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Semin Liver Dis 2001; 21(4): 535-544
DOI: 10.1055/s-2001-19034
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

FIC1 Disease: A Spectrum of Intrahepatic Cholestatic Disorders

Saskia W. C. van Mil1 , Leo W. J. Klomp2 , Laura N. Bull3 , Roderick H. J. Houwen1
  • 1Pediatric Gastroenterology, University Medical Center, Utrecht, The Netherlands
  • 2Metabolic Diseases, University Medical Center, Utrecht, The Netherlands
  • 3Liver Center Laboratory, San Francisco General Hospital, University of California, San Francisco, California, U.S.A
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Publication History

Publication Date:
17 December 2001 (online)

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ABSTRACT

FIC1 disease collectively refers to a group of autosomal-recessive familial liver disorders characterized by intrahepatic cholestasis due to mutations in the ATP8B1 gene (initially named FIC1). Classically, FIC1 disease comprises two different disorders: progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis (BRIC). However, we now view these two disorders as two ends of a continuum. Current therapeutic strategies for FIC1 disease, both medical and surgical, may relieve symptoms, but are presently insufficiently evaluated. ATP8B1 encodes a protein belonging to a recently defined subfamily of P-type ATPases. The biochemical and cellular functions of its product, FIC1, and the mechanisms by which its absence or dysfunction leads to cholestasis are currently elusive. Further studies to elucidate FIC1's function will be essential to unravel the pathogenesis of FIC1 disease. Such studies will also have a general impact on our understanding of the molecular mechanisms of bile formation and may therefore improve clinical management of both hereditary and acquired forms of cholestasis.

KEYWORD

FIC1 disease - cholestasis - bile acid secretion - P-type ATPases

REFERENCES

  • 1 Arrese M, Ananthananarayanan M, Suchy F J. Hepatobiliary transport: molecular mechanisms of development and cholestasis.  Pediatr Res . 1998;  44 141-147
    PubMedSearch in Google Scholar
  • 2 Jacquemin E, Hadchouel M. Genetic basis of progressive familial intrahepatic cholestasis.  J Hepatol . 1999;  31 377-381
    CrossrefPubMedSearch in Google Scholar
  • 3 Knisely A S. Progressive familial intrahepatic cholestasis: a personal perspective.  Pediatr Dev Pathol . 2000;  3 113-125
    PubMedSearch in Google Scholar
  • 4 Clayton R J, Iber F L, Ruebner B H. Byler disease.  Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child . 1969;  117 112-124
    PubMedSearch in Google Scholar
  • 5 Summerskill W HJ, Walshe J M. Benign recurrent intrahepatic obstructive jaundice.  Lancet . 1959;  2 686-690
    PubMedSearch in Google Scholar
  • 6 Nielsen I M, Ornvold K, Jacobsen B B. Fatal familial cholestatic syndrome in Greenland Eskimo children.  Acta Paediatr Scand . 1986;  75 1010-1016
    PubMedSearch in Google Scholar
  • 7 Klomp L W, Bull L N, Knisely A S. A missense mutation in FIC1 is associated with Greenland familial cholestasis.  Hepatology . 2000;  32 1337-1341
    CrossrefPubMedSearch in Google Scholar
  • 8 Kullak-Ublick G A, Stieger B. Hepatic transport of bile salts.  Semin Liver Dis . 2000;  20 273-292
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Jacquemin E, Setchell K D, O'Connell N C. A new cause of progressive intrahepatic cholestasis: 3 beta-hydroxy-C27-steroid dehydrogenase/isomerase deficiency.  J Pediatr . 1994;  125 379-384
