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

Allen RM, Marquart TJ, Albert CJ, Suchy FJ, Wang DQ, Ananthanarayanan M, Ford DA, Baldán A
EMBO Mol Med. 2012 4 (9): 882-95

PMID: 22767443 · PMCID: PMC3491822 · DOI:10.1002/emmm.201201228

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.

MeSH Terms (17)

Adenosine Triphosphatases Animals ATP-Binding Cassette Transporters ATP Binding Cassette Transporter, Subfamily B, Member 11 Bile Cells, Cultured Diet Gene Expression Regulation Hepatocytes Liver Male Mice Mice, Inbred C57BL MicroRNAs Models, Biological Phospholipid Transfer Proteins Simvastatin

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