Identification of miR-148a as a novel regulator of cholesterol metabolism

Identification of miR-148a as a novel regulator of cholesterol metabolism

The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL-cholesterol (LDL-C). While the transcriptional regulation of LDLR is well-characterized, the post-transcriptional mechanisms which govern LDLR expression are just beginning to emerge. Here, we devel...

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Main Authors: Goedeke, Leigh, Rotllan, Noemi, Canfrán-Duque, Alberto, Aranda, Juan F., Ramírez, Cristina M., Araldi, Elisa, Lin, Chin-Sheng, Anderson, Norma N., Wagschal, Alexandre, de Cabo, Rafael, Horton, Jay D., Lasunción, Miguel A., Näär, Anders M., Suárez, Yajaira, Fernández-Hernando, Carlos
Format: Online
Language:English
Published: 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711995/
id pubmed-4711995
recordtype oai_dc
spelling pubmed-47119952016-05-01 Identification of miR-148a as a novel regulator of cholesterol metabolism Goedeke, Leigh Rotllan, Noemi Canfrán-Duque, Alberto Aranda, Juan F. Ramírez, Cristina M. Araldi, Elisa Lin, Chin-Sheng Anderson, Norma N. Wagschal, Alexandre de Cabo, Rafael Horton, Jay D. Lasunción, Miguel A. Näär, Anders M. Suárez, Yajaira Fernández-Hernando, Carlos Article The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL-cholesterol (LDL-C). While the transcriptional regulation of LDLR is well-characterized, the post-transcriptional mechanisms which govern LDLR expression are just beginning to emerge. Here, we developed a high-throughput genome-wide screening assay to systematically identify microRNAs (miRNAs) that regulate LDLR activity in human hepatic cells. From this screen, we characterize miR-148a as a negative regulator of LDLR expression and activity, and define a novel SREBP1-mediated pathway by which miR-148a regulates LDL-C uptake. Importantly, inhibition of miR-148a increases hepatic LDLR expression and decreases plasma LDL-C in vivo. We also provide evidence that miR-148a regulates hepatic ABCA1 expression and circulating HDL-C levels. Collectively, these studies uncover miR-148a as an important regulator of hepatic LDL-C clearance through direct regulation of LDLR expression, and demonstrate the therapeutic potential of inhibiting miR-148a to ameliorate the elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease. 2015-10-05 2015-11 /pmc/articles/PMC4711995/ /pubmed/26437365 http://dx.doi.org/10.1038/nm.3949 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Goedeke, Leigh
Rotllan, Noemi
Canfrán-Duque, Alberto
Aranda, Juan F.
Ramírez, Cristina M.
Araldi, Elisa
Lin, Chin-Sheng
Anderson, Norma N.
Wagschal, Alexandre
de Cabo, Rafael
Horton, Jay D.
Lasunción, Miguel A.
Näär, Anders M.
Suárez, Yajaira
Fernández-Hernando, Carlos
spellingShingle Goedeke, Leigh
Rotllan, Noemi
Canfrán-Duque, Alberto
Aranda, Juan F.
Ramírez, Cristina M.
Araldi, Elisa
Lin, Chin-Sheng
Anderson, Norma N.
Wagschal, Alexandre
de Cabo, Rafael
Horton, Jay D.
Lasunción, Miguel A.
Näär, Anders M.
Suárez, Yajaira
Fernández-Hernando, Carlos
Identification of miR-148a as a novel regulator of cholesterol metabolism
author_facet Goedeke, Leigh
Rotllan, Noemi
Canfrán-Duque, Alberto
Aranda, Juan F.
Ramírez, Cristina M.
Araldi, Elisa
Lin, Chin-Sheng
Anderson, Norma N.
Wagschal, Alexandre
de Cabo, Rafael
Horton, Jay D.
Lasunción, Miguel A.
Näär, Anders M.
Suárez, Yajaira
Fernández-Hernando, Carlos
author_sort Goedeke, Leigh
title Identification of miR-148a as a novel regulator of cholesterol metabolism
title_short Identification of miR-148a as a novel regulator of cholesterol metabolism
title_full Identification of miR-148a as a novel regulator of cholesterol metabolism
title_fullStr Identification of miR-148a as a novel regulator of cholesterol metabolism
title_full_unstemmed Identification of miR-148a as a novel regulator of cholesterol metabolism
title_sort identification of mir-148a as a novel regulator of cholesterol metabolism
description The hepatic low-density lipoprotein receptor (LDLR) pathway is essential for clearing circulating LDL-cholesterol (LDL-C). While the transcriptional regulation of LDLR is well-characterized, the post-transcriptional mechanisms which govern LDLR expression are just beginning to emerge. Here, we developed a high-throughput genome-wide screening assay to systematically identify microRNAs (miRNAs) that regulate LDLR activity in human hepatic cells. From this screen, we characterize miR-148a as a negative regulator of LDLR expression and activity, and define a novel SREBP1-mediated pathway by which miR-148a regulates LDL-C uptake. Importantly, inhibition of miR-148a increases hepatic LDLR expression and decreases plasma LDL-C in vivo. We also provide evidence that miR-148a regulates hepatic ABCA1 expression and circulating HDL-C levels. Collectively, these studies uncover miR-148a as an important regulator of hepatic LDL-C clearance through direct regulation of LDLR expression, and demonstrate the therapeutic potential of inhibiting miR-148a to ameliorate the elevated LDL-C/HDL-C ratio, a prominent risk factor for cardiovascular disease.
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711995/
_version_ 1613523730736087040

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