    PubMedSearch in Google Scholar
  • 10 Setchell K D, Schwarz M, O'Connell N C. Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.  J Clin Invest . 1998;  102 1690-1703
    PubMedSearch in Google Scholar
  • 11 de Vree M J, Jacquemin E, Sturm E. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.  Proc Natl Acad Sci U S A . 1998;  95 282-287
    CrossrefPubMedSearch in Google Scholar
  • 12 Morton D H, Salen G, Batta A K. Abnormal hepatic sinusoidal bile acid transport in an Amish kindred is not linked to FIC1 and is improved by ursodiol.  Gastroenterology . 2000;  119 188-195
    PubMedSearch in Google Scholar
  • 13 Betard C, Rasquin-Weber A, Brewer C. Localization of a recessive gene for North American Indian childhood cirrhosis to chromosome region 16q22 and identification of a shared haplotype.  Am J Hum Genet . 2000;  67 222-228
    CrossrefPubMedSearch in Google Scholar
  • 14 Bull L N, Roche E, Song E J. Mapping of the locus for cholestasis-lymphedema syndrome (Aegenaes syndrome) to a 6.6-cM interval on chromosome 15q.  Am J Hum Genet . 2000;  67 994-999
    CrossrefPubMedSearch in Google Scholar
  • 15 Sinke R J, Carlton V E, Juijn J A. Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64.  Hum Genet . 1997;  100 382-387
    PubMedSearch in Google Scholar
  • 16 Floreani A, Molaro M, Mottes M. Autosomal dominant benign recurrent intrahepatic cholestasis (BRIC) unlinked to 18q21 and 2q24.  Am J Med Genet . 2000;  95 450-453
    CrossrefPubMedSearch in Google Scholar
  • 17 Lee J, Boyer J L. Molecular alterations in hepatocyte transport mechanisms in acquired cholestatic liver disorders.  Semin Liver Dis . 2000;  20 373-384
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Rotthauwe H W, Beseler W D, Kowalewski S. Benign recurrent intrahepatic cholestasis.  Klin Wochenschr . 1969;  47 140-149
    CrossrefPubMedSearch in Google Scholar
  • 19 Whitington P F, Freese D K, Alonso E M. Clinical and biochemical findings in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr . 1994;  18 134-141
    PubMedSearch in Google Scholar
  • 20 Tygstrup N, Steig B A, Juijn J A. Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity.  Hepatology . 1999;  29 506-508
    CrossrefPubMedSearch in Google Scholar
  • 21 De Koning J T, Sandkuijl L A, De Schryver E J. Autosomal-recessive inheritance of benign recurrent intrahepatic cholestasis.  Am J Med Genet . 1995;  57 479-482
    CrossrefPubMedSearch in Google Scholar
  • 22 Brenard R, Geubel A P, Benhamou J P. Benign recurrent intrahepatic cholestasis. A report of 26 cases.  J Clin Gastroenterol . 1989;  11 546-551
    CrossrefPubMedSearch in Google Scholar
  • 23 Bijleveld C M, Vonk R J, Kuipers F. Benign recurrent intrahepatic cholestasis: altered bile acid metabolism.  Gastroenterology . 1989;  97 427-432
    PubMedSearch in Google Scholar
  • 24 de Pagter G A, Berge Henegouwen P G, Bokkel Huinink A J, Brandt K H. Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives?.  Gastroenterology . 1976;  71 202-207
    PubMedSearch in Google Scholar
  • 25 Bull L N, Carlton V E, Stricker N L. Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.  Hepatology . 1997;  26 155-164
    CrossrefPubMedSearch in Google Scholar
  • 26 Ornvold K, Nielsen I M, Poulsen H. Fatal familial cholestatic syndrome in Greenland Eskimo children. A histomorphological analysis of 16 cases.  Virchows Arch [A] . 1989;  415 275-281
    PubMedSearch in Google Scholar
  • 27 Catano da Silva L, De Brito T. Benign recurrent intrahepatic cholestasis in two brothers.  Ann Intern Med . 1966;  65 330-341
