Genetic defects in hepatobiliary transport

Biochimica et Biophysica Acta 1586 (2002) 129^145 www.bba-direct.com

Review

Genetic defects in hepatobiliary transport Ronald Oude Elferink *, Albert K. Groen Laboratory for Experimental Hepatology, Academic Medical Center Amsterdam F0-116, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands Received 6 June 2001; received in revised form 9 November 2001; accepted 20 November 2001

Abstract Bile formation, the exocrine function of the liver, represents a process that is unique to the hepatocyte as a polarized epithelial cell. The generation of bile flow is an osmotic process and largely depends on solute secretion by primary active transporters in the apical membrane of the hepatocyte. In recent years an impressive progress has been made in the discovery of these proteins, most of which belong to the family of ABC transporters. The number of identified ABC transporter genes has been exponentially increasing and the mammalian subfamily now counts at least 52. This development has been of crucial importance for the elucidation of the mechanism of bile formation, and it is therefore not surprising that the development in this field has run in parallel with the discovery of the ABC genes. With the identification of these transporter genes, the background of a number of inherited diseases, which are caused by mutations in these solute pumps, has now been elucidated. We now know that at least six primary active transporters are involved in canalicular secretion of biliary components (MDR1, MDR3, BSEP, MRP2, BCRP and FIC1). Four of these transporter genes are associated with inherited diseases. In this minireview we will shortly describe our present understanding of bile formation and the associated inherited defects. ß 2002 Elsevier Science B.V. All rights reserved. Keywords: Bile; ABC transporter; P-type ATPase; Cholestasis ; Bile salt; Bile acid; Hepatocyte

1. Bile formation 1.1. Bile £ow The small apical (canalicular) domains of hepatocytes are arranged into a luminal meshwork of tubules between adjacent hepatocytes and these are the sites of primary bile formation. From this canalicular network bile £ows to the small ductules and subsequently to the larger ducts. Bile formation is an osmotic process, which means that the generation of

* Corresponding author. Fax: +31-20-566-9190. E-mail address: [email protected] (R. Oude Elferink).

water £ow is preceded by the active secretion of solutes, followed by the osmotic attraction of water. Solute secretion at the canalicular level is a process that is mediated by primary active transporters (¢g. 1). Water £ow is generally thought to be mainly through the tight junctions and not through specialized water channels (aquaporins) because these were not found in hepatocytes [1,2]. More recently, however, it has become clear that a new water channel, aquaporin 8, is expressed in hepatocytes [3]. This channel is inserted into the hepatocyte plasma membrane in a regulated fashion [4] and may therefore contribute to the net e¥ux of water across the cell. The main constituents of the primary biliary £uid are bile salts; hence £ow mainly depends on the extent of bile salt secretion. Indeed, classical experiments have

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demonstrated in several species [5,6] that there is a more or less linear relationship between bile salt output and bile £ow. Extrapolation of the £ow to very low rates of bile salt secretion suggests that a socalled bile salt-independent fraction of bile £ow also exists and more recent studies indeed indicated that canalicular glutathione secretion [7,8] and ductular bicarbonate secretion [1] also contribute to overall hepatic bile £ow. The main determinant of overall bile £ow is the volume of water generated at the canalicular level. However, between species there is considerable di¡erence in the extent to which the bile duct epithelial cells contribute to the generation of water [9]. The current model for the contribution of ductular £ow, proposed by the group of LaRusso [1], is that of a combined action of the chloride channel, CFTR, and the chloride/bicarbonate exchanger, AE2, leading to net bicarbonate secretion which is followed by water transport through aquaporin 1 (AQP1). Expression of all of these transporters has been demonstrated in the apical domain of bile duct epithelial cells [10^12]. 1.2. Bile salt transport First pass elimination of bile salts by the liver can be up to 90% and is mediated primarily by the Naþ taurocholate cotransporting peptide, NTCP [13] (of¢cial gene code SLC10A1). Since this transport is driven by the sodium gradient, it is capable of concentrating bile salts in the hepatocyte. This protein is exclusively expressed in the liver and localized in the basolateral membrane of the hepatocyte. Ntcp has a⁄nity for both conjugated and unconjugated bile salts [14^16]. Although the transporter also catalyzes

the uptake of estrone 3-sulfate [16], its substrate speci¢city seems to be largely con¢ned to bile salts. Members of the family of OATPs, such as OATP2 (SLC21A6) and OATP-A (SLC21A3), are also capable of transporting bile salts but contribute less and do not act in a concentrative fashion [17]. There has been a long-standing debate on the mechanism of intracellular transport of bile salts through the hepatocyte. It was thought for a long time that this might involve vesicular transport, but there is no de¢nitive proof for this and the current paradigm is that bulk bile salt transport does not require vesicular transport and only involves binding to cytosolic bile salt binding proteins. The most important of these proteins is 3KOH-steroid dehydrogenase which is present in extremely high concentration in the hepatocyte cytosol [18,19]. This binding seems important not only in view of the detergent properties of bile salts at higher concentrations but also because of their potent ability to induce apoptosis in hepatocytes at low concentrations [20,21]. It was originally thought that canalicular bile salt secretion was a process driven by the negative membrane potential inside the hepatocyte [22,23]. After the discovery of canalicular ATP-dependent processes for both amphipathic drugs [24] and organic anions [25,26] it became clear that also bile salts are transported in a primary active ATP-dependent fashion [27,28] (Table 1). Bile salts are pumped across the canalicular membrane via the bile salt export pump (BSEP, gene code ABCB11) (Fig. 1). The gene encoding this transporter was initially partially cloned from the pig and originally designated sister of P-glycoprotein (Spgp) [29]. Subsequently the full cDNA was isolated from rat [30], and murine liver

Table 1 Transporters involved in primary bile formation Transporter trivial name(s)

Gene code

Substrate(s)

