TY - JOUR
T1 - Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144
AU - Ramírez, Cristina M.
AU - Rotllan, Noemi
AU - Vlassov, Alexander V.
AU - Dávalos, Alberto
AU - Li, Mu
AU - Goedeke, Leigh
AU - Aranda, Juan F.
AU - Cirera-Salinas, Daniel
AU - Araldi, Elisa
AU - Salerno, Alessandro
AU - Wanschel, Amarylis
AU - Zavadil, Jiri
AU - Castrillo, Antonio
AU - Kim, Jungsu
AU - Suárez, Yajaira
AU - Fernández-Hernando, Carlos
PY - 2013/6/7
Y1 - 2013/6/7
N2 - RATIONALE:: Foam cell formation because of excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis, the major cause of morbidity and mortality in Western societies. Liver X nuclear receptors (LXRs) regulate the expression of the adenosine triphosphate-binding cassette (ABC) transporters, including adenosine triphosphate-binding cassette transporter A1 (ABCA1) and adenosine triphosphate-binding cassette transporter G1 (ABCG1). ABCA1 and ABCG1 facilitate the efflux of cholesterol from macrophages and regulate high-density lipoprotein (HDL) biogenesis. Increasing evidence supports the role of microRNA (miRNAs) in regulating cholesterol metabolism through ABC transporters. OBJECTIVE:: We aimed to identify novel miRNAs that regulate cholesterol metabolism in macrophages stimulated with LXR agonists. METHODS AND RESULTS:: To map the miRNA expression signature of macrophages stimulated with LXR agonists, we performed an miRNA profiling microarray analysis in primary mouse peritoneal macrophages stimulated with LXR ligands. We report that LXR ligands increase miR-144 expression in macrophages and mouse livers. Overexpression of miR-144 reduces ABCA1 expression and attenuates cholesterol efflux to apolipoproteinA1 in macrophages. Delivery of miR-144 oligonucleotides to mice attenuates ABCA1 expression in the liver, reducing HDL levels. Conversely, silencing of miR-144 in mice increases the expression of ABCA1 and plasma HDL levels. Thus, miR-144 seems to regulate both macrophage cholesterol efflux and HDL biogenesis in the liver. CONCLUSIONS:: miR-144 regulates cholesterol metabolism via suppressing ABCA1 expression and modulation of miRNAs may represent a potential therapeutical intervention for treating dyslipidemia and atherosclerotic vascular disease.
AB - RATIONALE:: Foam cell formation because of excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis, the major cause of morbidity and mortality in Western societies. Liver X nuclear receptors (LXRs) regulate the expression of the adenosine triphosphate-binding cassette (ABC) transporters, including adenosine triphosphate-binding cassette transporter A1 (ABCA1) and adenosine triphosphate-binding cassette transporter G1 (ABCG1). ABCA1 and ABCG1 facilitate the efflux of cholesterol from macrophages and regulate high-density lipoprotein (HDL) biogenesis. Increasing evidence supports the role of microRNA (miRNAs) in regulating cholesterol metabolism through ABC transporters. OBJECTIVE:: We aimed to identify novel miRNAs that regulate cholesterol metabolism in macrophages stimulated with LXR agonists. METHODS AND RESULTS:: To map the miRNA expression signature of macrophages stimulated with LXR agonists, we performed an miRNA profiling microarray analysis in primary mouse peritoneal macrophages stimulated with LXR ligands. We report that LXR ligands increase miR-144 expression in macrophages and mouse livers. Overexpression of miR-144 reduces ABCA1 expression and attenuates cholesterol efflux to apolipoproteinA1 in macrophages. Delivery of miR-144 oligonucleotides to mice attenuates ABCA1 expression in the liver, reducing HDL levels. Conversely, silencing of miR-144 in mice increases the expression of ABCA1 and plasma HDL levels. Thus, miR-144 seems to regulate both macrophage cholesterol efflux and HDL biogenesis in the liver. CONCLUSIONS:: miR-144 regulates cholesterol metabolism via suppressing ABCA1 expression and modulation of miRNAs may represent a potential therapeutical intervention for treating dyslipidemia and atherosclerotic vascular disease.
KW - ABCA1
KW - cardiovascular research
KW - cholesterol efflux
KW - cholesterol homeostatis
KW - high-density lipoprotein
KW - lipids and lipoprotein metabolism
KW - microRNAs
UR - http://www.scopus.com/inward/record.url?scp=84880031381&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880031381&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.112.300626
DO - 10.1161/CIRCRESAHA.112.300626
M3 - Article
C2 - 23519695
AN - SCOPUS:84880031381
SN - 0009-7330
VL - 112
SP - 1592
EP - 1601
JO - Circulation research
JF - Circulation research
IS - 12
ER -