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Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal

Authors

  • Johannes Schmitt,

    1. Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
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    • These authors contributed equally.
  • Bo Kong,

    1. Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy Rutgers University, Piscataway, NJ, USA
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    • These authors contributed equally.
  • Bruno Stieger,

    1. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich (USZ), Zurich, Switzerland
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  • Oliver Tschopp,

    1. Division of Endocrinology, Diabetes, & Nutrition, University Hospital of Zurich, Zurich, Switzerland
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  • Simon M. Schultze,

    1. Division of Endocrinology, Diabetes, & Nutrition, University Hospital of Zurich, Zurich, Switzerland
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  • Monika Rau,

    1. Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
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  • Achim Weber,

    1. Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich (USZ), Zurich, Switzerland
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  • Beat Müllhaupt,

    1. Department of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
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  • Grace L. Guo,

    1. Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy Rutgers University, Piscataway, NJ, USA
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    • These authors contributed equally.
  • Andreas Geier

    Corresponding author
    1. Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
    2. Department of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland
    • Correspondence

      Andreas Geier, MD, Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Oberdürrbacherstrasse 6, D-97080 Würzburg, Germany

      Tel: +49 931 201 40021

      Fax: +49 931 201 640201

      e-mail: geier_a2@medizin.uni-wuerzburg.de

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    • These authors contributed equally.

Abstract

Background & Aims

There is a growing evidence that bile acids are involved in the regulation of triglyceride-, cholesterol-homoeostasis and fat absorption. In this study organ-specific Fxr knockout mice were used to further investigate the influence of farnesoid X receptor FXR in lipogenesis.

Methods

Liver- and intestine-specific Fxr knockout mice were fed a 1% cholesterol diet for 28 days. Histological examination of frozen tissue sections included Sudan III/H&E, BODIPY staining and liver X receptor (LXR) immunohistochemistry. Liver triglycerides, serum cholesterol, serum bile acids and nuclear LXR protein were measured. mRNA expression of several genes involved in bile acid-, cholesterol-homoeostasis and lipogenesis was quantified by real-time PCR.

Results

Hepatic FXR deficiency contributes to lipid accumulation under 1% cholesterol administration which is not observed in intestinal Fxr knockout mice. Strong lipid accumulation, characterized by larger vacuoles could be observed in hepatic Fxr knockout sections, while intestinal Fxr knockout mice show no histological difference to controls. In addition, these mice have the ability to maintain normal serum cholesterol and bile acid levels. Hepatic Fxr knockouts were characterized by elevated triglycerides and bile acid levels. Expression level of LXR was significantly elevated under control and 1% cholesterol diet in hepatic Fxr knockout mice and was followed by concomitant lipogenic target gene induction such as Fas and Scd-1. This protective FXR effect against hepatic lipid accumulation was independent of intestinal Fgf15 induction.

Conclusion

These results show that the principal site of protective bile acid signalling against lipid accumulation is located in the liver since the absence of hepatic but not intestinal FXR contributes to lipid accumulation under cholesterol diet.

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