    PubMedSearch in Google Scholar
  • 28 Cissarek T, Schumacher B, Schwobel H. Follow-up of benign recurrent intrahepatic cholestasis (Summerskill-Walshe-Tygstrup syndrome) over 46 years.  Z Gastroenterol . 1998;  36 379-383
    PubMedSearch in Google Scholar
  • 29 Alonso E M, Snover D C, Montag A. Histologic pathology of the liver in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr . 1994;  18 128-133
    CrossrefPubMedSearch in Google Scholar
  • 30 Williams, Carter M A, Sherlock S. Ideopathic recurrent cholestasis: a study of the functional and pathological lesions in four cases.  Q J Med . 1964;  131 387-399
    PubMedSearch in Google Scholar
  • 31 Bircher J. Treatment of patients with benign recurrent intrahepatic cholestasis.  Hepatology . 1989;  10 1030-1032
    PubMedSearch in Google Scholar
  • 32 Crosignani A, Podda M, Bertolini E. Failure of ursodeoxycholic acid to prevent a cholestatic episode in a patient with benign recurrent intrahepatic cholestasis: a study of bile acid metabolism.  Hepatology . 1991;  13 1076-1083
    CrossrefPubMedSearch in Google Scholar
  • 33 Jacquemin E. Progressive familial intrahepatic cholestasis.  J Gastroenterol Hepatol . 1999;  14 594-599
    CrossrefPubMedSearch in Google Scholar
  • 34 Yerushalmi B, Sokol R J, Narkewicz M R. Use of rifampin for severe pruritus in children with chronic cholestasis.  J Pediatr Gastroenterol Nutr . 1999;  29 442-447
    CrossrefPubMedSearch in Google Scholar
  • 35 Cancado E L, Leitao R M, Carrilho F J. Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of gamma-glutamyl transpeptidase.  Am J Gastroenterol . 1998;  93 1510-1517
    PubMedSearch in Google Scholar
  • 36 Melter M, Rodeck B, Kardorff R. Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients.  Am J Gastroenterol . 2000;  95 3522-3528
    CrossrefPubMedSearch in Google Scholar
  • 37 Emond J C, Whitington P F. Selective surgical management of progressive familial intrahepatic cholestasis (Byler's disease).  J Pediatr Surg . 1995;  30 1635-1641
    CrossrefPubMedSearch in Google Scholar
  • 38 Ismail H, Kalicinski P, Markiewicz M. Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial external biliary diversion.  Pediatr Transplant . 1999;  3 219-224
    CrossrefPubMedSearch in Google Scholar
  • 39 Hollands C M, Rivera-Pedrogo F J, Gonzalez-Vallina R. Ileal exclusion for Byler's disease: an alternative surgical approach with promising early results for pruritus.  J Pediatr Surg . 1998;  33 220-224
    CrossrefPubMedSearch in Google Scholar
  • 40 Soubrane O, Gauthier F, DeVictor D. Orthotopic liver transplantation for Byler disease.  Transplantation . 1990;  50 804-806
    CrossrefPubMedSearch in Google Scholar
  • 41 Houwen R H, Baharloo S, Blankenship K. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis.  Nat Genet . 1994;  8 380-386
    PubMedSearch in Google Scholar
  • 42 Carlton V E, Knisely A S, Freimer N B. Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region.  Hum Mol Genet . 1995;  4 1049-1053
    CrossrefPubMedSearch in Google Scholar
  • 43 Kagalwalla A F, Al Amir R A, Khalifa A. Progressive familial intrahepatic cholestasis (Byler's disease) in Arab children.  Ann Trop Paediatr . 1995;  15 321-327
    PubMedSearch in Google Scholar
  • 44 Strautnieks S S, Kagalwalla A F, Tanner M S. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24.  Am J Hum Genet . 1997;  61 630-633
    CrossrefPubMedSearch in Google Scholar
  • 45 Bull L N, van Eijk J M, Pawlikowska L. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.  Nat Genet . 1998;  18 219-224