Defective in

FIC1 BSEP (sPgp) MDR3 Pgp (in mouse: Mdr2 Pgp) MDR1 Pgp (in mouse: Mdr1a and 1b Pgp) MRP2 (cMOAT) BCRP (MXR, ABCP) ABCG5 ABCG8

ATP8B1 ABCB11 ABCB4 ABCB1 ABCC2 ABCG2 ABCG5 ABCG8

? bile salts phosphatidylcholine amphipathic drugs (neutral and cationic) amphipathic drugs (anionic and neutral) amphipathic drugs (phytosterols) no direct evidence yet

PFIC type 1 PFIC type 2 PFIC type 3 ? Dubin^Johnson syndrome ? Sitosterolemia

Š

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Fig. 1. Transporters involved in canalicular bile formation. In the left canalicular membrane the ABC transporters are indicated, of which the function has been established. In the right canalicular membrane the heterodimer of ABCG5 and ABCG8 has been drawn, but this is speculative because the presence of these two half-transporters in the canalicular membrane has not been demonstrated yet. It has also not yet been proven that phytosterols are transported by this transporter pair. Also the P-type ATPase FIC1 is indicated; the presence of this protein in the canalicular membrane has recently been proven [98], but its substrate is as yet still unknown.

[31^33]. Bsep is a genuine ABC transporter according to the classical paradigm of 12 transmembrane spanning domains and two nucleotide binding folds. The gene product from di¡erent species behaves as a 140^160 kDa protein on SDS^PAGE. Gerlo¡ et al. [30] demonstrated that plasma membrane vesicles from Sf9 cells transfected with the rat Bsep cDNA were capable of taking up taurocholate in an ATPdependent fashion with a Km of 5.3 WM. These vesicles also transported the taurine conjugates of chenodeoxycholate and ursodeoxycholate. No transport could be observed of glycocholate and cholate [30]. Murine Bsep was shown to transport taurocholate, taurochenodeoxycholate and glycocholate [33]. The transport properties of human BSEP have not yet been reported on. Although initially Bsep expression was observed in the liver only, Lecureur et al. [31] reported weak expression of Bsep in mouse brain as determined by Western blotting. This may provide an explanation for the reported observation of bile salt transport across the blood^brain barrier [34]. After reaching the intestine, bile salts are e⁄ciently resorbed in the terminal ileum in a sodium-dependent mechanism by the apical bile salt transporter

(designated ASBT and formerly IBAT, o⁄cial gene code: SLC10A2) [35^37]. When transfected in COS cells, the human ASBT [37] recognizes both primary and secondary bile salts in their unconjugated as well as their taurine-conjugated form. Both the rabbit and the human ileal transporters have a more narrow substrate speci¢city than the hepatic sodium-dependent transporter [37,38]. While the hepatic transporter also transports compounds like estrone 3-sulfate, the ileal transporter seems to be more speci¢c for bile salts. Within the enterocyte bile salts are bound to the ileal bile salt binding protein. It was demonstrated recently that the expression of this protein is strongly regulated by the prevailing bile salt concentrations, suggesting that it may play a role in the regulation of the enterohepatic cycle of bile salts. This regulation is driven by the nuclear receptor pair FXR/RXR [39]. FXR recognizes dihydroxy bile salts like deoxycholate and chenodeoxycholate [40]. It is now becoming clear that nuclear receptors regulate several steps in bile salt metabolism and transport [41^47]. How bile salts leave the enterocyte at the basolateral pole is currently unknown. MRP3 (o⁄cial gene

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code ABCC3) is expressed in the basolateral membrane of enterocytes and it has been shown that rat Mrp3 transports taurocholate (with a Km of 16 WM [48]) and human MRP3 transports glycocholate (Km 248 WM [49]). Whether MRP3 is the physiologically relevant transporter for release of bile salts into the blood remains to be determined. The bile salts are carried by the mesenteric blood to the portal vein and e⁄ciently withdrawn from the blood by the liver. The above described mechanisms ensure that bile salts undergo extensive enterohepatic circulation during which only minor amounts (1^3% per cycle) are lost. It must be stressed that this description of the mechanism of enterohepatic bile salt cycling only holds for the main bile salts, i.e. taurine- or glycine-conjugated cholate and chenodeoxycholate. Within the gut there are extensive deconjugation and dehydroxylation, which give rise to many secondary bile salts and bile salt metabolites several of which have cholestatic properties. Depending on the species under study, these metabolites can be more or less e⁄ciently rehydroxylated and conjugated to yield less toxic bile salts. An important example of this is lithocholate, the bacterial dehydroxylation product of chenodeoxycholate. The exact mechanisms of enterohepatic cycling of such metabolites have not suf¢ciently been studied. This will nevertheless be very important in the face of the potent cholestatic properties of some of these compounds. 1.3. Transport of lipids The second most important class of biliary constituents are the lipids. Biliary lipids mainly consist of phospholipid (almost exclusively phosphatidylcholine) and cholesterol. The ratio in which these two lipids are secreted varies considerably between species. In rodents the phospholipid over cholesterol ratio is 5^10 while in man this is considerably lower. The relatively high concentration of cholesterol in human bile represents the major risk factor to gallstone formation. Upon production of a knockout mouse for the Mdr2 gene it was discovered that the encoded transporter is essential for biliary lipid secretion [50]. In the absence of Mdr2 Pgp, mice do not secrete phospholipid nor cholesterol. In di¡erent experimental systems it was subsequently demonstrated that the murine Mdr2 Pgp as well as the human

