title: Mechanism of tissue-specific farnesoid X receptor in suppressing the expression of genes in bile-acid synthesis in mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
authors.forename: Youcai
authors.initials: Y
authors.lastname: Zhang
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000235:genetics*; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated