Progressive Familial Intrahepatic Cholestasis Type 1

• ABSTRACT
• PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS TYPE 1
• Diagnosis
• Therapy
• BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS TYPE 1
• INTRAHEPATIC CHOLESTASIS OF PREGNANCY TYPE 1
• ETIOLOGY
• ATP8B1 is a Flippase for Phosphatidylserine
• ATP8B1 Increases the Detergent Resistance of the Canalicular Membrane
• ATP8B1 Signals through the Farnesoid X Receptor Pathway
• ANALYSES OF PFIC TYPE 1 AND BRIC TYPE 1 MUTATIONS
• EXTRAHEPATIC PHENOTYPES OF ATP8B1 DEFICIENCY
• CONCLUSION
• i ACKNOWLEDGMENTS
• ABBREVIATIONS
• REFERENCES

ABSTRACT

Progressive familial intrahepatic cholestasis type 1 is a rare genetic liver disease that presents in the first year of life. Bile salts are elevated and these patients are often jaundiced. Despite the cholestasis, serum gamma-glutamyltransferase activity is normal or reduced. Pruritus is a major symptom in these patients. Partial external biliary diversion is helpful in several patients as it reduces the pruritus and postpones or even avoids liver transplantation. The disease is caused by mutations in the gene ATP8B1 that preclude the normal expression of ATP8B1. ATP8B1 is a protein that acts as a lipid flippase, transporting phosphatidylserine from the exoplasmic to the cytoplasmic leaflet of the canalicular membrane of hepatocytes. The authors have shown that the canalicular membrane of ATP8B1-deficient hepatocytes is less stable as evidenced by enhanced extraction of membrane constituents by bile salts. Recent evidence suggests membrane instability in ATP8B1-deficient hair cells of the ear, providing an explanation for hearing loss in ATP8B1 deficiency. Although the exact etiology of cholestasis is incompletely understood, it is hypothesized that ATP8B1 deficiency results in enhanced cholesterol extraction from the canalicular membrane, which impairs the function of the bile salt export pump (BSEP), resulting in cholestasis. Mutations in ATP8B1 also cause benign recurrent intrahepatic cholestasis, a milder variant of the disease characterized by episodes of cholestasis. The onset and resolution of the cholestatic episodes in these patients is still not well understood.

Jaundice in the first month of life has an extensive differential diagnosis. In ~10 to 15% of cases the cause is progressive familial intrahepatic cholestasis (PFIC). The chance that a patient has PFIC is considerably enhanced when the family history is positive for pediatric cholestasis, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis, or a family history positive for (intrahepatic) gallstones at young age. PFIC patients often complain of pruritus. In PFIC types 1 and 2 pruritus is severe, in PFIC type 3 it is more variable and moderate. Cholestasis can occur without pruritus, but in patients with PFIC this is rare. In case the cholestasis in a newborn is transient or episodic, the diagnosis likely is PFIC type 1. Permanent cholestasis from the onset of the disease is more often seen in PFIC type 2. Cholestasis with only mild jaundice occurs in PFIC type 3. Elevated serum levels of primary bile salts are an invariable feature of all PFICs. In PFIC type 1 and 2, serum gamma-glutamyltransferase (GGT) levels are normal, whereas in PFIC type 3, and most other cholestatic syndromes, GGT is elevated.[1] Here we will focus on PFIC type 1.

PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS TYPE 1

PFIC type 1 is known under several names: Byler disease or syndrome[2] [3] and Greenland familial cholestasis.[4] The name Byler is associated with this disease because Jacob Byler and Nancy Kaufmann were the carriers of the original disease-causing mutation. They are descendants of Amish settlers who emigrated from Switzerland to the United States some 250 years ago and are considered the “founding fathers” of the disease. Members of the Old Order Amish population in Pennsylvania all have the same mutation of a gene called ATP8B1. This gene encodes a P-type ATPase that functions as a flippase for phosphatidylserine in the canalicular membrane of hepatocytes (see below). The protein is also expressed in the apical membrane of cholangiocytes, enterocytes, and acinar cells of the pancreas.[5] [6] Byler disease refers to PFIC type 1 caused by one particular mutation of the ATP8B1 gene, a homozygous G-T mutation, resulting in a glycine to valine substitution at amino acid 308. Many PFIC type 1 patients, mostly of European or Mediterranean descent, have been identified who do not belong to the Byler kindred. This patient group carries a great number of different mutations.[7]

