title: A regulatory role for microRNA 33* in controlling lipid metabolism gene expression.
abstract: hsa-miR-33a and hsa-miR-33b, intronic microRNAs (miRNAs) located within the sterol regulatory element-binding protein 2 and 1 genes (Srebp-2 and -1), respectively, have recently been shown to regulate lipid homeostasis in concert with their host genes. Although the functional role of miR-33a and -b has been highly investigated, the role of their passenger strands, miR-33a* and -b*, remains unclear. Here, we demonstrate that miR-33a* and -b* accumulate to steady-state levels in human, mouse, and nonhuman primate tissues and share a similar lipid metabolism target gene network as their sister strands. Analogous to miR-33, miR-33* represses key enzymes involved in cholesterol efflux (ABCA1 and NPC1), fatty acid metabolism (CROT and CPT1a), and insulin signaling (IRS2). Moreover, miR-33* also targets key transcriptional regulators of lipid metabolism, including SRC1, SRC3, NFYC, and RIP140. Importantly, inhibition of either miR-33 or miR-33* rescues target gene expression in cells overexpressing pre-miR-33. Consistent with this, overexpression of miR-33* reduces fatty acid oxidation in human hepatic cells. Altogether, these data support a regulatory role for the miRNA* species and suggest that miR-33 regulates lipid metabolism through both arms of the miR-33/miR-33* duplex.
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY, USA.
authors.forename: Leigh
authors.initials: L
authors.lastname: Goedeke
authors.forename: Frances M
authors.initials: FM
authors.lastname: Vales-Lara
authors.forename: Michael
authors.initials: M
authors.lastname: Fenstermaker
authors.forename: Daniel
authors.initials: D
authors.lastname: Cirera-Salinas
authors.forename: Aranzazu
authors.initials: A
authors.lastname: Chamorro-Jorganes
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.forename: Julie A
authors.initials: JA
authors.lastname: Mattison
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Yajaira
authors.initials: Y
authors.lastname: Suárez
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000502:physiology; D008253:Macaca mulatta / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D005227:Fatty Acids; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse
references.citation: PLoS One. 2010 Jun 30;5(6):e11387
references.pmid: 20613982
references.citation: J Biol Chem. 2012 Jun 22;287(26):21816-25
references.pmid: 22549785
references.citation: J Hepatol. 2009 Jun;50(6):1226-35
references.pmid: 19395110
references.citation: Nature. 2009 Jul 23;460(7254):479-86
references.pmid: 19536157
references.citation: Mol Cell. 2009 Nov 13;36(3):431-44
references.pmid: 19917251
references.citation: Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2707-14
references.pmid: 21885853
references.citation: Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2595-606
references.pmid: 21885851
references.citation: Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):703-8
references.pmid: 14764426
references.citation: Nucleic Acids Res. 2010 Sep;38(17):5919-28
references.pmid: 20466808
references.citation: Nat Rev Genet. 2008 Feb;9(2):102-14
references.pmid: 18197166
references.citation: Mol Cell. 2009 Nov 13;36(3):445-56
references.pmid: 19917252
references.citation: Nature. 2011 Oct 19;478(7369):404-7
references.pmid: 22012398
references.citation: Proc Natl Acad Sci U S A. 2011 May 31;108(22):9232-7
references.pmid: 21576456
references.citation: Crit Rev Eukaryot Gene Expr. 2010;20(2):141-8
references.pmid: 21133843
references.citation: J Biomed Inform. 2011 Oct;44(5):839-47
references.pmid: 21605702
references.citation: Nat Struct Mol Biol. 2008 Apr;15(4):354-63
references.pmid: 18376413
references.citation: Nature. 2010 Jun 3;465(7298):584-9
references.pmid: 20424607
references.citation: RNA. 2012 Mar;18(3):472-84
references.pmid: 22282338
references.citation: Nucleic Acids Res. 2007;35(17):5944-53
references.pmid: 17726050
references.citation: Blood. 2011 Sep 22;118(12):3350-8
references.pmid: 21628414
references.citation: PLoS One. 2011;6(8):e23854
references.pmid: 21909367
references.citation: EMBO Rep. 2011 Feb;12(2):172-7
references.pmid: 21212805
references.citation: Science. 2010 Jun 18;328(5985):1570-3
references.pmid: 20466885
references.citation: Cell. 2010 Apr 2;141(1):129-41
references.pmid: 20371350
references.citation: J Clin Invest. 2002 May;109(9):1125-31
references.pmid: 11994399
references.citation: Cell. 2009 Jan 23;136(2):215-33
references.pmid: 19167326
references.citation: Cell. 2003 Oct 17;115(2):209-16
references.pmid: 14567918
references.citation: Nature. 2004 Sep 16;431(7006):350-5
references.pmid: 15372042
references.citation: J Clin Invest. 2011 Jul;121(7):2921-31
references.pmid: 21646721
references.citation: Nature. 2008 Jun 5;453(7196):798-802
references.pmid: 18463631
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 24;107(34):15163-8
references.pmid: 20699384
references.citation: Genes Dev. 2010 May 15;24(10):992-1009
references.pmid: 20413612
references.citation: Cell. 2003 Oct 17;115(2):199-208
references.pmid: 14567917
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12228-32
references.pmid: 20566875
references.citation: RNA. 2011 Feb;17(2):312-26
references.pmid: 21177881
references.citation: J Clin Invest. 2012 Jan;122(1):33-47
references.pmid: 22156201
references.citation: Science. 2010 Jun 18;328(5985):1566-9
references.pmid: 20466882
references.citation: FASEB J. 2011 May;25(5):1758-66
references.pmid: 21285396
references.citation: J Biol Chem. 1998 Sep 11;273(37):23786-92
references.pmid: 9726988
references.citation: PLoS One. 2009 Sep 28;4(9):e7192
references.pmid: 19784364
references.citation: J Biol Chem. 2010 Oct 29;285(44):33652-61
references.pmid: 20732877
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17321-6
references.pmid: 20855588