miR-33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity

Authors

  • Ryan M. Allen,

    1. Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, USA
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  • Tyler J. Marquart,

    1. Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, USA
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  • Carolyn J. Albert,

    1. Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, USA
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  • Frederick J. Suchy,

    1. The Children's Hospital Research Institute, University of Colorado School of Medicine, Aurora, CO, USA
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  • David Q.-H. Wang,

    1. Department of Internal Medicine, Saint Louis University, Saint Louis, MO, USA
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  • Meenakshisundaram Ananthanarayanan,

    1. Department of Internal Medicine-Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
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  • David A. Ford,

    1. Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, USA
    2. Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO, USA
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  • Ángel Baldán

    Corresponding author
    1. Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, USA
    2. Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO, USA
    • Tel: +1 314 9779227; Fax: +1 314 9779206

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Abstract

Bile secretion is essential for whole body sterol homeostasis. Loss-of-function mutations in specific canalicular transporters in the hepatocyte disrupt bile flow and result in cholestasis. We show that two of these transporters, ABCB11 and ATP8B1, are functional targets of miR-33, a micro-RNA that is expressed from within an intron of SREBP-2. Consequently, manipulation of miR-33 levels in vivo with adenovirus or with antisense oligonucleotides results in changes in bile secretion and bile recovery from the gallbladder. Using radiolabelled cholesterol, we show that systemic silencing of miR-33 leads to increased sterols in bile and enhanced reverse cholesterol transport in vivo. Finally, we report that simvastatin causes, in a dose-dependent manner, profound hepatotoxicity and lethality in mice fed a lithogenic diet. These latter results are reminiscent of the recurrent cholestasis found in some patients prescribed statins. Importantly, pretreatment of mice with anti-miR-33 oligonucleotides rescues the hepatotoxic phenotype. Therefore, we conclude that miR-33 mediates some of the undesired, hepatotoxic effects of statins.

→See accompanying article http://dx.doi.org/10.1002/emmm.201201565

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