Diagnosis

Patients with PFIC type 1 present in the first year of life, usually in the first weeks after birth, with pruritus and jaundice. Cholestasis in these children can be episodic in the beginning, but will become permanent later on. They then become more or less jaundiced and they show a failure to thrive. Hearing loss has been reported in a large fraction of these patients.[8] Biochemical tests show a normal or even subnormal serum GGT activity, normal cholesterol levels, moderately elevated serum bilirubin, including conjugated bilirubin, moderately elevated transaminase activities, clotting abnormalities due to vitamin K deficiency, and a strongly elevated level of the primary bile salts chenodeoxycholic acid and cholic acid. Liver ultrasound, magnetic resonance imaging (MRI), or computed tomography (CT) shows no abnormalities, in particular, no dilated bile ducts either intra- or extrahepatic. Liver histology shows intrahepatic cholestasis with little hepatocellular necrosis or giant cell transformation. It is a rather “bland” picture of cholestasis.[9] In contrast, PFIC type 2 is associated with a more active liver histology with signs of giant cell hepatitis and necrosis and in PFIC type 3 there is ample ductular proliferation. Under the electron microscope, PFIC type 1bile has a coarse granular aspect, which distinguishes it from amorphous PFIC type 2 bile. Immunohistochemistry is particularly helpful to diagnose PFIC type 2 and 3, less so in PFIC type 1. This is mainly due to lack of standardized antibodies. Mutational analysis of the ATP8B1 gene is the cornerstone of the diagnosis. Because outside of Pennsylvania there is no dominant mutation, the entire gene needs to be sequenced.

Therapy

Children with PFIC type 1 may benefit from surgical partial external biliary diversion (PEBD).[10] In this technique, the gallbladder is connected to a stoma in the skin by a loop of small bowel. The mechanism of action is not entirely clear. Partial interruption of the enterohepatic circulation, caused by this procedure, leads to reduction of the bile salt pool and this has a beneficial effect on the cholestasis. The main reason may be that this induces a shift from the more hydrophobic secondary bile salts to more hydrophilic and less-toxic primary bile salts. The bile salt sequestrant colesevelam might be a useful alternative therapy, but data to prove its effect are not yet available. Ursodeoxycholic acid, very helpful in PFIC type 3, is less effective in PFIC type 1. When PEBD fails, liver transplantation is the only effective solution. Because the PFIC type 1 disease is not confined to the liver, extrahepatic manifestations may persist after transplantation, such as sensorineural hearing loss, or may become worse, such as watery diarrhea. The diarrhea in this situation usually reacts to bile salt sequestrants.[11] Also, a few cases of pancreatitis have been reported in this disease.[12] Interestingly, liver steatosis (sometimes with progression to steatohepatitis) may develop in the liver graft.[13] [14]

BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS TYPE 1

PFIC type 1 is an autosomal homozygous disease. Heterozygotes with a mutation of the ATP8B1 gene or homozygotes with a mutation that only partly affects the function of the protein may present with benign recurrent intrahepatic cholestasis (BRIC) type 1 or Tygstrup,[15] or Summerskill and Walshe cholestasis.[16] This disease usually becomes manifest in adolescence and is characterized by episodes of cholestasis with severe pruritus and jaundice. During these episodes patients often show significant weight loss and steatorrhea. Episodes of cholestasis come and go without apparent disease-causing events. Episodes usually last for weeks or months. A period of 2 to 3 months is very common. Later in life, the cholestatic episodes become less frequent. Proven effective therapy to avoid or to shorten the cholestatic episodes is not available. When pruritus becomes unbearable, partial external drainage of bile by a nasobiliary drain may be helpful.[17] Bile salt sequestrants like cholestyramine may occasionally give symptomatic relief. The value of colesevelam needs to be studied.