    CrossrefPubMedSearch in Google Scholar
  • 46 Bull L N, Juijn J A, Liao M. Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC.  Hum Genet . 1999;  104 241-248
    CrossrefPubMedSearch in Google Scholar
  • 47 Klomp L W, Bull L N, Juijn J A. Characterization of multiple different mutations in FIC1 associated with hereditary cholestasis.  Hepatology . 1999;  30 (Abst) 407
    PubMedSearch in Google Scholar
  • 48 Strautnieks S S, Bull L N, Knisely A S. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.  Nat Genet . 1998;  20 233-238
    CrossrefPubMedSearch in Google Scholar
  • 49 Lutsenko S, Kaplan J H. Organization of P-type ATPases: significance of structural diversity.  Biochemistry . 1995;  34 15607-15613
    CrossrefPubMedSearch in Google Scholar
  • 50 Scarborough G A. Structure and function of the P-type ATPases.  Curr Opin Cell Biol . 1999;  11 517-522
    CrossrefPubMedSearch in Google Scholar
  • 51 Sudbrak R, Brown J, Dobson-Stone C. Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump.  Hum Mol Genet . 2000;  9 1131-1140
    CrossrefPubMedSearch in Google Scholar
  • 52 Sakuntabhai A, Ruiz-Perez V, Carter S. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease.  Nat Genet . 1999;  21 271-277
    PubMedSearch in Google Scholar
  • 53 Yamaguchi Y, Heiny M E, Gitlin J D. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease.  Biochem Biophys Res Commun . 1993;  197 271-277
    CrossrefPubMedSearch in Google Scholar
  • 54 Bull P C, Thomas G R, Rommens J M. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.  Nat Genet . 1993;  5 327-337
    CrossrefPubMedSearch in Google Scholar
  • 55 Petrukhin K, Fischer S G, Pirastu M. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene.  Nat Genet . 1993;  5 338-343
    CrossrefPubMedSearch in Google Scholar
  • 56 Vulpe C, Levinson B, Whitney S. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.  Nat Genet . 1993;  3 7-13
    CrossrefPubMedSearch in Google Scholar
  • 57 Mercer J F, Livingston J, Hall B. Isolation of a partial candidate gene for Menkes disease by positional cloning.  Nat Genet . 1993;  3 20-25
    CrossrefPubMedSearch in Google Scholar
  • 58 Chelly J, Monaco A P. Cloning the Wilson disease gene.  Nat Genet . 1993;  5 317-318
    CrossrefPubMedSearch in Google Scholar
  • 59 Tanzi R E, Petrukhin K, Chernov I. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.  Nat Genet . 1993;  5 344-350
    CrossrefPubMedSearch in Google Scholar
  • 60 Palmgren M G, Axelsen K B. Evolution of P-type ATPases.  Biochim Biophys Acta . 1998;  1365 37-45
    PubMedSearch in Google Scholar
  • 61 Catty P, de Kerchove d'Exarde A, Goffeau A. The complete inventory of the yeast Saccharomyces cerevisiae P-type transport ATPases.  FEBS Lett . 1997;  409 325-332
    CrossrefPubMedSearch in Google Scholar
  • 62 Halleck M S, Lawler Jr F J, Blackshaw S. Differential expression of putative transbilayer amphipath transporters.  Physiol Genomics . 1999;  1 139-150
    PubMedSearch in Google Scholar
  • 63 Halleck M S, Pradhan D, Blackman C. Multiple members of a third subfamily of P-type ATPases identified by genomic sequences and ESTs.  Genome Res . 1998;  8 354-361
    PubMedSearch in Google Scholar
  • 64 Chen C Y, Ingram M F, Rosal P H. Role for Drs2p, a P-type ATPase and potential aminophospholipid translocase, in yeast late Golgi function.  J Cell Biol . 1999;  147 1223-1236
    CrossrefPubMedSearch in Google Scholar
