Clinical-liver, pancreas, and biliary tractProgressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity☆
Section snippets
Materials and methods
ASBT,10 FIC1,2 ileal lipid-binding protein (ILBP),11 short heterodimer partner (SHP),12 farnesoid X receptor (FXR),13 ATP8B2,14 and 28S15 messenger RNA (mRNA) levels were quantified by PhosphorImager (Molecular Dynamics, Sunnyvale, CA) analysis of Northern blots of total RNA from excess ileal tissue obtained at the time of ileal exclusion in 5 children with intractable pruritus associated with intrahepatic cholestasis (Table 1). Endogenous FIC1 expression in Caco-2 cells was knocked down by
Results
Quantitative Northern blot analysis of ASBT mRNA found that levels in ileum from the 3 children with PFIC1 were 4-fold higher than those found in the children with FIC1-positive cholestasis (Figure 1). FIC1 mRNA could not be shown in the 3 children with PFIC1, but it was found in the other 2 children (one with high γ-glutamyl transpeptidase cholestasis and the other with PFIC2). Northern analysis of intestinal expression of FIC1 may thus, in certain cases, be a rapid means of diagnosing FIC1
Discussion
These studies provide fundamental insights into the novel mechanisms by which defects in FIC1 may lead to human disease. FIC1, an apical membrane protein, seems to activate the FXR gene product, presumably via posttranslational modifications that lead to nuclear translocation of FXR (Figure 8). In the absence of FIC1, either in human disease or in Caco-2 cell knock-down studies, FXR activity is reduced. This is noted in both circumstances by the downstream effects of its reduced activity,
Acknowledgements
The authors would like to acknowledge the technical assistance of Xiaoping Li, Julie Vargas, and Venus Mahmoodi.
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Supported by grants NIH DK 54165 (to B.L.S.) and HD 20632 (to F.J.S.).