INTRAHEPATIC CHOLESTASIS OF PREGNANCY TYPE 1

Intrahepatic cholestasis of pregnancy (ICP) has been reported in two patients with missense mutations in ATP8B1. ICP, though rare, may occur in families of PFIC type 1 or BRIC type 1 patients.[18] [19] This type of ICP is best called ICP type 1, as to differentiate this condition from ICP type 2, with a mutation in the ABCB11/BSEP gene, or the most common ICP type 3, with a mutation in ABCB4/MDR3 gene.

ETIOLOGY

The etiology of ATP8B1 deficiency is not completely understood and is the subject of controversy. The molecular activity of ATP8B1 and the relation between ATP8B1 deficiency and intrahepatic cholestasis has been extensively studied in vivo and in vitro and will be highlighted below.

ATP8B1 is a Flippase for Phosphatidylserine

ATP8B1 is a member of the type 4 subfamily of P-type ATPases (P4 ATPase). P4 ATPases are multispan transmembrane proteins that are implicated in phospholipid translocation from the exoplasmic to the cytoplasmic leaflet of biologic membranes.[20] [21] In most eukaryotic cells phosphatidylcholine and (glycol)sphingolipids are concentrated in the exoplasmic leaflet, whereas the aminophospholipids phosphatidylserine (PS) and phosphatidylethanolamine are largely confined to the cytoplasmic leaflet of the plasma membrane.[22] This asymmetric distribution is actively maintained by proteins termed floppases and flippases.[23] [24] To study whether ATP8B1 is an aminophospholipid flippase, Ujhazy and coworkers expressed the protein in Chinese hamster ovary (CHO) cells.[25] In these cells, they demonstrated ATP8B1-dependent uptake of a model substrate for lipid flippases – fluorescently labeled PS (NBD-PS). Work from our laboratory demonstrated that this system is more complex in that ATP8B1-mediated PS translocation requires coexpression of a putative β-subunit termed CDC50A.[26] Only when ATP8B1 and CDC50A were coexpressed, ATP8B1 was released from the endoplasmic reticulum and localized to the plasma membrane of CHO cells. This coincided with a significant increase in NBD-PS and natural PS internalization. Recently, Cai and coworkers showed in rat hepatocyte sandwich cultures that Atp8b1 deficiency resulted in enhanced accumulation of NBD-PS in the canalicular lumen compared with control.[27] All together these observations indicate that ATP8B1 functions as a flippase for PS.

ATP8B1 Increases the Detergent Resistance of the Canalicular Membrane

The canalicular membrane is a highly rigid, detergent-resistant membrane that is enriched in cholesterol and sphingomyelin (SM).[28] [29] This allows tight packing of the membrane lipids into a so-called liquid-ordered state and makes the membrane extremely resistant to bile salt-mediated lipid extraction.[30] Previous work from Jim Boyers' and our laboratory indicates that ATP8B1 is indispensable in maintaining this detergent resistant state of the canalicular membrane, as will be discussed below.

To study the mechanism whereby impaired ATP8B1 function results in cholestasis, a mouse model for PFIC type 1, the Atp8b1^G308V/G308V mouse was generated.[31] Atp8b1^{G308V / G308V} mutant mice (further referred to as Atp8b1-deficient) are knock-in mice for the prototypic PFIC type 1 mutation from the Byler family that results in near absence of the protein. For the past few years we have extensively studied bile formation in these mice. In contrast to human patients, Atp8b1-deficient mice have only marginally increased serum bile salt levels and display no liver pathology.[31] These mice do have a twofold enlarged bile salt pool size compared with wild-type mice, indicating a very mild cholestasis. Challenge of these mice with bile salt-supplemented diets resulted in a dramatic increase in serum bile salt levels and a fourfold larger bile salt pool size compared with controls. Despite the rise in serum bile salts, liver pathology is not dramatic and biliary bile salt output is normal, indicating that hepatocellular bile salt secretion is not severely impaired. These observations illustrate that the liver phenotype of the mouse model is less severe than that of human PFIC type 1/BRIC type 1 patients. This discrepancy between mice and human phenotypes can be explained by the strong difference in the composition of the bile salt pool between mice and man. Due to the ability of mice to detoxify hydrophobic bile salts by (re)hydroxylation, mouse bile contains predominantly trihydroxy bile salts (cholate and muricholate). Humans cannot rehydroxylate toxic bile salts and have mainly dihydroxy bile salts (chenodeoxycholate and deoxycholate) with ~30% trihydroxy bile salt (cholate).

