title: miR-33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity.
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.
authors: Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, MO, USA.
authors: Ryan M
authors: RM
authors: Allen
authors: Tyler J
authors: TJ
authors: Marquart
authors: Carolyn J
authors: CJ
authors: Albert
authors: Frederick J
authors: FJ
authors: Suchy
authors: David Q-H
authors: DQ
authors: Wang
authors: Meenakshisundaram
authors: M
authors: Ananthanarayanan
authors: David A
authors: DA
authors: Ford
authors: Angel
authors: A
authors: Baldán
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000251:Adenosine Triphosphatases / Q000096:biosynthesis*; D000818:Animals; D001646:Bile / Q000378:metabolism; D002478:Cells, Cultured; D004032:Diet / Q000379:methods; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D049294:Phospholipid Transfer Proteins; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D049294:Phospholipid Transfer Proteins; D019821:Simvastatin; D000251:Adenosine Triphosphatases; C491742:Atp8b1 protein, mouse