orthologue MDR3 Pgp are phosphatidylcholine (PC) translocators [51^53]. On the basis of available data, we have proposed a model [54] in which PC, after delivery to the inner lea£et of the canalicular plasma membrane, is translocated to the outer lea£et and subsequently resides in PC-rich lipid domains that are laterally separated from the more rigid sphingolipid-rich lipids of the outer canalicular membrane lea£et. This rigid lipid layer is necessary to prevent solubilization of the canalicular membrane by high bile salt concentrations in the canaliculus. Interaction between sphingomyelin and cholesterol greatly enhances this rigidity and increases resistance towards bile salts [55]. Sphingomyelin has high a⁄nity for cholesterol [56] and these two lipids tend to segregate in lateral domains [57,58]. The more £uid PC-rich microdomains are destabilized by the canalicular bile salt molecules and, in combination with the continuous pumping of PC into these domains, vesiculation of PC-rich membrane bilayer occurs. These vesicles then pinch o¡ to give rise to typical biliary lipid vesicles [54]. In a meticulous morphometric study at the electron microscopy (EM) level, Crawford et al. [59,60] have provided morphological evidence for such a mechanism. The mechanism of cholesterol secretion into bile is still largely unknown. As yet, no direct evidence exists for the involvement of a translocator protein which, in analogy with Mdr2/MDR3 Pgp for phospholipids, would catalyze the translocation of cholesterol across the membrane. Controversy exists on the rate of spontaneous £ip-£op of cholesterol across biological membranes. Cholesterol is not secreted into bile in the absence of phospholipid secretion; this is caused by the fact that simple bile salt micelles have very poor cholesterol solubilizing capacity, especially those of the more hydrophilic bile salt species, such as muricholate (the main murine bile salt) and ursodeoxycholate. This observation does, however, not exclude the possibility that cholesterol translocation needs a transporter protein. Indeed, recent evidence suggests that the two half-transporters ABCG5 and ABCG8 are involved in the elimination of plant sterols. Transport has thus far not been demonstrated directly, but this function can be inferred from accumulation of plant sterols in patients with sitosterolemia, who have a mutation in either of

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the two genes encoding these proteins (see below). ABCG5 and ABCG8 are expressed in the intestine and the liver. Recently, yet another ABC transporter, ABCA1, has been implicated in the transport of cholesterol. Several groups simultaneously discovered that ABCA1 is the causative gene for Tangier disease [61^64]. Tangier disease is a rare inherited disorder characterized by the virtual absence of high density lipoprotein (HDL). Fibroblasts from these patients are incapable of donating cholesterol and phospholipid to lipid-poor apolipoprotein (apo) A-I, a step that is essential for maturation of the lipoprotein. When the association between ABCA1 defects and Tangier disease was discovered, the initial suggestion was that ABCA1 transports cholesterol, but recent evidence demonstrates that this is not the case [65]. Most likely ABCA1 functions primarily as an outward phospholipid translocase rather than a cholesterol transporter. Translocation of phospholipid to lipid-poor apoA-I probably secondarily facilitates the transfer of cholesterol. Recently, Vaisman et al. [66] reported a study on transgenic mice that overexpress ABCA1. As expected, these mice had increased plasma levels of HDL. The authors also reported that the concentration of cholesterol in bile was increased. This could mean that ABCA1 also ful¢lls a function in lipid secretion in the canalicular membrane. To investigate this aspect in a more rigorous model, Groen et al. [67] measured cholesterol secretion rates into bile in Abca1 (3/3) mice during bile diversion. They observed no di¡erence between Abca1 (3/3) mice and controls. This rules out the possibility that Abca1 contributes to biliary cholesterol e¥ux, unless this function would be completely taken over by another gene with compensatory expression, which is rather unlikely. 1.4. Transport of amphipaths Thus far, three ABC transporters for amphipaths have been localized to the canalicular membrane: MDR1 P-glycoprotein (gene code ABCB1), MRP2 (gene ABCC2) and BCRP (gene code ABCG2). In transfected cells and/or selected cell lines all three transporters confer multidrug resistance against a wide spectrum of cytotoxic agents. MDR1 P-glycoprotein pumps many neutral and positively charged

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organic compounds across the plasma membrane out of the cell. In view of the diversity of transported compounds, the de¢nition of its substrate speci¢city has remained di⁄cult. Clearly, molecular weight, bulkiness of the molecule and charge of the molecule are important parameters [68]. The role of MDR1 Pgp in the protection against xenobiotics has been ¢rmly established by the generation of knockout mice for both the Mdr1a and the Mdr1b gene (in mice two Mdr1 genes ful¢ll the function of the single MDR1 gene in man). This knockout animal is hypersensitive for a number of toxic compounds and important sites of expression are the blood^brain barrier, the intestinal epithelium and the hepatocanalicular membrane [69,70]. Thus far, no human disorders are known that are associated with a defect in the MDR1 gene. It is of interest to note, however, that Panwala et al. [71] detected a high incidence of colitis in Mdr1a3/3 mice. This chronic intestinal in£ammation could be prevented by treatment with a mix of broad spectrum antibiotics, suggesting that intestinal bacteria and/or their products play a role in this phenomenon. Polymorphisms have been detected in the MDR1 gene [72,73] and these may be associated with alterations in the oral bioavailability of certain pharmaca [74]. The polymorphism C3435T was found to be associated with reduced MDR1 Pgp expression in the duodenum and this correlated with increased oral bioavailability of digoxin [72]. On the other hand no change in the bioavailability of cyclosporin A was observed [75]. MRP2 (formerly also called cMOAT for canalicular multispeci¢c organic anion transporter, gene code ABCC2) was discovered as the liver speci¢c homologue of another multidrug resistance transporter, MRP1 [76,77]. The two transporters have, however, opposite membrane localizations; MRP1 is expressed in the basolateral membrane and MRP2 in the apical membrane of epithelia. While MRP1 is expressed in most cell types, MRP2 is only found in hepatocytes and to a lesser extent in enterocytes and kidney proximal tubule cells [78,79]. MRP1 and MRP2 have highly similar substrate speci¢cities [78,79]. Both transporters recognize a wide spectrum of organic anions; this includes unconjugated anions but also anionic conjugates of glucuronic acid, glutathione and sulfate. More recently, it has become clear that

