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.

microRNAs in lipoprotein and lipid metabolism: from biological function to clinical application

“…All these pathways are well described with more details in the references mentioned above. Several miRNAs with validated target genes (*) involved in these lipoprotein metabolism pathways (in blue) have been identified so far (detailed in have been found to target other genes associated with cholesterol metabolism, including the Niemann-Pick disease type C1 (NPC1) [84], cholesterol 7α-hydroxylase (CYP7A1), ATPase aminophospholipid transporter class 1 type 8B member 1 (ATP8B1), and ATP-binding cassette subfamily B member 11 (ABCB11) genes [85,86]. In addition to their role in cholesterol metabolism homeostasis, miR-33a/b have been found to regulate the cellular fatty acid metabolism by repressing many genes contributing to fatty acid oxidation in hepatocytes [e.g.…”

MicroRNA-33a/b in Lipid Metabolism

“…Anti-miR-33 therapy contributes to enhancing of this pathway not only by increasing HDL-C through ABCA1 upregulation but also by increasing bile secretion through upregulation of ABCB11 and ATP8B1, which are the other targets of miR-33s. 40 It has already been proven that…”

“…Both the ABCB11 and ATP8B1 transporters promote hepatic clearance, and have been shown to be the target genes of miR-33a. 40 LDLR, low-density lipoprotein receptor. ONO K et al…”

Function and clinical potential of microRNAs in hepatocellular carcinoma

“…Furthermore, miR122 forms a positive feedback loop with FOXA1 and HNF4α to regulate hepatocyte maturation (34). Several other miRNAs are involved in the regulation of liver development and differentiation, including miR148a (35) and miR33 (36).…”