title: Regulation of ABCA1 protein expression and function in hepatic and pancreatic islet cells by miR-145.
abstract: OBJECTIVE
  The ATP-binding cassette transporter A1 (ABCA1) protein maintains cellular cholesterol homeostasis in several different tissues. In the liver, ABCA1 is crucial for high-density lipoprotein biogenesis, and in the pancreas ABCA1 can regulate insulin secretion. In this study, our aim was to identify novel microRNAs that regulate ABCA1 expression in these tissues.
  
  
  RESULTS
  We combined multiple microRNA prediction programs to identify 8 microRNAs that potentially regulate ABCA1. A luciferase reporter assay demonstrated that 5 of these microRNAs (miR-148, miR-27, miR-144, miR-145, and miR-33a/33b) significantly repressed ABCA1 3'-untranslated region activity with miR-145 resulting in one of the larger decreases. In hepatic HepG2 cells, miR-145 can regulate both ABCA1 protein expression levels and cholesterol efflux function. In murine islets, an increase in miR-145 expression decreased ABCA1 protein expression, increased total islet cholesterol levels, and decreased glucose-stimulated insulin secretion. Inhibiting miR-145 produced the opposite effect of increasing ABCA1 protein levels and improving glucose-stimulated insulin secretion. Finally, increased glucose levels in media significantly decreased miR-145 levels in cultured pancreatic beta cells. These findings suggest that miR-145 is involved in glucose homeostasis and is regulated by glucose concentration.
  
  
  CONCLUSIONS
  Our studies demonstrate that miR-145 regulates ABCA1 expression and function, and inhibiting this microRNA represents a novel strategy for increasing ABCA1 expression, promoting high-density lipoprotein biogenesis in the liver, and improving glucose-stimulated insulin secretion in islets.
authors.affiliation: From the Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Kang
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Zhang
authors.forename: Nadeeja
authors.initials: N
authors.lastname: Wijesekara
authors.forename: Willeke
authors.initials: W
authors.lastname: de Haan
authors.forename: Stefanie
authors.initials: S
authors.lastname: Butland
authors.forename: Alpana
authors.initials: A
authors.lastname: Bhattacharjee
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D064286:ATP Binding Cassette Transporter 1; D002784:Cholesterol; D005947:Glucose; D007328:Insulin; D008075:Lipoproteins, HDL; D035683:MicroRNAs; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse; C541010:MIRN145 microRNA, human; C543499:MIRN145a microRNA, mouse
keywords: ABCA1 protein; cholesterol efflux regulatory protein; lipid metabolism; microRNAs