Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis
- 4 January 2011
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (1), 86-95
- https://doi.org/10.1172/jci42846
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.Keywords
This publication has 76 references indexed in Scilit:
- Effects of feeding bile acids and a bile acid sequestrant on hepatic bile acid composition in miceJournal of Lipid Research, 2010
- TGR5-Mediated Bile Acid Sensing Controls Glucose HomeostasisCell Metabolism, 2009
- Fasting-Induced Hepatic Production of DHEA Is Regulated by PGC-1α, ERRα, and HNF4αMolecular Endocrinology, 2009
- The GOA database in 2009--an integrated Gene Ontology Annotation resourceNucleic Acids Research, 2009
- Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7α-hydroxylase gene expressionHepatology, 2008
- Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary DiversionBMC Gastroenterology, 2008
- lumi: a pipeline for processing Illumina microarrayBioinformatics, 2008
- Model-based variance-stabilizing transformation for Illumina microarray dataNucleic Acids Research, 2008
- Comparison of progesterone and glucocorticoid receptor binding and stimulation of gene expression by progesterone, 17-alpha hydroxyprogesterone caproate, and related progestinsAmerican Journal of Obstetrics and Gynecology, 2007
- The Enzymes, Regulation, and Genetics of Bile Acid SynthesisAnnual Review of Biochemistry, 2003