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these transporters can also pump uncharged compounds. It appears that the transporters can accommodate uncharged amphipathic compounds together with a glutathione molecule in a co-transport mechanism. Experiments with plasma membrane vesicles containing MRP1 revealed that this transporter does not pump vincristine to any signi¢cant extent. However, addition of GSH strongly stimulated the translocation of vincristine [80]. A similar involvement of GSH was found for MRP2-mediated transport of the uncharged carcinogen PhIP [81]. This mechanism greatly enhances the versatility of these transporters. In the intestine MRP2 may play a similar role as MDR1 Pgp in the defence against toxic compounds in the gut lumen [81]. Another member of this subfamily, MRP3, was already mentioned above. This transporter is also expressed in the basolateral membrane of cholangiocytes and portal hepatocytes. During cholestasis its expression is highly induced in both cell types. It may function as a rescue mechanism for the cholestatic hepatocytes to prevent intracellular accumulation of bile salts and organic anions (see below). More recently, BCRP (breast cancer related protein, also termed MXR or ABCP, gene code ABCG2) was identi¢ed as yet another ABC transporter that is overexpressed in anthracycline-resistant cell lines [82]. Upon cloning of its cDNA, it turned out to be a half-transporter, i.e. a protein consisting of only six transmembrane helices and one nucleotide binding domain as opposed to the classical duplicate motif. Other members of the ABCG subfamily (as well as some members from other subfamilies) are also half-transporters. Examples are ALDP (adenoleukodystrophy protein), which is localized in the peroxisomal membrane and is thought to catalyze the transport of activated long chain fatty acids, and TAP1 and 2, which mediate peptide transport across the endoplasmic reticulum membrane, necessary for antigen presentation. In general, the halftransporters are believed to dimerize, either as homodimers or as heterodimers, into functional pumps. Transfection of the ABCG2 cDNA in cells confers resistance against mitoxantrone, topotecan, doxorubicin, daunorubicin and rhodamine 123 [82]. Using monoclonal antibodies against the ABCG2 gene product, Maliepaard et al. [83] recently demonstrated that this protein is present in the plasma membrane

of endothelial cells and in the apical membrane of intestinal epithelial cells (both colon and small intestine) and hepatocytes. The latter strongly suggests that it is also involved in biliary secretion of amphipaths. Using a speci¢c inhibitor of BCRP, GF120918, Jonker et al. [84] showed that this transporter reduces the oral bioavailability of topotecan and other BCRP substrates in the intestine by pumping these compounds back into the lumen. Thus, BCRP as well as MDR1 and MRP2 are important in determining the oral bioavailability of drugs and toxins.

2. Defects in canalicular transport 2.1. Progressive familial intrahepatic cholestasis It has been known for a long time that a group of pediatric patients exists, who su¡er from an inherited form of progressive intrahepatic cholestasis. This group has been described under various other synonyms such as fatal familial intrahepatic cholestasis [85], or progressive idiopathic cholestasis [86]. The ¢rst report identi¢ed this disease entity in an Amish family (the Byler family), where seven members of four related sibships su¡ered from the same symptoms [85]. These children presented with steatorrhea, diarrhea, jaundice with intermittent exacerbations, hepatosplenomegaly and failure to thrive. Because of the patient family history it was clear that this represented a recessively inherited disease which was called Byler’s disease after the family. Subsequent studies showed that a similar disease phenotype also existed outside the Amish community [87^ 89]. Patients with the same disease phenotype that did not belong to the Byler pedigree were generally described as su¡ering from Byler syndrome, due to the uncertainty of the genetic cause of this form. The outcome of the disease was generally fatal due to liver failure within the ¢rst decade of life. The advent of liver transplantation for children provided the opportunity to cure these patients. In further studies biochemical and histological features provided support for heterogeneity of this disease entity, although the clinical development was very similar. First and foremost the group fell into two parts, one subgroup of patients with a high serum Q-glutamyltranspepti-

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dase (GGT) activity and the other with a normal serum GGT activity [90,91]. The latter form was the most frequent and included the patient group from the original Byler pedigree. Further analysis learned that these subgroups di¡ered in more aspects than only the serum GGT. Liver histology of patients with high GGT PFIC revealed prominent bile duct proliferation and cirrhosis which were absent or much less prominent in patients with low GGT. In the last few years considerable progress was made in identifying the genetic background of this group of patients, although it must be stressed that not all involved genes have been identi¢ed yet. There are at least three groups which are now commonly designated by PFIC type 1, type 2 and type 3. Type 1 and type 2 patients have a low serum GGT activity, while type 3 patients have a high serum GGT activity. 2.2. Progressive familial intrahepatic cholestasis type 1 (formerly called Byler’s disease) Byler’s disease primarily manifests itself as a chronic intrahepatic cholestasis. Bile salt concentrations are high in serum and very low in bile, suggesting that hepatic transport is impaired. The jaundice in these patients is regarded as a secondary consequence of insu⁄cient bile £ow, the latter being dependent on bile salt secretion. This also holds for the fat-soluble vitamin de¢ciency and steatorrhea which are the consequence of impaired fat absorption, due to the absence of bile salts from the intestine. Liver transplantation is presently the main therapeutic option for this progressive disease that ends in liver failure. It is of importance to note, however, that interruption of the enterohepatic circulation (chronic bile diversion) was reported to improve the clinical picture of these patients dramatically. Whitington et al. [92] described a procedure in which chronic external partial bile diversion was achieved through a jejunal stoma in four patients. In these patients pruritus dramatically improved and serum bile salt levels fell from s 200 WM to less than 10 WM. Several later studies have reported similar results [93^95]. This did not occur in all patients, however, and it would be of great interest to distinguish the bene¢cial e¡ect of this procedure in PFIC type 1 vs. type 2 patients (see below).