Despite the very mild cholestatic phenotype, the canalicular membrane of hepatocytes in Atp8b1-deficient mice was more sensitive to the detergent action of hydrophobic bile salts[32] [33]: infusion of taurocholate (TC) resulted in a twofold enhanced biliary recovery of cholesterol and sphingomyelin compared with wild type. The enhanced biliary cholesterol output is most likely due to extraction from the canalicular membrane as it was independent of the sterol transporter Abcg5/g8; Atp8b1-deficient mice in which Abcg5/g8 was also inactivated still displayed enhanced TC-induced cholesterol output.[33] The most remarkable observation was the presence of significant amounts of phosphatidylserine (PS) in bile from Atp8b1-deficient mice, whereas it was not detectable in bile from controls.[32] [33] This suggests that PS is exposed in the exoplasmic canalicular membrane leaflet in Atp8b1-deficient mice, where it is extracted by TC. Ultrastructural analysis revealed that bile canaliculi of Atp8b1-deficient mice contained multilamellar lipid structures, which are very reminiscent of those found in PFIC type 1 patients (i.e., Byler bile).[32] Another observation indicative of membrane damage was a dramatic rise in canalicular ectoenzyme activity (alkaline phosphatase and aminopeptidase N) in bile of Atp8b1-deficient mice. Similar observations were made by histochemical analysis of liver tissue from PFIC type 1 patients.[32] GGT and neutral endopeptidase were not detectable in the canalicular membrane, but were present in the apical membranes of cholangiocytes. Similarly, in Atp8b1-deficient rat hepatocytes, canalicular membrane areas were disrupted after exposure to chenodeoxycholic acid as demonstrated by transmission electron microscopy.[27]

From all these observations we have hypothesized that ATP8B1 is important to reduce the outer leaflet content of phosphatidylserine, so as to maintain a rigid, liquid-ordered, membrane that is resistant toward bile salts. How would this lead to cholestasis? We have recently demonstrated that canalicular membranes of bile salt-fed cholestatic Atp8b1-deficient mice have a dramatically reduced cholesterol-to-phospholipid ratio compared with bile salt-fed wild-type controls.[34] Cholesterol content of the membrane is an essential determinant of the activity of the major bile salt transporter BSEP and of the conjugated bilirubin transporter MRP2 (encoded by the ABCC2 gene). In fact, there is a linear relationship between membrane cholesterol content and BSEP activity.[34] In line with these observations, Cai and coworkers recently demonstrated that BSEP activity was reduced by 40% compared with control in Atp8b1-deficient rat hepatocytes.[27] ATP8B1-deficiency thus leads to loss of the normal phospholipid asymmetry of the canalicular membrane. As a result, the canalicular membrane becomes more sensitive to extraction of cholesterol by hydrophobic bile salts, which impairs the activity of BSEP and, as a consequence, causes cholestasis (see Fig. [1]).

