Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
EMBO Mol Med. 2012 Sep;4(9):882-95. doi: 10.1002/emmm.201201228. Epub 2012 Jul 5.

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

Author information

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

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.

Copyright © 2012 EMBO Molecular Medicine.

Comment in

PMID:
22767443
[PubMed - indexed for MEDLINE]
PMCID:
PMC3491822
Free PMC Article

Images from this publication.See all images (8)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk