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Research ArticleDrug Discovery and Translational Medicine

Synthetic Farnesoid X Receptor Agonists Induce High-Density Lipoprotein-Mediated Transhepatic Cholesterol Efflux in Mice and Monkeys and Prevent Atherosclerosis in Cholesteryl Ester Transfer Protein Transgenic Low-Density Lipoprotein Receptor (−/−) Mice

Eva Hambruch, Shinobu Miyazaki-Anzai, Ulrike Hahn, Silke Matysik, Alfred Boettcher, Sanja Perović-Ottstadt, Thomas Schlüter, Olaf Kinzel, Helen Desiree Krol, Ulrich Deuschle, Michael Burnet, Moshe Levi, Gerd Schmitz, Makoto Miyazaki and Claus Kremoser
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 556-567; DOI: https://doi.org/10.1124/jpet.112.196519
Eva Hambruch
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Shinobu Miyazaki-Anzai
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Ulrike Hahn
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Silke Matysik
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Alfred Boettcher
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Sanja Perović-Ottstadt
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Thomas Schlüter
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Olaf Kinzel
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Helen Desiree Krol
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Ulrich Deuschle
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Michael Burnet
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Moshe Levi
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Gerd Schmitz
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Makoto Miyazaki
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Claus Kremoser
Phenex Pharmaceuticals AG, Heidelberg, Germany (E.H., S.P.-O., T.S., O.K., H.D.K., U.D., C.K.); Division of Renal Diseases and Hypertension, University of Colorado, Denver, Colorado (S.M.-A., M.L., M.M.); Synovo GmbH, Tübingen, Germany (U.H., M.B.); and Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany (S.M., A.B., G.S.)
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Abstract

Farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor, plays an important role in the regulation of cholesterol and more specifically high-density lipoprotein (HDL) homeostasis. Activation of FXR is reported to lead to both pro- and anti-atherosclerotic effects. In the present study we analyzed the impact of different FXR agonists on cholesterol homeostasis, plasma lipoprotein profiles, and transhepatic cholesterol efflux in C57BL/6J mice and cynomolgus monkeys and atherosclerosis development in cholesteryl ester transfer protein transgenic (CETPtg) low-density lipoprotein receptor (LDLR) (−/−) mice. In C57BL/6J mice on a high-fat diet the synthetic FXR agonists isopropyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (FXR-450) and 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl]benzoic acid (PX20606) demonstrated potent plasma cholesterol-lowering activity that affected all lipoprotein species, whereas 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064) and 6-ethyl chenodeoxycholic acid (6-ECDCA) showed only limited effects. In FXR wild-type mice, but not FXR(−/−) mice, the more efficacious FXR agonists increased fecal cholesterol excretion and reduced intestinal cholesterol (re)uptake. In CETPtg-LDLR(−/−) mice PX20606 potently lowered total cholesterol and, despite the observed HDL cholesterol (HDLc) reduction, caused a highly significant decrease in atherosclerotic plaque size. In normolipidemic cynomolgus monkeys PX20606 and 6-ECDCA both reduced total cholesterol, and PX20606 specifically lowered HDL2c but not HDL3c or apolipoprotein A1. That pharmacological FXR activation specifically affects this cholesterol-rich HDL2 subclass is a new and highly interesting finding and sheds new light on FXR-dependent HDLc lowering, which has been perceived as a major limitation for the clinical development of FXR agonists.

Footnotes

  • This work was supported in part by the German Federal Ministry of Education and Research [Grant 0315470].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.196519.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    FXR
    farnesoid X receptor
    ABC
    ATP-binding cassette
    Apo
    apolipoprotein
    BSEP
    bile salt export pump
    CETPtg
    cholesteryl ester transfer protein transgenic
    6-ECDCA
    6-ethyl chenodeoxycholic acid
    EL
    endothelial lipase
    FGF
    fibroblast growth factor
    FPLC
    fast performance liquid chromatography
    FRET
    fluorescence resonance energy transfer
    FXR-450
    isopropyl 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate
    GST
    glutathione transferase
    GW4064
    3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid
    HDL
    high-density lipoprotein
    HDLc
    HDL cholesterol
    HFD
    high-fat diet
    LBD
    ligand binding domain
    LDL
    low-density lipoprotein
    LDLc
    LDL cholesterol
    LDLR
    LDL receptor
    PX20350
    4-[[[6-[[5-cyclopropyl-3-(2,6-dichlorophenyl)4-isoxazolyl]methoxy]-2-(trifluoromethyl)-3-pyridinyl]methylamino]methyl]benzoic acid
    PX20606
    4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl]benzoic acid
    SHP
    small heterodimeric partner
    SR-BI
    scavenger-receptor B1
    TC
    plasma total cholesterol
    TG
    total triglycerides
    VLDLc
    very-low-density lipoprotein cholesterol
    wt
    wild type.

  • Received May 23, 2012.
  • Accepted August 22, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleDrug Discovery and Translational Medicine

FXR Agonists Induce Transhepatic Cholesterol Flux

Eva Hambruch, Shinobu Miyazaki-Anzai, Ulrike Hahn, Silke Matysik, Alfred Boettcher, Sanja Perović-Ottstadt, Thomas Schlüter, Olaf Kinzel, Helen Desiree Krol, Ulrich Deuschle, Michael Burnet, Moshe Levi, Gerd Schmitz, Makoto Miyazaki and Claus Kremoser
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 556-567; DOI: https://doi.org/10.1124/jpet.112.196519

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Research ArticleDrug Discovery and Translational Medicine

FXR Agonists Induce Transhepatic Cholesterol Flux

Eva Hambruch, Shinobu Miyazaki-Anzai, Ulrike Hahn, Silke Matysik, Alfred Boettcher, Sanja Perović-Ottstadt, Thomas Schlüter, Olaf Kinzel, Helen Desiree Krol, Ulrich Deuschle, Michael Burnet, Moshe Levi, Gerd Schmitz, Makoto Miyazaki and Claus Kremoser
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 556-567; DOI: https://doi.org/10.1124/jpet.112.196519
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