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With the patients from the Byler pedigree and their family members a genetic screen was performed to identify the disease locus [96]. This was located on chromosome 18q21-q22, the same chromosomal region on which a very similar disease type, benign recurrent intrahepatic cholestasis, was localized (see below). A combined search for the two disease loci led to the identi¢cation of the mutated gene, FIC1 (gene code ATP8B1), and its mutations in a group of patients, including those from the original Byler pedigree [97]. More recently it became possible to stain the protein by Western blotting and immunohistochemistry [98]. It is a 140 kDa protein which is localized in the canalicular membrane of the hepatocyte as well as in the apical membrane of bile duct epithelial cells. The protein was virtually absent from a liver specimen of a patient with the common Amish mutation. Many issues concerning this protein remain puzzling, however. Expression of FIC1 in liver is actually quite low, while the gene is highly expressed in intestine and pancreas [97]. Expression is also found in many other tissues. Thus, it is unclear why the absence of FIC1 from many tissues leads primarily to a phenotype in the liver. On the basis of sequence homology this gene must be a member of the P-type ATPase family. Within this family, subgroups of transporters with di¡erent functions have been identi¢ed. The subgroup of cation pumps harbors the plasma membrane (Naþ +Kþ )-ATPase and the gastric (Kþ +Hþ )-ATPase. A second subgroup contains metal ion transporters, such as the hepatic copper transporter, mutated in Wilson’s disease [99], and the extrahepatic copper transporter that is defective in Menke’s disease [100]. The function of FIC1 as a transporter is as yet unknown, but it has highest homology with the drs2 protein from yeast and with the bovine ATPase II (gene code ATP8A1), which form the third subgroup of P-type ATPases [97, 101]. Evidence was presented that drs2 would be an aminophospholipid £ippase, that translocates phosphatidylserine and phosphatidylethanolamine from the outer lea£et to the inner lea£et of the cell membrane [101]. This is a controversial issue, however, because later publications showed that the protein was unable to translocate lipids [102,103] and suggested that it might be involved in metal ion transport [104]. A mutant yeast strain has been produced in which the drs2 gene is disrupted and this yeast

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strain has a defect in ribosome assembly as well as a cold sensitive phenotype [105]. To our knowledge no publications have reported on the function of either the ATPase II or FIC1 by transfection of their respective cDNAs in cells. Thus, it remains to be demonstrated what the function of the two gene products is. It also remains enigmatic how the absence of FIC1 can lead to defective canalicular bile salt transport. Given the fact that BSEP is the main canalicular bile salt transporter, that FIC1 is mainly expressed in the intestine, and that chronic bile diversion leads to disappearance or reduction of PFIC type 1 symptoms, it can be speculated that FIC1 activity plays a role in the enterohepatic circulation of bile salts and that the intrahepatic cholestasis in these patients is a secondary consequence of dysregulation of the enterohepatic circulation [106]. In the line of this hypothesis several possible functions of FIC1 can be envisioned. FIC1 may be an aminophospholipid £ippase, as originally suggested; the (inward) £ipping of aminophospholipids could be of importance for the regulation of the activity of other transporters such as the bile salt transporters in liver and intestine. It would have to be assumed then that lipid asymmetry is of major regulatory function for normal bile salt transport. Alternatively, the inward £ipping of PS might be important for the binding of auxiliary proteins to, or fusion of vesicles with, the cytosolic lea£et of the plasma membrane of hepatocytes and/or enterocytes. It is known that binding of certain proteins (like annexin) as well as fusion of exocytotic vesicles critically depend on the PS concentration in the cytosolic membrane lea£et [107]. Another possibility is that FIC1 is a bile salt pump itself. FIC1 could have a⁄nity for hydrophobic bile salts and/or cholestatic bile salt metabolites. The latter mostly concern metabolites from the primary bile salts, cholate and chenodeoxycholate, produced by bacteria in the gut. The high expression of FIC1 in the gut might serve as a direct defense against such compounds. In the absence of an outward pump function of FIC1 for hydrophobic bile salt (metabolites), these cholestatic agents might accumulate in plasma and induce cholestasis. This function would also explain why chronic bile diversion improves the disease phenotype. In line with this hypothesis it has been observed that bile from PFIC type 1 de¢cient patients contains very low amounts

of bile salts with a disproportionately low content of the hydrophobic bile salts [88,108]. If this hypothesis is right, FIC1 would represent a multidrug resistancelike gene rather than a speci¢c lipid translocator. It should be noted in this context that the homologous Neo1 gene in yeast confers resistance against aminoglycosides [109]. It is not clear, however, whether this resistance is mediated at the level of transport. 2.3. Benign recurrent intrahepatic cholestasis (BRIC) With the identi¢cation of the disease locus for PFIC type 1 and the responsible gene, FIC1, it became clear that the same gene is mutated in BRIC. BRIC most likely represents a mild form of PFIC type 1. PFIC type 1 may start with bouts of cholestasis and progressively develops into chronic persistent cholestasis, but in BRIC patients the phenotype remains restricted to periods of cholestasis that resolve after days to months. Importantly, when cholestasis resolves it leaves no detectable liver damage. The main features of BRIC are elevated serum bile salt concentrations, jaundice and pruritus. The milder phenotype of BRIC compared to PFIC type 1 seems to correlate with the mutations found in these two patient groups [97]. DNA sequencing of the FIC1 gene learned that deletions, frameshifts and nonsense mutations appear to lead to the PFIC type 1 phenotype, while in BRIC patients generally missenses are found. This allows the hypothesis that the FIC1 protein with BRIC mutations may have residual activity, while the protein is absent or nonfunctional in PFIC type 1 patients [97]. Pruritus is a very prominent feature of both PFIC type 1 and BRIC. The pathophysiological mechanism of cholestasis-associated pruritus is still unknown. Indirect evidence exists for the association of pruritus with high levels of opioids (enkephalins). Indeed, experiments with cholestatic rats demonstrated increased plasma enkephalin levels and treatment of cholestatic pruritic patients with opioid antagonists such as naltrexone has relieved itching in many but not all cases [110]. On the other hand, pruritus is thought to be associated with high serum and tissue bile salt concentrations, but a quantitative relation between peripheral bile salt levels and the severity of pruritus has never been established [111]. It is interesting to note, however, that rifampi-

