title: MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis.
abstract: BACKGROUND
  A strong risk factor for atherosclerosis- the leading cause of heart attacks and strokes- is the elevation of low-density lipoprotein cholesterol (LDL-C) in blood. The LDL receptor (LDLR) is the primary pathway for LDL-C removal from circulation, and their levels are increased by statins -the main treatment for high blood LDL-C. However, statins have low efficiency because they also increase PCSK9 which targets LDLR for degradation. Since microRNAs have recently emerged as key regulators of cholesterol homeostasis, our aim was to identify potential microRNA-based therapeutics to decrease blood LDL-C and prevent atherosclerosis.
  
  
  RESULTS
  We over expressed and knocked down miR-27a in HepG2 cells to assess its effect on the expression of key players in the LDLR pathway using PCR Arrays, Elisas, and Western blots. We found that miR-27a decreases LDLR levels by 40% not only through a direct binding to its 3' untranslated region but also indirectly by inducing a 3-fold increase in PCSK9, which enhances LDLR degradation. Interestingly, miR-27a also directly decreases LRP6 and LDLRAP1, two other key players in the LDLR pathway that are required for efficient endocytosis of the LDLR-LDL-C complex in the liver. The inhibition of miR-27a using lock nucleic acids induced a 70% increase in LDLR levels and, therefore, it would be a more efficient treatment for hypercholesterolemia because of its desirable effects not only on LDLR but also on PCSK9.
  
  
  CONCLUSIONS
  The results presented here provide evidence supporting the potential of miR-27a as a novel therapeutic target for the prevention of atherosclerosis.
authors: Diabetes, Cardiovascular and Metabolic Diseases Division, Translational Genomics Research Institute, 445 Fifth Street, Phoenix, AZ 85004, USA. Electronic address: lucrecia.alvarez@asu.edu.
authors: M Lucrecia
authors: ML
authors: Alvarez
authors: Diabetes, Cardiovascular and Metabolic Diseases Division, Translational Genomics Research Institute, 445 Fifth Street, Phoenix, AZ 85004, USA.
authors: Mahdieh
authors: M
authors: Khosroheidari
authors: Diabetes, Cardiovascular and Metabolic Diseases Division, Translational Genomics Research Institute, 445 Fifth Street, Phoenix, AZ 85004, USA.
authors: Elena
authors: E
authors: Eddy
authors: Diabetes, Cardiovascular and Metabolic Diseases Division, Translational Genomics Research Institute, 445 Fifth Street, Phoenix, AZ 85004, USA.
authors: Stefania C
authors: SC
authors: Done
mesh_terms: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D050197:Atherosclerosis / Q000517:prevention & control; D002784:Cholesterol / Q000378:metabolism*; D019295:Computational Biology; D004705:Endocytosis; D004797:Enzyme-Linked Immunosorbent Assay; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000378:metabolism*; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; C573412:LDLR protein, human; C469745:LDLRAP1 protein, human; D008074:Lipoproteins; C552430:MIRN23a microRNA, human; C543845:MIRN24 microRNA, human; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D011973:Receptors, LDL; D002784:Cholesterol; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Atherosclerosis; Cholesterol homeostasis; LDLR; LDLRAP1; LRP6; PCSK9; miR-27a