  • 65 Tang X, Halleck M S, Schlegel R A. A subfamily of P-type ATPases with aminophospholipid transporting activity.  Science . 1996;  272 1495-1497
    CrossrefPubMedSearch in Google Scholar
  • 66 Futerman A H, Ghidoni R, van Meer G. Lipids: regulatory functions in membrane traffic and cell development.  EMBO J . 1998;  17 6772-6775
    CrossrefPubMedSearch in Google Scholar
  • 67 Bevers E M, Comfurius P, Dekkers D W. Regulatory mechanisms of transmembrane phospholipid distributions and pathophysiological implications of transbilayer lipid scrambling.  Lupus . 1998 (suppl 2);  7 (S126-S131)
    PubMedSearch in Google Scholar
  • 68 Verkleij A J, Post J A. Membrane phospholipid asymmetry and signal transduction.  J Membr Biol . 2000;  178 1-10
    CrossrefPubMedSearch in Google Scholar
  • 69 Siegmund A, Grant A, Angeletti C. Loss of Drs2p does not abolish transfer of fluorescence-labeled phospholipids across the plasma membrane of Saccharomyces cerevisiae J Biol Chem .  1998;  273 34399-34405
    PubMedSearch in Google Scholar
  • 70 Mouro I, Halleck M S, Schlegel R A. Cloning, expression, and chromosomal mapping of a human ATPase II gene, member of the third subfamily of P-type ATPases and orthologous to the presumed bovine and murine aminophospholipid translocase.  Biochem Biophys Res Commun . 1999;  257 333-339
    CrossrefPubMedSearch in Google Scholar
  • 71 Gomes E, Jakobsen M K, Axelsen K B. Chilling tolerance in Arabidopsis involves ALA1, a member of a new family of putative aminophospholipid translocases.  Plant Cell . 2000;  12 2441-2454
    CrossrefPubMedSearch in Google Scholar
  • 72 Dhar M, Webb L S, Smith L. A novel ATPase on mouse chromosome 7 is a candidate gene for increased body fat.  Physiol Genomics . 2000;  4 93-100
    PubMedSearch in Google Scholar
  • 73 Mansharamani M, Hewetson A, Chilton B S. Cloning and characterization of an atypical type IV P-type ATPase that binds to the RING motif of RUSH transcription factors.  J Biol Chem . 2000;  276 3641-3649
    PubMedSearch in Google Scholar
  • 74 Muteru A, Bull L, Pawlikowska L. Cloning and tissue distribution of the rat homologue of the human gene involved in familial intrahepatic cholestasis type 1.  Hepatology . 1998;  28 (Abst) 530
    CrossrefPubMedSearch in Google Scholar
  • 75 Ujhazy P, Ortiz D F, Misra S. ATP-dependent aminophospholipid translocase activity in rat canalicular membrane vesicles and its relationship to FIC1.  Hepatology . 1999;  30 (Abst) 462
    CrossrefPubMedSearch in Google Scholar
  • 76 van Helvoort A, Smith A J, Sprong H. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine.  Cell . 1996;  87 507-517
    CrossrefPubMedSearch in Google Scholar
  • 77 Smit J J, Schinkel A H, Oude Elferink P R. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease.  Cell . 1993;  75 451-462
    CrossrefPubMedSearch in Google Scholar
  • 78 Jansen P L, Muller M. The molecular genetics of familial intrahepatic cholestasis.  Gut . 2000;  47 1-5
    CrossrefPubMedSearch in Google Scholar
  • 79 Keppler D, Konig J, Buchler M. The canalicular multidrug resistance protein, cMRP/MRP2, a novel conjugate export pump expressed in the apical membrane of hepatocytes.  Adv Enzyme Regul . 1997;  37 321-333
    PubMedSearch in Google Scholar
  • 80 Meier P J, Eckhardt U, Schroeder A. Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver.  Hepatology . 1997;  26 1667-1677
    PubMedSearch in Google Scholar
  • 81 Wang R, Salem M, Yousef I M. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis.  Proc Natl Acad Sci USA . 2001;  98 2011-2016
    CrossrefPubMedSearch in Google Scholar
