Mechanism Of Tissue-specific Farnesoid X Receptor In Suppressing The Expression Of Genes In Bile-acid Synthesis In Mice

Title

Mechanism Of Tissue-specific Farnesoid X Receptor In Suppressing The Expression Of Genes In Bile-acid Synthesis In Mice

Creator

Kong B; Wang L; Chiang J Y L; Zhang Y C; Klaassen C D; Guo G L

Publisher

Hepatology

Date

2012
2012-09

Description

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;56:10341043)

Subject

7-alpha-hydroxylase; activation; biosynthesis; cholesterol; feedback-regulation; fxr; Gastroenterology & Hepatology; homeostasis; molecular-basis; orphan nuclear receptor; signal; small heterodimer partner

Identifier

Format

Journal Article or Conference Abstract Publication

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

1034-1043

Issue

3

Volume

56

Citation

Kong B; Wang L; Chiang J Y L; Zhang Y C; Klaassen C D; Guo G L, “Mechanism Of Tissue-specific Farnesoid X Receptor In Suppressing The Expression Of Genes In Bile-acid Synthesis In Mice,” NEOMED Bibliography Database, accessed January 21, 2021, https://neomed.omeka.net/items/show/10520.

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