels of the gallbladder,3, 10 suggesting a potential functional role of this AQP in facilitating water transport from plasma to bile.

Pathophysiology of AQP-Mediated Water Transport in the Hepatobiliary System

  1. Top of page
  2. Abstract
  3. Molecular Physiology of AQPs
  4. Expression, Cellular Localization, and Physiological Significance of AQPs in the Hepatobiliary System
  5. Pathophysiology of AQP-Mediated Water Transport in the Hepatobiliary System
  6. Concluding Remarks
  7. References

A variety of disorders exist in which AQP-mediated water transport is abnormal. Most of them are primary renal disorders such as central and nephrogenic diabetes insipidus, and some of them reflect abnormalities of AQP-mediated water transport in other organs [e.g., brain edema, lung edema, Sjögren's syndrome (an autoimmune disease characterized by persistent inflammation of lachrymal and salivary glands and by abnormal distribution of AQP5 in the epithelial cells leading to reduction of tear and saliva production)].1–3, 5, 6 AQPs are also involved in such disorders as tumor angiogenesis, glaucoma, epilepsy, and microbial infection.5, 6, 50 They are also critical for fat metabolism, and, thus, might be important in some forms of obesity.6

The direct involvement of AQPs in disorders of the hepatobiliary system has not been established, and only a few studies exist suggesting the involvement of AQPs in liver pathophysiology. First, recent work employing a bile duct–ligated rat model showed that extrahepatic cholestasis induced by bile duct ligatation results in posttranscriptional downregulation of AQP8 expression in hepatocytes.37 Second, in rats with streptozotocin-induced diabetes, expression of AQP9 in liver was increased more than two-fold, whereas treatment of diabetic rats with long-acting insulin restored AQP9 to control levels.17 This observation was interpreted as suggesting that in insulin-dependent type 1 diabetes mellitus, AQP9 is involved in an increase of glucose production by transporting glycerol into hepatocytes. Third, deletion of the gene encoding AQP11 in mice resulted in the development of polycystic kidneys, which caused renal failure and death. Moreover, the epithelial cells of the kidney and liver of AQP11 knockout mice contained multiple vacuoles, which likely were the result of osmotic imbalance and water accumulation.14

Recently we reported a novel pathophysiological role for AQP1 related to mechanisms of invasion of cholangiocytes by an intracellular parasite, Cryptosporidium parvum.50C. parvum infects a number of epithelial cells, including cholangiocytes, and this invasion process is characterized by host–cell membrane protrusion to encapsulate the parasite. In mouse cholangiocytes, C. parvum recruits a Na+-dependent glucose transporter, SGLT1, and AQP1 to the attachment site, generating a localized glucose-driven AQP1-mediated water influx, thereby facilitating the localized host–cell membrane protrusion required for parasitic cellular invasion.

Thus, evidence for a pathophysiological role of AQPs expressed in the epithelial cells of the hepatobiliary system is limited. However, initial observations suggest that several hepatobiliary disorders, such as cholestasis, insulin resistance syndrome, and infectious diseases, may be associated with changes in AQP-mediated water and solute transport.

Concluding Remarks

  1. Top of page
  2. Abstract
  3. Molecular Physiology of AQPs
  4. Expression, Cellular Localization, and Physiological Significance of AQPs in the Hepatobiliary System
  5. Pathophysiology of AQP-Mediated Water Transport in the Hepatobiliary System
  6. Concluding Remarks
  7. References

Recent observations discussed in this review indicate that the epithelial cells of the hepatobiliary system express multiple AQPs that are likely involved in a variety of physiological and cellular functions such as bile formation, gluconeogenesis, and membrane remodeling. These observations have both physiological and pathophysiological relevance. However, additional work is required to provide more insights into hepatic epithelial cell physiology and pathophysiology of AQP-mediated water and solute transport, as well as to discover novel AQPs and novel roles of existing multiple AQPs expressed in the epithelial cells of the hepatobiliary system. Potentially, hepatic AQPs may have specific functions in intracellular organelles and be involved in processes of liver regeneration and tumor metastasis given a recently discovered role of AQPs in cell migration. Such insights have the potential for leading to novel therapeutic strategies for hepatobiliary disorders associated with impaired bile production, diabetes, obesity, trauma, and others.

References

  1. Top of page
  2. Abstract
  3. Molecular Physiology of AQPs
  4. Expression, Cellular Localization, and Physiological Significance of AQPs in the Hepatobiliary System
  5. Pathophysiology of AQP-Mediated Water Transport in the Hepatobiliary System
  6. Concluding Remarks
  7. References