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cin was shown to relieve cholestasis-associated pruritus in several cases [112]. It was found recently that rifampicin is a ligand for the nuclear receptor SXR/ PXR and ligand activation of this receptor induces expression of the cytochrome P-450 isoforms that are capable of detoxifying hydrophobic bile salts [113,114]. 2.4. Progressive familial intrahepatic cholestasis type 2 The phenotype of this form of PFIC is very similar to that of type 1. Also for this form of PFIC the only therapy is liver transplantation, because it develops into liver failure. It was demonstrated by Strautnieks et al. [115] that the disease locus of this subgroup of patients resides on chromosome 2q24. They subsequently found that these patients have mutations in the BSEP gene, which is present in this region [116]. Actually, until the genetic elucidation of PFIC types 1 and 2, it was di⁄cult to distinguish these forms. The clinical, biochemical and histological features are virtually indistinguishable. However, PFIC type 2 patients do not seem to su¡er from watery diarrhea, an aspect that may further emphasize the role of FIC1 in the intestine. Electron microscopic analysis of liver tissue from PFIC type 2 revealed amorphous material in the canalicular space, while liver specimens from type 1 patients displayed coarsely granular bile [117]. The basis of this observation is unknown, but might provide a clue to the function of the FIC1. The outcome of the EM analysis is quite likely to be very much dependent on the processing of the tissue, so that this feature cannot be used for diagnostic purposes. The fact that mutations in the BSEP gene lead to a virtual absence of bile salts from bile has led to the conclusion that BSEP is the main bile salt transporter in the canalicular membrane. This is supported by studies in which rat and murine Bsep were transfected in Sf9 cells and shown to transport several bile salts [30,33]. Both nonsense, missense mutations and deletions in the BSEP gene were found in some patients with low GGT PFIC, and these are now described as having type 2 PFIC [115]. Very importantly, further screening by Strautnieks et al. [118] seems to indicate that still another subgroup of patients exists in whom the disease locus neither local-

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izes to the FIC1 region nor to the BSEP region. This would mean that yet another gene is involved in low GGT PFIC. Very recently, Wang et al. [119] reported on a knockout mouse for the Bsep gene. This animal did not quite have the same phenotype as PFIC type 2 patients. Bsep3/3 mice are cholestatic in the sense that taurocholate accumulates in the liver and little taurocholate is excreted into bile. However, in contrast to the patients, these mice excrete substantial amounts of tauromuricholate into bile as well as a hitherto unde¢ned tetrahydroxy bile salt. Apparently, Bsep is not the only bile salt transporting system in the canalicular membrane and another system is capable of excreting tauromuricholate and the tetrahydroxy bile salt. This escape route prevents severe and progressive cholestasis in these mice and as a consequence these animals have hardly any histopathological signs of liver injury. Because humans are not capable of converting bile salts into muricholate or tetrahydroxy bile salts to any signi¢cant extent, this escape route is not present in man. Interestingly, Bsep3/3 mice were found to have an increased phospholipid and cholesterol secretion rate into bile. The reason for this is unclear, but the accumulation of taurocholate in the plasma might lead to an induction of Mdr2 expression which will cause an increased phospholipid and cholesterol secretion, because Mdr2 Pgp activity is the rate controlling step in biliary lipid secretion [120,121]. It was shown in rats that enlarging the bile salt pool increases the expression of Mdr2 and phospholipid secretion into bile [120]. 2.5. Progressive familial intrahepatic cholestasis type 3 As mentioned above, this form of PFIC is fundamentally di¡erent from types 1 and 2 in that these patients have a high serum GGT activity. The onset of this disease is somewhat later than in the other two forms, but the histological picture is more severe; there is strong bile duct proliferation and cirrhosis. The most prominent features of the disease are portal hypertension, hepatosplenomegaly, jaundice and pruritus. If untreated the disease develops into liver failure. The genetic background of this subgroup of PFIC patients was elucidated after it

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was found that mice with a disruption in the Mdr2 gene, the murine orthologue of MDR3, develop a similar phenotype (see below). This led Deleuze et al. [122] to investigate the possible involvement of this gene in PFIC. Subsequently, in a group of 31 patients with high GGT PFIC, 17 were found to have a mutation in the MDR3 gene [123,124]. Since the gene was not completely sequenced in all these patients it is not clear whether the remaining 14 patients have as yet unidenti¢ed mutations or that another gene might be involved in this form of PFIC. MDR3 P-glycoprotein functions in the translocation of phosphatidylcholine, thereby facilitating the secretion of this phospholipid into bile. The secretion of phospholipid is of crucial importance in the protection of the cellular membranes of the biliary tree against the high concentrations of bile salt detergents [54]. Treatment of patients with ursodeoxycholate (UDCA) appeared to be bene¢cial in about half of the cases [123]. Given the fact that the hepatic damage is caused by bile salts, this is a rational treatment, because UDCA is a hydrophilic bile salt that has low cytotoxicity. Indeed, in Mdr23/3 mice with the equivalent defect, feeding of this bile salt also halted the disease process [125,126]. The observation that not all patients improve on UDCA treatment may be explained by the fact that administration of this bile salt insu⁄ciently replaces the endogenous bile salt pool. Thus, in patients who have no MDR3 Pgp activity at all, the reduction of bile salt cytotoxicity by UDCA is insu⁄cient, while in patients with residual phospholipid secretion, UDCA might bring the overall bile salt cytotoxicity below a critical threshold. Indeed, none of the patients with a truncated MDR3 gene improved on UDCA, while some of those with missense mutations did [123]. Interestingly, it became clear more recently that defects in the MDR3 gene do not only give rise to pediatric liver disease. Jacquemin et al. reported [127] that the mother of a patient with PFIC type 3 and several other women from this family su¡ered from intrahepatic cholestasis of pregnancy. These women turned out to be heterozygotes for the mutation in the MDR3 gene, that caused PFIC type 3 in the homozygous index patient. Moreover, Rosmorduc et al. [128] reported on six gallstone patients, in whom mutations in the MDR3 gene were found.

