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

Ryan M. Allen, Tyler J. Marquart, Carolyn J. Albert, Frederick J. Suchy, David Q.H. Wang, Meenakshisundaram Ananthanarayanan, David A. Ford, Ángel Baldán

Research output: Contribution to journalArticle

121 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)882-895
Number of pages14
JournalEMBO Molecular Medicine
Volume4
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

Keywords

  • ABCB11
  • ATP8B1
  • Cholestasis
  • MiR-33
  • Statins

ASJC Scopus subject areas

  • Molecular Medicine

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