miR-199a-5p inhibits the expression of ABCB11 in obstructive cholestasis

J Biol Chem. 2021 Dec;297(6):101400. doi: 10.1016/j.jbc.2021.101400. Epub 2021 Nov 12.


ATP-binding cassette, subfamily B member 11 (ABCB11) is an efflux transporter for bile acids on the liver canalicular membrane. The expression of this transporter is reduced in cholestasis; however, the mechanisms contributing to this reduction are unclear. In this study, we sought to determine whether miR-199a-5p contributes to the depletion of ABCB11/Abcb11 in cholestasis in mice. In a microRNA (miRNA) screen of mouse liver after common bile duct ligation (CBDL), we found that miR-199a-5p was significantly upregulated by approximately fourfold. In silico analysis predicted that miR-199a-5p would target the 3'-untranslated region (3'-UTR) of ABCB11/Abcb11 mRNA. The expression of ABCB11-3'-UTR luciferase construct in Huh-7 cells was markedly inhibited by cotransfection of a miRNA-199a-5p mimic, which was reversed by an miRNA-199a-5p mimic inhibitor. We also show treatment of mice after CBDL with the potent nuclear receptor FXR agonist obeticholic acid (OCA) significantly increased Abcb11 mRNA and protein and decreased miR-199a-5p expression. Computational mapping revealed a well-conserved FXR-binding site (FXRE) in the promoter of the gene encoding miR-199a-5, termed miR199a-2. Electromobility shift, chromatin immunoprecipitation, and miR199a-2 promoter-luciferase assays confirmed that this binding site was functional. Finally, CBDL in mice led to depletion of nuclear repressor NcoR1 binding at the miR199a-2 promoter, which facilitates transcription of miR199a-2. In CBDL mice treated with OCA, NcoR1 recruitment to the miR199a-2 FXRE was maintained at levels found in sham-operated mice. In conclusion, we demonstrate that miR-199a-5p is involved in regulating ABCB11/Abcb11 expression, is aberrantly upregulated in obstructive cholestasis, and is downregulated by the FXR agonist OCA.

Keywords: ATP-dependent efflux transporter; bile acids; biliary; canalicular; cholestasis; microRNA.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / biosynthesis*
  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / genetics
  • Animals
  • Chenodeoxycholic Acid / analogs & derivatives
  • Chenodeoxycholic Acid / pharmacology
  • Cholestasis / drug therapy
  • Cholestasis / genetics
  • Cholestasis / metabolism*
  • Cholestasis / pathology
  • Disease Models, Animal
  • Gene Expression Regulation*
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Nuclear Receptor Co-Repressor 1 / genetics
  • Nuclear Receptor Co-Repressor 1 / metabolism


  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • Abcb11 protein, mouse
  • MicroRNAs
  • Mirn199 microRNA, mouse
  • Ncor1 protein, mouse
  • Nuclear Receptor Co-Repressor 1
  • obeticholic acid
  • Chenodeoxycholic Acid