LDL Receptor Pathway Regulation by miR-224 and miR-520d

Frontiers in Cardiovascular Medicine
Alessandro G SalernoKathryn J Moore

Abstract

MicroRNAs (miRNA) have emerged as important post-transcriptional regulators of metabolic pathways that contribute to cellular and systemic lipoprotein homeostasis. Here, we identify two conserved miRNAs, miR-224, and miR-520d, which target gene networks regulating hepatic expression of the low-density lipoprotein (LDL) receptor (LDLR) and LDL clearance. In silico prediction of miR-224 and miR-520d target gene networks showed that they each repress multiple genes impacting the expression of the LDLR, including the chaperone molecules PCSK9 and IDOL that limit LDLR expression at the cell surface and the rate-limiting enzyme for cholesterol synthesis HMGCR, which is the target of LDL-lowering statin drugs. Using gain- and loss-of-function studies, we tested the role of miR-224 and miR-520d in the regulation of those predicted targets and their impact on LDLR expression. We show that overexpression of miR-224 or miR-520d dose-dependently reduced the activity of PCSK9, IDOL, and HMGCR 3'-untranslated region (3'-UTR)-luciferase reporter constructs and that this repression was abrogated by mutation of the putative miR-224 or miR-520d response elements in the PCSK9, IDOL, and HMGCR 3'-UTRs. Compared to a control miRNA, overexpression o...Continue Reading

References

Jul 1, 1979·Proceedings of the National Academy of Sciences of the United States of America·M S Brown, J L Goldstein
May 6, 2003·Nature Genetics·Marianne AbifadelCatherine Boileau
Sep 17, 2004·Nature·Victor Ambros
Jan 18, 2006·Cell·Joseph L GoldsteinMichael S Brown
Mar 24, 2006·The New England Journal of Medicine·Jonathan C CohenHelen H Hobbs
Jan 17, 2008·Nature Reviews. Genetics·Witold FilipowiczNahum Sonenberg
May 24, 2008·The New England Journal of Medicine·Sekar Kathiresan, UNKNOWN Myocardial Infarction Genetics Consortium
Aug 1, 2008·Nature·Matthias SelbachNikolaus Rajewsky
Nov 21, 2008·Journal of Lipid Research·Jay D HortonHelen H Hobbs
May 15, 2010·Science·S Hani Najafi-ShoushtariAnders M Näär
May 15, 2010·Science·Katey J RaynerCarlos Fernández-Hernando
Jun 23, 2010·Proceedings of the National Academy of Sciences of the United States of America·Tyler J MarquartAngel Baldán
Jun 8, 2011·The Journal of Clinical Investigation·Katey J RaynerKathryn J Moore
Jun 21, 2011·Genes & Development·Li ZhangJohn W R Schwabe
Sep 3, 2011·Arteriosclerosis, Thrombosis, and Vascular Biology·Cristina M RamirezCarlos Fernández-Hernando
Nov 24, 2011·Proceedings of the National Academy of Sciences of the United States of America·Anna C CalkinPeter Tontonoz
Mar 23, 2013·Circulation Research·Cristina M RamírezCarlos Fernández-Hernando
Mar 29, 2013·The New England Journal of Medicine·Harry L A JanssenMichael R Hodges
Oct 19, 2013·Arteriosclerosis, Thrombosis, and Vascular Biology·Martin H KangMichael R Hayden
Nov 19, 2013·Journal of the American College of Cardiology·Neil J StoneUNKNOWN American College of Cardiology/American Heart Association Task Force on Practice Guidelines
Dec 20, 2013·Circulation·Alan S GoUNKNOWN American Heart Association Statistics Committee and Stroke Statistics Subcommittee
Sep 24, 2014·Proceedings of the National Academy of Sciences of the United States of America·Kasey C VickersAlan T Remaley
Dec 3, 2014·Cell Metabolism·Cynthia HongPeter Tontonoz
Mar 15, 2015·Cell·Joseph M LunaRobert B Darnell
Aug 9, 2015·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Wei ChenJin-Hai Tang
Oct 6, 2015·Nature Medicine·Leigh GoedekeCarlos Fernández-Hernando
Oct 27, 2015·Nature Medicine·Alexandre WagschalAnders M Näär
Jan 1, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Ning WuZhiming Chen
Dec 13, 2017·Frontiers in Genetics·Parisa NaeliSeyed J Mowla
Nov 19, 2018·European Journal of Medicinal Chemistry·Shengtao XuJinyi Xu

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Citations

Feb 2, 2021·Annals of the New York Academy of Sciences·Kathryn M CitrinYajaira Suárez
Mar 20, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Ningning MaJin Ren
Mar 30, 2021·Metabolism: Clinical and Experimental·Xiaoding XuJin Ren
May 11, 2021·Current Atherosclerosis Reports·Pablo Fernández-TussyCarlos Fernández-Hernando
Jul 30, 2021·Frontiers in Cardiovascular Medicine·Coen van SolingenKathryn J Moore

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Datasets Mentioned

BETA
GSE144751
GSE64680

Methods Mentioned

BETA
ubiquitination
Assay
PCR
ELISA
Infrared Imaging
enzyme-linked immunosorbent assay
crosslinking immunoprecipitation
antisense oligonucleotide
transfection
antisense oligonucleotides

Software Mentioned

GraphPad Prism
GraphPad
ImageJ
Integrative Genomics Viewer
TargetScan
miRanda

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