ATP8B1 Signals through the Farnesoid X Receptor Pathway

An alternative hypothesis for why ATP8B1 deficiency results in cholestasis is based on findings that ATP8B1 deficiency impairs farnesoid X Receptor (FXR) signaling.[35] [36] [37] [38] [39] [40] FXR is activated in response to elevated bile salt levels. In the liver, FXR induces BSEP expression, thereby stimulating biliary bile salt output. In the intestine, FXR represses ASBT expression, thus reducing intestinal bile salt reabsorption. Chen and coworkers reported that in ileal biopsies of PFIC type 1 patients and in Caco-2 cells, ATP8B1 deficiency is associated with reduced FXR and enhanced ASBT transcript levels.[36] Subsequent studies in CHO cells and in primary human hepatocytes indicated that impaired FXR signaling is caused by impaired PKCζ-mediated phosphorylation of cytosolic FXR and subsequent absence of nuclear translocation.[37] [38] Inhibition of PKCζ activity coincided with reduced BSEP and enhanced ASBT promoter activation, whereas PKCζ overexpression resulted in activation of BSEP promoter activity. Based on these findings, the authors hypothesized that ATP8B1 activity is essential for PKCζ activation, which leads to FXR phosphorylation, nuclear translocation, and transcriptional regulation of target genes. Thus far, however, no experimental evidence is published that ATP8B1-mediated PS flipping is essential for PKCζ activation. Similar observations in one PFIC type 1 patient and in HepG2 cells were published by Alvarez and coworkers and Koh and coworkers.[35] [39] [40] Cai and coworkers also studied FXR signaling in cultured human and rat Atp8b1-depleted hepatocytes, but did not find any ATP8B1-dependent signaling to FXR.[27] Moreover, data by Demeilliers and coworkers indicated that FXR downregulation in PFIC type 1 is secondary to the cholestasis because a similar downregulation is observed in patients with other cholestatic diseases.[41] In addition, in Atp8b1-deficient mice hepatic and ileal expression of FXR was found to be intact and only reduced in liver upon induction of cholestasis by bile salt feeding.[31] [33] Even under these conditions, intestinal bile salt resorption was not increased. Finally, and most convincingly, Cyp7a1 expression in liver of Atp8b1-deficient mice on a bile salt supplemented diet was completely downregulated.[31] It has become clear more recently, that hepatic CYP7A1 expression is mainly regulated by FGF15, which is secreted by terminal ileocytes into portal blood.[42] Ileal FGF15 expression is FXR dependent, hence, these data demonstrate that the FXR-dependent gut–liver axis of bile salt synthesis regulation is fully intact under all conditions in Atp8b1-deficient mice. Thus, reduced FXR expression in PFIC type 1 appears to be a consequence rather than a cause of the cholestatic phenotype in ATP8B1 deficiency.

ANALYSES OF PFIC TYPE 1 AND BRIC TYPE 1 MUTATIONS

PFIC type 1 and BRIC type 1 are caused by different mutations in ATP8B1. Recently, the consequences of several PFIC type 1 and BRIC type 1 mutations on ATP8B1 protein stability, folding, and localization have been studied.[43] [44] Folmer and coworkers demonstrated reduced protein stability for all PFIC type 1- and BRIC type 1-causing missense mutations. Similarly, two missense mutations associated with ICP also resulted in reduced protein stability. Importantly, the authors showed that all PFIC type 1 mutant proteins localized to the endoplasmic reticulum of the hepatocyte model cell line WIF-B9; all BRIC type 1 and ICP mutants, on the other hand displayed canalicular localization comparable with the wild-type protein.[43] Also, Van der Velden and coworkers reported reduced protein expression for a panel of PFIC type 1- and BRIC type 1-causing missense (and one nonsense) mutations.[44] Several mutants were partially retained in the endoplasmic reticulum of nonpolarized human bone osteosarcoma epithelial cells. Via molecular modeling the authors propose that reduced protein expression is caused by improper folding, which could be ameliorated by the pharmacologic chaperone 4-phenylbutyrate. The factors that cause onset and resolution of the cholestatic episodes in BRIC type 1 remain elusive; however, two possible explanations have been postulated. First, Van der Velden and coworkers report an anecdotal observation of BRIC type 1 patients in which cholestatic attacks are sometimes preceded by fever.[44] From this and their observation that plasma membrane expression of the I661T BRIC type 1 mutant is further reduced when cells are grown at 40°C, they speculate fever to be a potential initiating factor of a cholestatic attack, at least in I661T BRIC type 1 patients.[44] Second, Folmer and coworkers propose that a cholestatic episode coincides with impaired BSEP activity.[43] This explanation is based on the model in which ATP8B1 deficiency results in loss of the rigid, liquid-ordered state of the canalicular membrane followed by bile salt-induced extraction of membrane cholesterol, which in turn impairs BSEP activity (see Fig. [1]). In a noncholestatic period, ATP8B1 activity is just sufficient to maintain a membrane environment in which BSEP activity is not impaired. Infections associated with a proinflammatory cytokine response may initiate a cholestatic attack in BRIC type 1. Endotoxin/lipopolysaccharide (LPS) causes posttranscriptional downregulation of human BSEP.[45] In mice, downregulation of Abcb11/Bsep was observed upon exposure to LPS, interleukin-6, tumor necrosis factor-α, or interleukin-1β.[46] [47]