  • 82 Gerloff T, Stieger B, Hagenbuch B. The sister of P- glycoprotein represents the canalicular bile salt export pump of mammalian liver.  J Biol Chem . 1998;  273 10046-10050
    CrossrefPubMedSearch in Google Scholar
  • 83 Green R M, Hoda F, Ward K L. Molecular cloning and characterization of the murine bile salt export pump.  Gene . 2000;  241 117-123
    CrossrefPubMedSearch in Google Scholar
  • 84 Chiang J Y, Kimmel R, Weinberger C. Farnesoid X receptor responds to bile acids and represses cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription.  J Biol Chem . 2000;  275 10918-10924
    CrossrefPubMedSearch in Google Scholar
  • 85 Lu T T, Makishima M, Repa J J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.  Mol Cell . 2000;  6 507-515
    CrossrefPubMedSearch in Google Scholar
  • 86 Repa J J, Mangelsdorf D J. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis.  Annu Rev Cell Dev Biol . 2000;  16 459-481
    CrossrefPubMedSearch in Google Scholar
  • 87 Parks D J, Blanchard S G, Bledsoe R K. Bile acids: natural ligands for an orphan nuclear receptor.  Science . 1999;  284 1365-1368
    CrossrefPubMedSearch in Google Scholar
  • 88 Makishima M, Okamoto A Y, Repa J J. Identification of a nuclear receptor for bile acids.  Science . 1999;  284 1362-1365
    CrossrefPubMedSearch in Google Scholar
  • 89 Sinal C J, Tohkin M, Miyata M. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.  Cell . 2000;  102 731-744
    CrossrefPubMedSearch in Google Scholar
  • 90 Xie W, Radominska-Pandya A, Shi Y. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.  Proc Natl Acad Sci USA . 2001;  98 3375-3380
    Search in Google Scholar
  • 91 Knisely A S, Boyle J T, Naylor E W. Pancreatic disfunction in Byler disease [Abstract].  J Pediatr Gastroenterol Nutr . 1995;  21 328
    PubMedSearch in Google Scholar
  • 92 Staudinger J L, Goodwin B, Jones S A. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.  Proc Natl Acad Sci U S A . 2001;  98 3369-3374
    CrossrefPubMedSearch in Google Scholar
  • 93 Muller M. Transcriptional control of hepatocanalicular transporter gene expression.  Semin Liver Dis . 2000;  20 323-337
    Thieme ConnectPubMedSearch in Google Scholar
  • 94 Goodwin B, Jones S A, Price R R. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.  Mol Cell . 2000;  6 517-526
    CrossrefPubMedSearch in Google Scholar
  • 95 Castillo-Olivares A, Gil G. Role of FXR and FTF in bile acid-mediated suppression of cholesterol 7alpha-hydroxylase transcription.  Nucl Acids Res . 2000;  28 3587-3593
    CrossrefPubMedSearch in Google Scholar
  • 96 Endo T, Uchida K, Amuro Y. Bile acid metabolism in benign recurrent intrahepatic cholestasis. Comparative studies on the icteric and anicteric phases of a single case.  Gastroenterology . 1979;  76 1002-1006
    PubMedSearch in Google Scholar
  • 97 Bourke B, Goggin N, Walsh D. Byler-like familial cholestasis in an extended kindred.  Arch Dis Child . 1996;  75 223-227
    PubMedSearch in Google Scholar
  • 98 Grompe M. Therapeutic liver repopulation for the treatment of metabolic liver diseases.  Hum Cell . 1999;  12 171-180
    PubMedSearch in Google Scholar
  • 99 Sundback C A, Vacanti J P. Alternatives to liver transplantation: from hepatocyte transplantation to tissue-engineered organs.  Gastroenterology . 2000;  118 438-442
    PubMedSearch in Google Scholar
  • 100 Kren B T, Metz R, Kumar R, Steer C J. Gene repair using chimeric RNA/DNA oligonucleotides.  Semin Liver Dis . 1999;  19 93-104
    PubMedSearch in Google Scholar