Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice

Activation of farnesoid X receptor (Fxr, Nr1h4) is a major mechanism in suppressing bile‐acid synthesis by reducing the expression levels of genes encoding key bile‐acid synthetic enzymes (e.g., cytochrome P450 [CYP]7A1/Cyp7a1 and CYP8B1/Cyp8b1). FXR‐mediated induction of hepatic small heterodimer p...

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Published in:Hepatology (Baltimore, Md.) Md.), 2012-09, Vol.56 (3), p.1034-1043
Main Authors: Kong, Bo, Wang, Li, Chiang, John Y.L., Zhang, Youcai, Klaassen, Curtis D., Guo, Grace L.
Format: Article
Language:English
Subjects:
Acids
Animals
Bile Acids and Salts - biosynthesis
Bile Acids and Salts - genetics
Biological and medical sciences
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression
Hepatology
Kinases
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Medical sciences
Mice
Mice, Knockout
Receptors, Cytoplasmic and Nuclear - physiology
Rodents
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Summary:Activation of farnesoid X receptor (Fxr, Nr1h4) is a major mechanism in suppressing bile‐acid synthesis by reducing the expression levels of genes encoding key bile‐acid synthetic enzymes (e.g., cytochrome P450 [CYP]7A1/Cyp7a1 and CYP8B1/Cyp8b1). FXR‐mediated induction of hepatic small heterodimer partner (SHP/Shp, Nr0b2) and intestinal fibroblast growth factor 15 (Fgf15; FGF19 in humans) has been shown to be responsible for this suppression. However, the exact contribution of Shp/Fgf15 to this suppression, and the associated cell‐signaling pathway, is unclear. By using novel genetically modified mice, the current study showed that the intestinal Fxr/Fgf15 pathway was critical for suppressing both Cyp7a1 and Cyp8b1 gene expression, but the liver Fxr/Shp pathway was important for suppressing Cyp8b1 gene expression and had a minor role in suppressing Cyp7a1 gene expression. Furthermore, in vivo administration of Fgf15 protein to mice led to a strong activation of extracellular signal‐related kinase (ERK) and, to a smaller degree, Jun N‐terminal kinase (JNK) in the liver. In addition, deficiency of either the ERK or JNK pathway in mouse livers reduced the basal, but not the Fgf15‐mediated, suppression of Cyp7a1 and Cyp8b1 gene expression. However, deficiency of both ERK and JNK pathways prevented Fgf15‐mediated suppression of Cyp7a1 and Cyp8b1 gene expression. Conclusion: The current study clearly elucidates the underlying molecular mechanism of hepatic versus intestinal Fxr in regulating the expression of genes critical for bile‐acid synthesis and hydrophobicity in the liver. (HEPATOLOGY 2012;56:1034–1043)
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.25740