EXTRAHEPATIC PHENOTYPES OF ATP8B1 DEFICIENCY

Apart from a mild cholestasis, Atp8b1-deficient mice do not display overt diarrhea or pancreatitis; however, as in some patients they do develop hearing loss.[8] [48] ATP8B1 is expressed in the apical region of the stereocilia of the cochlear hair cells in the Organ of Corti. In the Organ of Corti (sound) pressure-induced fluid movements are converted into action potentials. The stereocilia of the hair cells contain different ion channels, which are activated by mechanostimulation of the stereocilia. Atp8b1-deficiency is associated with a progressive degeneration of stereocilia and hair cells, which was already obvious in 16-day-old mice. Hearing loss was displayed after 1 month in the frequency range 8 to 32 kHz. Analogous to our model proposed for the hepatic phenotype in ATP8B1 deficiency (Fig. [1]), the hearing phenotype can also be explained by an impaired PS flippase that affects mechanotransduction.[48] First, the altered membrane composition may lead to reduced stereociliar stability. Second, the altered membrane composition may lead to impaired ion channel activity. Third, the altered membrane composition may impair phosphoinositide signaling.

CONCLUSION

PFIC type 1 is a cholestatic disease that presents itself during the first year of life with pruritus, jaundice, and elevated liver enzymes. The disease is caused by mutations of the ATP8B1 gene. BRIC type 1 and possibly ICP type 1 occur in patients heterozygous for one of the many ATP8B1 mutations.

Studies on the etiology of the disease have revealed insights that may be of relevance to other, less rare, cholestatic liver diseases. ATP8B1 encodes a protein that acts as a flippase, mediating the transfer of phosphatidylserine from the outer to the inner leaflet of the canalicular membrane of hepatocytes. This renders the outer leaflet resistant to the detergent action of bile salts that are present in high concentration in the canalicular lumen. In the absence of the flippase, the canalicular membrane becomes sensitive to the detergent action of bile salts that results in the loss of membrane cholesterol, which impairs the function of BSEP. We render this a likely explanation for the onset of the cholestasis in ATP8B1 deficiency. As a consequence of the cholestasis, impaired FXR signaling may aggravate the pathology. The factors, which initiate the episodes of cholestasis that characterize BRIC type 1, are still elusive. Often, fever occurs prior to a cholestatic episode, suggesting that a slight elevation of temperature or an accompanying systemic inflammatory response may decrease BSEP activity: this may be instrumental in the onset of cholestasis in these patients. A canalicular membrane that is more sensitive to the inherent toxicity of bile remains key to understanding this disease.

ACKNOWLEDGMENTS

P.J., R.O.E., and C.C.P. received grants from the Dutch Digestive Disease Foundation.

