title: MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor.
abstract: BACKGROUND
  The bile acid receptor farnesoid X receptor (FXR) regulates many aspects of lipid metabolism by variouscomplex and incompletely understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism.
  
  
  OBJECTIVE
  To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism.
  
  
  RESULTS
  ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma high-density lipoprotein (HDL)-cholesterol levels. Here, we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lowers hepatic ABCA1 and plasma HDL levels. We identified 2 complementary sequences to miR-144 in the 3' untranslated region of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I protein, whereas overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL-cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL-cholesterol. In addition, we used tissue-specific FXR-deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal, FXR. Finally, we identified functional FXR response elements upstream of the miR-144 locus, consistent with direct FXR regulation.
  
  
  CONCLUSIONS
  We have identified a novel pathway involving FXR, miR-144, and ABCA1 that together regulate plasma HDL-cholesterol.
authors.affiliation: Departments of Biological Chemistry, University of California, Los Angeles, 90095-7345, USA. tvallim@mednet.ucla.edu
authors.forename: Thomas Q
authors.initials: TQ
authors.lastname: de Aguiar Vallim
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Tarling
authors.forename: Tammy
authors.initials: T
authors.lastname: Kim
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.forename: Ángel
authors.initials: Á
authors.lastname: Baldán
authors.forename: Christine
authors.initials: C
authors.lastname: Esau
authors.forename: Peter A
authors.initials: PA
authors.lastname: Edwards
mesh_terms: D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D045744:Cell Line, Tumor; D008076:Cholesterol, HDL / Q000097:blood*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D013997:Time Factors; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D007555:Isoxazoles; D035683:MicroRNAs; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C577836:ABCA1 protein, human; C558292:GSK 2324; C554293:MIRN144 microRNA, human; C551064:MIRN144 microRNA, mouse; C550758:Mirn451 microRNA, mouse; C412815:GW 4064
keywords: FXR; HDL-cholesterol; miRNA; nuclear receptor