Original ResearchFull Report: Basic and Translational—Alimentary TractIntestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice
Section snippets
Animal Experiments
Male age-matched, wild-type (WT) C57Bl/6J mice, intestine-specific FXR knock-out (iFXR KO; generated by crossing mice expressing Cre-recombinase under the control of the villin18 promoter with Fxr-floxed mice19; kindly provided by Dr Frank J. Gonzalez), intestine-specific FXR-transgenic mice (iFXR TG; see the Supplementary Materials and Methods section) and their nontransgenic littermates (FXR KO),20 as well as ABCG8 knock-out (ABCG8 KO) mice and their WT littermates21 were housed in a light
Pharmacologic Activation of FXR Markedly Enhances Fecal Neutral Sterol Excretion in Mice
To delineate the role of bile salts in control of body cholesterol fluxes, we chose to modify bile salt synthesis and pool composition via modulation of the activity of the bile salt–activated nuclear receptor FXR. C57BL/6J mice were treated with the FXR agonist PX20606 for 2 weeks. In line with data obtained in hyperlipidemic mice and monkeys,23 the compound was well tolerated and had no effect on body weight or food intake (data not shown). PX treatment decreased plasma cholesterol and
Discussion
In this study we show that the intestine itself has the capability to facilitate elimination of enormous amounts of cholesterol from the body via the TICE pathway. The large capacity of TICE that became evident from the current studies highlights the potential of the intestine as a target for future cholesterol-lowering therapies. The induction of TICE in response to FXR activation appears to be mediated by hydrophilic bile salts. The fact that the magnitude of induction of FNS excretion and
Acknowledgments
The authors are grateful to Dr Frank J. Gonzalez (National Cancer Institute, National Institutes of Health, Bethesda, MD) for providing the Fxr-floxed mice.
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2022, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsCitation Excerpt :Taken together, our data suggest that OCA treatment does activate FXR in our study. We have previously shown that FXR activation by the pharmacological FXR agonist PX20606 leads to a marked increase in hydrophilicity of the BA pool in WT mice due to a strong suppression of Cyp8b1 expression [18,31]. In mice lacking Cyp2c70, MCAs cannot be formed and FXR activation will lead to a higher proportion of hydrophobic CDCA and consequently to a more hydrophobic BA pool with a higher cytotoxic potential [18].
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Conflicts of interest This author discloses the following: Claus Kremoser is the CEO of Phenex Pharmaceuticals AG, Heidelberg, Germany. The remaining authors disclose no conflicts.
Funding Supported within the framework of Top Institute Pharma, The Netherlands, project T2-110, and in part by European Union grant FP7-HEALTH 305707.
Author names in bold designate shared co-first authorship
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Authors share co-first authorship.