ABBREVIATIONS

• ABC ATP-binding cassette

• BRIC benign recurrent intrahepatic cholestasis

• BSEP bile salt export pump

• CHO Chinese ovary cells

• FXR farnesoid X-receptor

• GGT gamma-glutamyltransferase

• ICP intrahepatic cholestasis of pregnancy

• MRP multidrug resistance associated protein

• PEBD partial external biliary diversion

• PFIC progressive familial intrahepatic cholestasis

• PS phosphatidylserine

• TC taurocholate

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• 32 Paulusma C C, Groen A, Kunne C et al.. ATP8B1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport.  Hepatology. 2006;  44(1) 195-204
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• 33 Groen A, Kunne C, Jongsma G et al.. ABCG5/8 independent biliary cholesterol excretion in ATP8B1-deficient mice.  Gastroenterology. 2008;  134(7) 2091-2100
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• 34 Paulusma C C, de Waart D R, Kunne C, Mok K S, Elferink R P. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content.  J Biol Chem. 2009;  284(15) 9947-9954
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• 35 Alvarez L, Jara P, Sánchez-Sabaté E et al.. Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1.  Hum Mol Genet. 2004;  13(20) 2451-2460
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• 36 Chen F, Ananthanarayanan M, Emre S et al.. Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity.  Gastroenterology. 2004;  126(3) 756-764
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• 39 Koh S, Takada T, Kukuu I, Suzuki H. FIC1-mediated stimulation of FXR activity is decreased with PFIC1 mutations in HepG2 cells.  J Gastroenterol. 2009;  44(6) 592-600
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• 42 Inagaki T, Choi M, Moschetta A et al.. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis.  Cell Metab. 2005;  2(4) 217-225
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• 43 Folmer D E, van der Mark V A, Ho-Mok K S, Oude Elferink R P, Paulusma C C. Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular localization of ATP8B1.  Hepatology. 2009;  50(5) 1597-1605
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• 44 van der Velden L M, Stapelbroek J M, Krieger E et al.. Folding defects in P-type ATP 8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate.  Hepatology. 2010;  51(1) 286-296
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• 45 Elferink M G, Olinga P, Draaisma A L et al.. LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttranscriptional process.  Am J Physiol Gastrointest Liver Physiol. 2004;  287(5) G1008-G1016
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• 46 Geier A, Dietrich C G, Voigt S et al.. Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver.  Am J Physiol Gastrointest Liver Physiol. 2005;  289(5) G831-G841
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• 47 Siewert E, Dietrich C G, Lammert F et al.. Interleukin-6 regulates hepatic transporters during acute-phase response.  Biochem Biophys Res Commun. 2004;  322(1) 232-238
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• 48 Stapelbroek J M, Peters T A, van Beurden D H et al.. ATP8B1 is essential for maintaining normal hearing.  Proc Natl Acad Sci U S A. 2009;  106(24) 9709-9714
  CrossrefPubMedSearch in Google Scholar

Peter L.M JansenM.D. Ph.D. 

Department of Gastroenterology and Liver Disease, Academic Medical Center

Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Email: p.l.jansen@amc.uva.nl

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  CrossrefPubMedSearch in Google Scholar
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• 40 Martínez-Fernández P, Hierro L, Jara P, Alvarez L. Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064.  Am J Physiol Gastrointest Liver Physiol. 2009;  296(5) G1119-G1129
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  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
• 43 Folmer D E, van der Mark V A, Ho-Mok K S, Oude Elferink R P, Paulusma C C. Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular localization of ATP8B1.  Hepatology. 2009;  50(5) 1597-1605
  CrossrefPubMedSearch in Google Scholar
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  PubMedSearch in Google Scholar
• 45 Elferink M G, Olinga P, Draaisma A L et al.. LPS-induced downregulation of MRP2 and BSEP in human liver is due to a posttranscriptional process.  Am J Physiol Gastrointest Liver Physiol. 2004;  287(5) G1008-G1016
  CrossrefPubMedSearch in Google Scholar
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  CrossrefPubMedSearch in Google Scholar
• 47 Siewert E, Dietrich C G, Lammert F et al.. Interleukin-6 regulates hepatic transporters during acute-phase response.  Biochem Biophys Res Commun. 2004;  322(1) 232-238
  CrossrefPubMedSearch in Google Scholar
• 48 Stapelbroek J M, Peters T A, van Beurden D H et al.. ATP8B1 is essential for maintaining normal hearing.  Proc Natl Acad Sci U S A. 2009;  106(24) 9709-9714
  CrossrefPubMedSearch in Google Scholar

Peter L.M JansenM.D. Ph.D. 

Department of Gastroenterology and Liver Disease, Academic Medical Center

Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Email: p.l.jansen@amc.uva.nl