Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity

Gastroenterology. 2004 Mar;126(3):756-64. doi: 10.1053/j.gastro.2003.12.013.


Background & aims: The mechanisms by which mutations in the familial intrahepatic cholestasis-1 gene cause Byler's disease (progressive familial intrahepatic cholestasis type 1) are unknown.

Methods: Interactions among the apical sodium-dependent bile acid transporter, the farnesoid X receptor (FXR), and familial intrahepatic cholestasis-1 were studied in the ileum of children with progressive familial intrahepatic cholestasis type 1 and in Caco-2 cells.

Results: Increased ileal apical sodium-dependent bile acid transporter messenger RNA (mRNA) expression was detected in 3 patients with progressive familial intrahepatic cholestasis type 1. Paradoxically, ileal lipid-binding protein mRNA expression was repressed, suggesting a central defect in bile acid response. Ileal FXR and short heterodimer partner mRNA levels were reduced in the same 3 patients. In Caco-2 cells, antisense-mediated knock-down of endogenous familial intrahepatic cholestasis-1 led to up-regulation of apical sodium-dependent bile acid transporter and down-regulation of FXR, ileal lipid-binding protein, and short heterodimer partner mRNA. In familial intrahepatic cholestasis-1-negative Caco-2 cells, the activity of the human apical sodium-dependent bile acid transporter promoter was enhanced, whereas the human FXR and bile salt excretory pump promoters' activities were reduced. Overexpression of short heterodimer partner but not of the FXR abrogated the effect of familial intrahepatic cholestasis-1 antisense oligonucleotides. FXR cis-element binding and FXR protein were reduced primarily in nuclear but not cytoplasmic extracts from familial intrahepatic cholestasis-1-negative Caco-2 cells.

Conclusions: Loss of familial intrahepatic cholestasis-1 leads to diminished nuclear translocation of the FXR, with the subsequent potential for pathologic alterations in intestinal and hepatic bile acid transporter expression. Marked hypercholanemia and cholestasis are predicted to develop, presumably because of both enhanced ileal uptake of bile salts via up-regulation of the apical sodium-dependent bile acid transporter and diminished canalicular secretion of bile salts secondary to down-regulation of the bile salt excretory pump.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / genetics
  • Adenosine Triphosphatases / deficiency
  • Adenosine Triphosphatases / genetics
  • Caco-2 Cells
  • Carrier Proteins / genetics
  • Cell Nucleus / metabolism
  • Child
  • Child, Preschool
  • Cholestasis / genetics*
  • Cholestasis / metabolism*
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease Progression
  • Down-Regulation
  • Humans
  • Infant
  • Mutation
  • Oligonucleotides, Antisense / pharmacology
  • Organic Anion Transporters, Sodium-Dependent*
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear
  • Symporters*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Up-Regulation


  • ABCB11 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Carrier Proteins
  • DNA-Binding Proteins
  • Oligonucleotides, Antisense
  • Organic Anion Transporters, Sodium-Dependent
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Symporters
  • Transcription Factors
  • farnesoid X-activated receptor
  • sodium-bile acid cotransporter
  • Adenosine Triphosphatases
  • ATP8B1 protein, human