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

  • Signaling and cell physiology
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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.

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Acknowledgments

This work was supported by grants from the National Institutes of Health (R01 DK53366 to D.D.M., RC4 DK90849 to P.W., R01 DK54208 to G.D.L., R01 DK080440 to L.W., R01 DK062975, and DK76898), from the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White Hospital to G.A., and from the National Natural Science Foundation of China (no. 81270868 to X.X.).

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Author notes

  1. Dongju Jung

    Present address: Department of Physiology, University of Oklahoma Health Science Center, Oklahoma City, OK, 73104, USA

Authors and Affiliations

  1. Center for Genomic Medicine and Diabetes Research, Houston Methodist Research Institute, Weill Cornell School of Medicine, Weill Cornell Medical College, 6670 Bertner Street, Houston, TX, 77030, USA

    J. Philippe York, Aijun Zhang, Paul Webb & Xuefeng Xia

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA

    Dongju Jung & David D. Moore

  3. Departments of Medicine and Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA

    Li Wang

  4. Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, 77030, USA

    Chaofeng Yang & Wallace L. McKeehan

  5. Department of Research, Central Texas Veterans Health Care System, Temple, TX, 77807, USA

    Heather L. Francis & Gianfranco Alpini

  6. Scott & White Digestive Disease Research Center, Division of Gastroenterology, Department of Medicine College of Medicine, Research Education Scott & White and Texas A&M Health Science Center, Temple, TX, 77807, USA

    Heather L. Francis & Gianfranco Alpini

  7. Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA

    Gene D. LeSage

  8. The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China

    Xuefeng Xia

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  1. Dongju Jung
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Correspondence to Xuefeng Xia.

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Dongju Jung and J. Philippe York contributed equally to this work.

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Jung, D., York, J.P., Wang, L. et al. FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway. Pflugers Arch - Eur J Physiol 466, 1011–1019 (2014). https://doi.org/10.1007/s00424-013-1364-3

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