However, the exact contribution Idelalisib 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 Selleck Copanlisib the expression of genes critical for bile-acid synthesis and hydrophobicity in the liver. (HEPATOLOGY 2012;56:1034–1043)
Bile-acid synthesis is the major mechanism to remove extra cholesterol from the body. Bile acids are required for the absorption of lipids and lipid-soluble vitamins from the intestine. Bile acids activate members of the nuclear receptor superfamily, including farnesoid X receptor (FXR/Fxr; encoded by the NR1H4/Nr1h4 gene), pregnane X receptor, vitamin D receptor,1-5 and a G-protein-coupled receptor, TGR5,6 which is a critical mechanism for maintaining endobiotic and Idoxuridine xenobiotic homeostasis. Two
enzymatic pathways are responsible for bile-acid synthesis in the liver. The classical pathway generates cholic acid (CA), and the alternative pathway produces chenodeoxycholic acid (CDCA). The cholesterol, 7α-hydroxylase, encoded by the cytochrome P450 (CYP) 7A1/7a1 (CYP7A1/Cyp7a1) gene, is the rate-limiting enzyme in the classical pathway. The sterol, 12α-hydroxylase, encoded by the CYP8b1/Cyp8b1 gene, mediates the production of CA, and cholesterol is converted only to CDCA when CYP8b1/Cyp8b1 is deficient. Because CA is less hydrophobic than CDCA, CYP8B1/Cyp8b1 is critical in regulating the hydrophobicity of the bile-acid pool by regulating the CA/CDCA ratio. Bile-acid synthesis is tightly regulated because disruption of bile-acid homeostasis leads to hepatobiliary and intestinal disorders, including cholestasis, gallstone disease, and inflammatory bowel disease, as well as systemic diseases, such as atherosclerosis.7 Feedback suppression of CYP7A1/Cyp7a1 and CYP8B1/Cyp8b1 gene transcription by nuclear receptors and inflammatory cytokines is the most important mechanism in maintaining bile-acid homeostasis in humans and mice.