Muricholic bile acids are potent regulators of bile acid synthesis via a positive feedback mechanism

Authors

  • X. Hu,

    1. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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    • These authors contributed equally to this work.
  • Y. Bonde,

    1. Metabolism Unit, Department of Medicine, Center for Endocrinology, Metabolism, and Diabetes, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    2. Molecular Nutrition Unit, Department of Biosciences and Nutrition, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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    • These authors contributed equally to this work.
  • G. Eggertsen,

    1. Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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  • M. Rudling

    Corresponding author
    1. Metabolism Unit, Department of Medicine, Center for Endocrinology, Metabolism, and Diabetes, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    2. Molecular Nutrition Unit, Department of Biosciences and Nutrition, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    • Correspondence: Mats Rudling, Karolinska Institutet, C2-94 Karolinska University Hospital at Huddinge, S-141 86 Stockholm, Sweden.

      (fax: +46 8 711 07 10; e-mail: mats.rudling@ki.se).

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Errata

This article is corrected by:

  1. Errata: Corrigendum Volume 278, Issue 1, 97, Article first published online: 15 June 2015

  • During the proof editing of this manuscript, a paper by Yu et al. [35] was published. The authors showed, using a novel in house ELISA that FGF15 plasma levels in normal mice are around 100 pg mL−1, a level in parity with FGF19 levels reported in humans (about 150 pg mL−1) [36]. Therefore, it will now be important to establish to which extent regulation of BA synthesis occurs by direct FGF15/19 actions on the liver versus regulation from direct effects of BAs on this organ.

Abstract

Objective

Bile acid (BA) synthesis is regulated by negative feedback end-product inhibition, initiated by farnesoid X receptors (FXRs) in liver and gut. Studies on cholic acid (CA)-free Cyp8b1−/− mice have concluded that CA is a potent suppressor of BA synthesis. Cyp8b1−/− mice have increased BA synthesis and an enlarged BA pool, a phenotype shared with bile-duct-ligated, antibiotics-administered and with germ-free mice. Studies on such mice have concluded BA synthesis is induced due to reduced hormonal signalling by fibroblast growth factor (FGF)15 from intestine to liver. A mutual finding in these models is that potent FXR-agonistic BAs are reduced. We hypothesized that the absence of the potent FXR agonist deoxycholic acid (DCA) may be important for the induction of BA synthesis in these situations.

Design

Two of these models were investigated, antibiotic treatment and Cyp8b1−/− mice and their combination. Secondary BA formation was inhibited by ampicillin (AMP) given to wild-type and Cyp8b1−/− mice. We then administered CA, chenodeoxycholic acid (CDCA) or DCA to AMP-treated Cyp8b1−/− mice.

Results

Our data show that the phenotype of AMP-treated wild-type mice resembles that of Cyp8b1−/− mice with fourfold induced Cyp7a1 expression, increased intestinal apical sodium-dependent BA transporter expression and increased hepatic BA levels. We also show that reductions in the FXR-agonistic BAs CDCA, CA, DCA or lithocholic acid cannot explain this phenotype; instead, it is likely due to increases in levels of α- and β-muricholic BAs and ursodeoxycholic acid, three FXR-antagonistic BAs.

Conclusions

Our findings reveal a potent positive feedback mechanism for regulation of BA synthesis in mice that appears to be sufficient without endocrine effects of FGF15 on Cyp7a1. This mechanism will be fundamental in understanding BA metabolism in both mice and humans.

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