title: The nuclear receptor FXR uncouples the actions of miR-33 from SREBP-2.
abstract: OBJECTIVE
  To determine whether activation of farnesoid X receptor (FXR) alters cellular and plasma cholesterol homeostasis as a result of regulation of Srebp-2 and miR-33.
  
  
  RESULTS
  Chromatin immunoprecipitation sequencing data identified an FXR response element within intron 10 of the Srebp-2 gene. Consistent with this observation, treatment of mice with FXR-specific agonists (GSK2324 or GW4064) rapidly increased hepatic levels of Srebp-2 mRNA, precursor sterol response element binding protein 2 (pSREBP-2) protein, and miR-33. Furthermore, miR-33 targets, that include ABCA1 (ATP binding cassette transporter A1), NSF (N-ethylmaleimide-sensitive factor), and CPT1 (carnitine palmitoyltransferase 1), were all reduced in GSK2324-treated mice. In contrast, neither nuclear SREBP-2 protein (nSREBP-2) nor SREBP-2 target genes were induced after FXR activation. The inability to process pSREBP-2 to nSREBP-2 is likely a consequence of the induction of insulin INSIG-2A (induced gene 2A) by FXR agonists. Finally, we show that FXR-dependent induction of both Srebp-2 and miR-33 is ablated in Scap(-/-) mice that lack nuclear SREBP-2.
  
  
  CONCLUSIONS
  We demonstrate that the activation of FXR uncouples the expression of nuclear SREBP-2 and miR-33, and the regulation of their respective target genes. Further, we conclude that the FXR agonist-dependent increase in miR-33 requires transcription of the Srebp-2 gene.
authors.affiliation: From the Division of Cardiology, Departments of Medicine (E.J.T., H.A., T.Q.d.A.V.), and The Molecular Biology Institute (E.J.T.), University of California, Los Angeles.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Tarling
authors.affiliation: From the Division of Cardiology, Departments of Medicine (E.J.T., H.A., T.Q.d.A.V.), and The Molecular Biology Institute (E.J.T.), University of California, Los Angeles.
authors.forename: Hannah
authors.initials: H
authors.lastname: Ahn
authors.affiliation: From the Division of Cardiology, Departments of Medicine (E.J.T., H.A., T.Q.d.A.V.), and The Molecular Biology Institute (E.J.T.), University of California, Los Angeles. tvallim@mednet.ucla.edu.
authors.forename: Thomas Q
authors.initials: TQ
authors.lastname: de Aguiar Vallim
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics; D007438:Introns; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D064286:ATP Binding Cassette Transporter 1; D002334:Carnitine O-Palmitoyltransferase; D002784:Cholesterol; D047908:Intracellular Signaling Peptides and Proteins; D007555:Isoxazoles; D008565:Membrane Proteins; D035683:MicroRNAs; D011804:Quinolines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051782:Sterol Regulatory Element Binding Protein 2; D000099150:Receptor, Farnesoid X-Activated; C577833:Abca1 protein, mouse; C558292:GSK 2324; C506120:Insig2 protein, mouse; C550417:Mirn33 microRNA, mouse; C102196:SREBP cleavage-activating protein; C497391:Srebf2 protein, mouse; C412815:GW 4064
keywords: FXR; Nr1h4 protein, mouse; cholesterol; miR-33, mouse; sterol regulatory element binding protein 2