title: MicroRNA-758 regulates cholesterol efflux through posttranscriptional repression of ATP-binding cassette transporter A1.
abstract: OBJECTIVE
  The ATP-binding cassette transporter A1 (ABCA1) is a major regulator of macrophage cholesterol efflux and protects cells from excess intracellular cholesterol accumulation; however, the mechanism involved in posttranscriptional regulation of ABCA1 is poorly understood. We previously showed that microRNA-33 (miR-33) is 1 regulator. Here, we investigated the potential contribution of other microRNAs (miRNAs) to posttranscriptional regulation of ABCA1 and macrophage cholesterol efflux.
  
  
  RESULTS
  We performed a bioinformatic analysis for identifying miRNA target prediction sites in ABCA1 gene and an unbiased genome-wide screen to identify miRNAs modulated by cholesterol excess in mouse peritoneal macrophages. Quantitative real-time reverse transcription-polymerase chain reaction confirmed that miR-758 is repressed in cholesterol-loaded macrophages. Under physiological conditions, high dietary fat excess in mice repressed miR-758 both in peritoneal macrophages and, to a lesser extent, in the liver. In mouse and human cells in vitro, miR-758 repressed the expression of ABCA1, and conversely, the inhibition of this miRNA by using anti-miR-758 increased ABCA1 expression. In mouse cells, miR-758 reduced cellular cholesterol efflux to apolipoprotein A1 (apoA1), and anti-miR-758 increased it. miR-758 directly targets the 3'-untranslated region of Abca1 as assessed by 3'-untranslated region luciferase reporter assays. Interestingly, miR-758 is highly expressed in the brain, where it also targets several genes involved in neurological functions, including Slc38a1, Ntm, Epha7, and Mytl1.
  
  
  CONCLUSIONS
  We identified miR-758 as a novel miRNA that posttranscriptionally controls ABCA1 levels in different cells and regulates macrophage cellular cholesterol efflux to apoA1, opening new avenues to increase apoA1 and raise high-density lipoprotein levels.
authors: Department of Medicine, Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY, USA.
authors: Cristina M
authors: CM
authors: Ramirez
authors: Alberto
authors: A
authors: Dávalos
authors: Leigh
authors: L
authors: Goedeke
authors: Alessandro G
authors: AG
authors: Salerno
authors: Nikhil
authors: N
authors: Warrier
authors: Daniel
authors: D
authors: Cirera-Salinas
authors: Yajaira
authors: Y
authors: Suárez
authors: Carlos
authors: C
authors: Fernández-Hernando
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000502:physiology; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism* / Q000494:pharmacology; D023421:Models, Animal; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; C569441:MIRN758 microRNA, human; C569442:MIRN758 microRNA, mouse; D035683:MicroRNAs; D002784:Cholesterol