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2. FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway

Author

Jung, Dongju, York, J Philippe, Wang, Li, Yang, Chaofeng, Zhang, Aijun, Francis, Heather L, Webb, Paul, McKeehan, Wallace L, Alpini, Gianfranco, LeSage, Gene D, Moore, David D, and Xia, Xuefeng

Subjects
Biochemistry and Cell Biology, Biological Sciences, Digestive Diseases, Liver Disease, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Animals, Bile Acids and Salts, Bile Ducts, Cells, Cultured, Cytochrome P-450 Enzyme System, Epithelial Cells, Fibroblast Growth Factors, Hep G2 Cells, Humans, Mice, Rats, Receptor, Fibroblast Growth Factor, Type 4, Receptors, Cytoplasmic and Nuclear, p38 Mitogen-Activated Protein Kinases, Physiology, Human Movement and Sports Sciences, Medical Physiology, Biochemistry and cell biology, Zoology, Medical physiology
Abstract

Cholangiocytes, bile duct lining cells, actively adjust the amount of cholesterol and bile acids in bile through expression of enzymes and channels involved in transportation and metabolism of the cholesterol and bile acids. Herein, we report molecular mechanisms regulating bile acid biosynthesis in cholangiocytes. Among the cytochrome p450 (Cyp) enzymes involved in bile acid biosynthesis, sterol 27-hydroxylase (Cyp27) that is the rate-limiting enzyme for the acidic pathway of bile acid biosynthesis expressed in cholangiocytes. Expression of other Cyp enzymes for the basic bile acid biosynthesis was hardly detected. The Cyp27 expression was negatively regulated by a hydrophobic bile acid through farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. Activated FXR exerted the negative effects by inducing an expression of fibroblast growth factor 15/19 (FGF15/19). Similar to its repressive function against cholesterol 7α-hydroxylase (Cyp7a1) expression in hepatocytes, secreted FGF15/19 triggered Cyp27 repression in cholangiocytes through interaction with its cognate receptor fibroblast growth factor receptor 4 (FGFR4). The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 repression were confirmed in vivo using knockout mouse models. Different from the signaling in hepatocytes, wherein the FGF15/19-induced repression signaling is mediated by c-Jun N-terminal kinase (JNK), FGF15/19-induced Cyp27 repression in cholangiocytes was mediated by p38 kinase. Thus, the results collectively suggest that cholangiocytes may be able to actively regulate bile acid biosynthesis in cholangiocytes and even hepatocyte by secreting FGF15/19. We suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in addition to the enterohepatic feedback loop against bile acid biosynthesis in the liver.

Published
2014

9. Supplemental Table 1 from Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer

Author

Liu, Junchen, primary, Chen, Guo, primary, Liu, Zezhen, primary, Liu, Shaoyou, primary, Cai, Zhiduan, primary, You, Pan, primary, Ke, Yuepeng, primary, Lai, Li, primary, Huang, Yun, primary, Gao, Hongchang, primary, Zhao, Liangcai, primary, Pelicano, Helene, primary, Huang, Peng, primary, McKeehan, Wallace L., primary, Wu, Chin-Lee, primary, Wang, Cong, primary, Zhong, Weide, primary, and Wang, Fen, primary

Published
2023
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10. Data from Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer

Author

Liu, Junchen, primary, Chen, Guo, primary, Liu, Zezhen, primary, Liu, Shaoyou, primary, Cai, Zhiduan, primary, You, Pan, primary, Ke, Yuepeng, primary, Lai, Li, primary, Huang, Yun, primary, Gao, Hongchang, primary, Zhao, Liangcai, primary, Pelicano, Helene, primary, Huang, Peng, primary, McKeehan, Wallace L., primary, Wu, Chin-Lee, primary, Wang, Cong, primary, Zhong, Weide, primary, and Wang, Fen, primary

Published
2023
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11. Fig s1-s8 from Aberrant FGFR Tyrosine Kinase Signaling Enhances the Warburg Effect by Reprogramming LDH Isoform Expression and Activity in Prostate Cancer

Author

Liu, Junchen, primary, Chen, Guo, primary, Liu, Zezhen, primary, Liu, Shaoyou, primary, Cai, Zhiduan, primary, You, Pan, primary, Ke, Yuepeng, primary, Lai, Li, primary, Huang, Yun, primary, Gao, Hongchang, primary, Zhao, Liangcai, primary, Pelicano, Helene, primary, Huang, Peng, primary, McKeehan, Wallace L., primary, Wu, Chin-Lee, primary, Wang, Cong, primary, Zhong, Weide, primary, and Wang, Fen, primary

Published
2023
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