This included homozygous and heterozygous missense mutations as well as a heterozygous 1 bp insertion leading to frameshift and truncation. None of these mutations were observed in s 100 chromosomes from control subjects, suggesting that they may be associated with the disease phenotype. These two publications suggest that, apart from the severe phenotype associated with complete or nearly complete absence of MDR3 function, also milder phenotypes exist that are associated with reduction but not complete absence of MDR3 Pgp function. 2.6. Serum cholesterol level in PFIC patients In several studies on patients with low GGT PFIC, it was observed that these patients have a normal plasma cholesterol level as opposed to other pediatric and adult forms of cholestasis [85,129,130]. Very recently, this was also reported for PFIC type 3 patients [123]. The plasma lipoprotein pro¢le of cholestatic patients reveals an abnormal lipoprotein fraction in the low density lipoprotein (LDL) region. This abnormal ‘cholestatic’ lipoprotein was characterized as a unilamellar vesicle with an aqueous lumen, and was designated lipoprotein X (LpX) [131]. Using Mdr23/3 mice it could be shown that the formation of LpX depends on the function of the canalicular secretion machinery [132]. Wild type mice develop hypercholesterolemia upon bile duct ligation and this is associated with the presence of massive amounts of LpX in the plasma, but LpX was completely absent in plasma of Mdr23/3 mice [132]. Apparently, during cholestasis the formation of biliary vesicles continues and the release of these vesicles is redirected to the plasma compartment. Indeed, it was shown that during bile duct ligation, the expression of Bsep as well as Mdr2 are not down-regulated and that the proteins are redistributed from the canalicular membrane into an intracellular, subapical compartment, where they may continue to function in the formation of biliary vesicles. The conclusion from these data is that during obstructive cholestasis the continued formation of lipid vesicles by Mdr2/ MDR3 Pgp and the release into plasma lead to a dysregulation of cholesterol homeostasis. In patients with all forms of PFIC the process of biliary lipid vesicle formation is impaired, because both bile salt transport and phospholipid translocation are neces-

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sary for this process. The absence of either of these two processes precludes the formation of biliary vesicles and therefore during cholestasis also no LpX will be formed. Thus the normal serum cholesterol level represents an important diagnostic tool to distinguish all forms of PFIC from other inherited or acquired cholestatic syndromes. 2.7. Sitosterolemia Sitosterolemia is a very rare, recessively inherited, disease. The clinical presentation includes tendon xanthomas, accelerated atherosclerosis particularly a¡ecting males at a young age, hemolytic episodes, and arthritis and arthralgias [133]. The hallmark biochemical feature of the disease is the elevated concentration of plant sterols in plasma. Because sitosterol (24-ethyl cholesterol) is the most important accumulated sterol in plasma of these patients (as well as the most abundant plant sterol in the diet), this disease is referred to as sitosterolemia. A host of other sterol variants, such as campesterol, stigmasterol and brassicasterol, are present in plants and other components of the diet like shell¢sh. Several studies have indicated that absorption of plant sterols in the intestine is strongly increased in sitosterolemic patients. Control subjects absorb about 50^70% of dietary cholesterol, but only less than 5% of the ingested plant sterols. In stark contrast, sitosterolemic patients absorb plant sterols to about the same extent (30^60%) as cholesterol. As a consequence there is marked accumulation of these sterols in plasma and this leads to similar accumulation in tissues like liver, lung heart and red blood cells. The brain content of plant sterols is low, indicating that the blood^brain barrier is intact with respect to these exogenous sterols [133]. Importantly, in normal subjects the low amounts of absorbed sitosterol are quickly secreted into bile so that only trace amounts of it can be found in blood [133]. However, in sitosterolemic patients the biliary secretion of sitosterol and other phytosterols is impaired [134^136]. Bile and plasma analysis in two patients revealed a more than 30-fold reduced bile/plasma ratio of total plant sterols compared to controls [136]. These data show that phytosterol handling in these patients is impaired at two levels: absorption in the intestine and secretion into bile.

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The disease locus had been localized to chromosome 2p21 [137] and more recently ABCG5 and ABCG8, the genes involved in this disease, were identi¢ed [138,139]. These encode two ABC half-transporters from the G-subfamily. Separated by only 374 bp they are located in opposite orientation on chromosome 2p21. Lee et al. [139] reported mutations in the ABCG5 gene in nine patients, while Berge et al. [138] identi¢ed mutations in the ABCG8 gene of eight patients and in the ABCG5 gene of one patient. Both genes are expressed mainly in liver and intestine [138,139]. As described above, ABC half-transporters are thought to dimerize into functional pumps. The fact that mutations in either ABCG5 or ABCG8 cause sitosterolemia suggests that these two halftransporters indeed form a functional (and obligatory) heterodimer. No studies have been reported yet in which the cDNAs have been transfected in cell lines in order to perform transport studies, nor has the localization of the proteins in normal human tissues been described yet. However, on basis of the description of the increased sterol absorption and the decreased biliary secretion in patients with sitosterolemia, it is tempting to speculate on the localization and function of a potential heterodimer of ABCG5 and ABCG8. The minimum hypothesis would be that this represents an outward pump for plant sterols present in the apical membrane, which in the intestine reduces absorption and in the liver mediates canalicular secretion of these unwanted sterols. 2.8. The Dubin^Johnson syndrome The Dubin^Johnson syndrome is a rare and benign disorder which ¢rst has been described in 1954 [140]. The syndrome is characterized by a chronic, predominantly conjugated, non-hemolytic hyperbilirubinemia, caused by an impaired hepatobiliary transport system for non-bile salt organic anions in the canalicular membrane of the hepatocyte. Furthermore, liver histology is normal except for the, syndrome-characteristic, lysosomal accumulation of a black pigment. This pigment was thought to be melanin-like material but this remains controversial [141]. Studies in the Mrp2-de¢cient GY/TR3 rat, the animal model for this disease [76], suggest that it is derived from accumulated, polymerized metab-

