Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis

Sayeepriyadarshini Anakk, Mitsuhiro Watanabe, Scott A. Ochsner, Neil J. McKenna, Milton J. Finegold, David D. Moore

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Abstract

Bile acid homeostasis is tightly regulated via a feedback loop operated by the nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP). Contrary to current models, which place FXR upstream of SHP in a linear regulatory pathway, here we show that the phenotypic consequences in mice of the combined loss of both receptors are much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. Fxr-/-Shp -/- mice exhibited cholestasis and liver injury as early as 3 weeks of age, and this was linked to the dysregulation of bile acid homeostatic genes, particularly cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1). In addition, double-knockout mice showed misregulation of genes in the C21 steroid biosynthesis pathway, with strong induction of cytochrome P450, family 17, subfamily a, polypeptide 1 (Cyp17a1), resulting in elevated serum levels of its enzymatic product 17-hydroxyprogesterone (17-OHP). Treatment of WT mice with 17-OHP was sufficient to induce liver injury that reproduced many of the histopathological features observed in the double-knockout mice. Therefore, our data indicate a pathologic role for increased production of 17-hydroxy steroid metabolites in liver injury and suggest that Fxr-/-Shp-/- mice could provide a model for juvenile onset cholestasis.

Original languageEnglish
Pages (from-to)86-95
Number of pages10
JournalJournal of Clinical Investigation
Volume121
Issue number1
DOIs
Publication statusPublished - 2011 Jan 4

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Cholestasis
Bile Acids and Salts
Knockout Mice
Liver
Wounds and Injuries
Steroids
17-alpha-Hydroxyprogesterone
Peptides
Cytoplasmic and Nuclear Receptors
Genes
Homeostasis
Serum

ASJC Scopus subject areas

  • Medicine(all)

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Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis. / Anakk, Sayeepriyadarshini; Watanabe, Mitsuhiro; Ochsner, Scott A.; McKenna, Neil J.; Finegold, Milton J.; Moore, David D.

In: Journal of Clinical Investigation, Vol. 121, No. 1, 04.01.2011, p. 86-95.

Research output: Contribution to journalArticle

Anakk, Sayeepriyadarshini ; Watanabe, Mitsuhiro ; Ochsner, Scott A. ; McKenna, Neil J. ; Finegold, Milton J. ; Moore, David D. / Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 1. pp. 86-95.
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