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olites of aromatic amino acids [142]. In addition, the urinary coproporphyrin excretion in these patients is abnormal [143]. Serum levels of endogenous bile salt are normal and the hepatobiliary transport of bile salts in these patients is una¡ected [78,144]. Cloning of MRP2 [145] provided the opportunity to elucidate the genetic background of this inherited disease. Several mutations have now been reported and these include missense, nonsense mutations, premature stops, deletions etc. (for a review see [79]). The Dubin^Johnson syndrome is generally regarded as a benign syndrome of which the hyperbilirubinemia is the only problem. In the literature anecdotal reports exist on the occurrence of primary hepatocellular carcinoma [146^149]. Since the disease is very rare it is impossible to assess whether the occurrence of HCC is signi¢cant or not. The animal models for the human Dubin^Johnson syndrome are the GY/TR3 and the EHBR rat; two naturally occurring mutants from the Wistar and Sprague^Dawley colonies, respectively. The mutations in the Mrp2 gene of both animal models have been identi¢ed. The mutation in the TR3 rat is a single nucleotide deletion which leads to a frameshift and stop codon. A very low mRNA level and no Mrp2 protein are detected in this animal [76]. In the EHBR rat a one-nucleotide substitution results in the introduction of a stop codon [150]. It is interesting to note that both in the Dubin^Johnson syndrome and in the GY/TR3 rat the hyperbilirubinemia causes a dramatic induction of MRP3 expression. Also under conditions of obstructive cholestasis Mrp3 was found to be strongly induced [151^ 154]. MRP3 was recently cloned and identi¢ed as yet another organic anion transporter [49,151,155^158]. Like MRP1 and in contrast to MRP2, MRP3 is localized in the basolateral membrane of epithelial cells including hepatocytes [157,159]. Thus, increased MRP3 expression may represent an escape route for the excretion of accumulated organic anions that are normally excreted into bile, but in the absence of MRP2 cannot leave the hepatocyte. 2.9. Cholestasis of pregnancy Intrahepatic cholestasis of pregnancy (ICP) is a reversible form of cholestasis that may develop in the third trimester of pregnancy and usually rapidly

resolves after delivery. The incidence of ICP lies between 10 and 100 cases per 10 000 pregnancies, but there is a strong ethnical background to this phenomenon. Notably, in the Chilean population ICP develops in as much as 16% of pregnancies and within the Araucanian Indian subpopulation it is even as high as 28% [160]. The main symptoms are pruritus and, to a lesser extent, jaundice. Serum bile salt levels are increased [161^163]. Increased incidence of fetal distress, premature birth and even stillbirth in association with ICP has been reported (for a review see [164]). The reason for discussing ICP in this review is the fact that genetic factors appear to be involved in the development of this syndrome. As mentioned above, ethnicity plays a role, but more recently it was also found that heterozygosity for mutations in the MDR3 gene predispose for ICP. Jacquemin et al. [127] reported on the coexistence of PFIC type 3 and ICP in a consanguineous family. In this family, six women had at least one episode of ICP and of these six four were heterozygous for the mutation in the MDR3 gene. DNA of the other two was not analyzed. These data suggest that a reduced MDR3 Pgp activity predisposes for the development of ICP. A predisposition for ICP is not only observed with MDR3 mutations; already in the original description of the Byler syndrome by Clayton et al. [85] it was noted that the mother of a patient with this inherited disease (now characterized as a defect in the FIC1 gene, see above) su¡ered from ICP. This has subsequently been con¢rmed in later studies [165,166]. Pregnancy may also unmask hitherto undiagnosed Dubin^Johnson syndrome [167^169]. All in all, these data suggest that during pregnancy there is a more or less generalized reduction in bile formation and, combined with a preexisting subclinical defect in any of these transport systems, this may induce clinical symptoms of cholestasis. The mechanism of reduced bile formation during pregnancy is unknown but the prevailing hypothesis is that it is related to the high levels of circulating hormones during the last trimester. The most important observation in support of this hypothesis is that the use of oral contraceptives may also induce intrahepatic cholestasis. Indeed, women with a history of ICP are also prone to cholestasis induced by oral contraceptives and vice versa [170]. Which hormones or hormonal

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metabolites are responsible is also unclear. In vivo experiments in rats suggest that conjugated estrogen metabolites can be cholestatic, but progesterones may also play a role since these are produced at high rates during the last phase of pregnancy [164]. These hormones may have an inhibitory e¡ect on canalicular transporters, but since several transport processes are a¡ected, it is also possible that the membrane composition is changed or that there is a generalized reduction in expression of transporters or an increased degradation.

[13] [14] [15] [16]

[17] [18]

Note added in proof: After completion of this manuscript a report by the group of Arias has been published providing data to suggest that FIC1 is a phospholid translocator that is capable of translocating phosphatidylserine (PS). P. Ujhazy, D. Ortiz, S. Misra, S. Li, J. Moseley, H. Jones, IM. Arias, Familial intrahepatic cholestasis 1: studies of localization and function. Hepatology 34 (2001) 768^775.

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