MicroRNA-758 Regulates Cholesterol Efflux Through Posttranscriptional Repression of ATP-Binding Cassette Transporter A1

Ramírez, Cristina M.; Dávalos, Alberto; Goedeke, Leigh; Salerno, Alessandro G.; Warrier, Nikhil; Cirera‐Salinas, Daniel; Suárez, Yajaira; Fernández‐Hernando, Carlos

doi:10.1161/atvbaha.111.232066

Cited by 225 publications

(167 citation statements)

References 39 publications

(47 reference statements)

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“…This represents the fi rst such example of a transcription by guest, on May 12, 2018 www.jlr.org Downloaded from reported to repress this pathway, including miR-26, miR-106b, and miR-758 (40)(41)(42). Like miR-33, miR-758 is expressed in macrophages and its expression is downregulated in the setting of excess cholesterol ( 41 ). Overexpression of miR-758 reduces cellular ABCA1 and cholesterol effl ux, and conversely, its inhibition increases this pathway.…”

Section: Mir-33: a Master Regulator Of Lipid Metabolismmentioning

confidence: 84%

“…Overexpression of miR-758 reduces cellular ABCA1 and cholesterol effl ux, and conversely, its inhibition increases this pathway. However, despite targeting distinct sites in the 3 ′ UTR of ABCA1, the effects of miR-758 and miR-33 inhibitors are not additive ( 41 ). Interestingly, miR-758 is enriched in the brain ( Fig.…”

Section: Mir-33: a Master Regulator Of Lipid Metabolismmentioning

confidence: 96%

“…Notably, recent studies demonstrated that miR-33a and miR-33b are cotranscribed with SREBF2 and SREBF1 , and act to repress genes that oppose these SREBP functions, e.g., genes involved in cholesterol effl ux (ABCA1, NPC1) and fatty acid oxidation (HADHB, CPT1A, CROT) ( 33,34 ). This represents the fi rst such example of a transcription by guest, on May 12, 2018 www.jlr.org Downloaded from reported to repress this pathway, including miR-26, miR-106b, and miR-758 (40)(41)(42). Like miR-33, miR-758 is expressed in macrophages and its expression is downregulated in the setting of excess cholesterol ( 41 ).…”

Section: Mir-33: a Master Regulator Of Lipid Metabolismmentioning

confidence: 97%

“…Interestingly, miR-758 is enriched in the brain ( Fig. 1 ), and manipulating miR-758 expression in human neuroglioma cells regulates ABCA1 expression and cholesterol effl ux in vitro ( 41 ). As ABCA1-mediated cholesterol effl ux to apoE, the predominant apolipoprotein in the brain, is inversely correlated with A ␤ fi brillogenesis ( 43 ), such ABCA1-targeting miRNAs represent potential new therapeutic targets in Alzheimer's disease.…”

Section: Mir-33: a Master Regulator Of Lipid Metabolismmentioning

confidence: 99%

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A big role for small RNAs in HDL homeostasis

Ouimet

Moore

2013

Journal of Lipid Research

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in a comprehensive knowledge of the pathways regulating plasma LDL levels and its translation into highly effective existing (e.g., statin) and emerging (e.g., PCSK9 inhibition) LDL-targeted therapeutics ( 2 ). By comparison, our understanding of the regulatory network controlling plasma HDL levels and function has somewhat lagged. Numerous animal studies have demonstrated that raising HDL particle number by HDL infusion or apoA-I overexpression reduces atherosclerosis ( 3, 4 ), yet the development of a therapy that harnesses these protective effects of HDL remains elusive. As our understanding of the complexity of this lipoprotein has grown, it has become clear that a better understanding of the molecular mechanisms regulating not only plasma levels of HDL-cholesterol (HDLC), but also its functionality, will be needed to achieve this goal ( 5 ).In mammals, somatic cells do not catabolize cholesterol, thus the removal of excess cellular cholesterol by HDL is central to the maintenance of sterol homeostasis, both at the cellular and whole-body level. A major component of HDL's atheroprotective function is thought to be the removal of cholesterol from lipid-loaded macrophages in the vessel wall and its delivery to the liver for excretion. This process, termed reverse cholesterol transport (RCT), is a multistep process, beginning with the hydrolysis of cytoplasmic lipid droplet-associated cholesteryl esters by neutral cholesteryl ester hydrolases and/or autophagymediated lysosomal acid lipase ( 6 ). The resulting free cholesterol is then effl uxed from the cell by passive diffusion of cholesterol, as well as active cholesterol transfer onto lipid-poor apoA-I and HDL by the ATP binding cassette transporters A1 (ABCA1) and G1 (ABCG1), respectively. Not only are the ABC transporters required for active macrophage cholesterol effl ux, but ABCA1 is essential for

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Section: Mir-33: a Master Regulator Of Lipid Metabolismmentioning

confidence: 84%

Section: Mir-33: a Master Regulator Of Lipid Metabolismmentioning

confidence: 96%

Section: Mir-33: a Master Regulator Of Lipid Metabolismmentioning

confidence: 97%

Section: Mir-33: a Master Regulator Of Lipid Metabolismmentioning

confidence: 99%

See 2 more Smart Citations

A big role for small RNAs in HDL homeostasis

Ouimet

Moore

2013

Journal of Lipid Research

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“…miRNAs are a class of small (19-23 nt) noncoding RNAs that bind to the 3 ′ untranslated regions (3 ′ UTRs) of target mRNAs promoting degradation and/or translational repression by forming incomplete base pairing with its target mRNA (7)(8)(9). Recently, we and others have shown that ABCA1 expression is regulated by several miRNAs including miR-33, miR-758, miR-106b, and miR-144, thus revealing a novel layer of regulation of cholesterol homeostasis (10)(11)(12)(13)(14)(15)(16).…”

Section: Western Blot Analysismentioning

confidence: 99%

RNA binding protein HuR regulates the expression of ABCA1

Ramírez

Lin

Abdelmohsen

et al. 2014

Journal of Lipid Research

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miR‐92a enhances recombinant protein productivity in CHO cells by increasing intracellular cholesterol levels

Loh

Yang

Lam

2017

Biotechnology Journal

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BackgroundMicroRNAs (miRNAs) have emerged as promising targets for engineering of CHO cell factories to enhance recombinant protein productivity. Manipulation of miRNA levels in CHO cells have been shown to improve product yield by their effects on cellular processes such as increasing proliferation, resisting apoptosis and enhancing specific productivity (qP). We previously demonstrated increases in qP and titer of CHO-IgG cells by over-expressing miR-92a [1]. Stably-transfected pools showed 27% increase in qP and 21% increase in titer compared to parental clone, without significant alteration in proliferation rates. The highest producing clone isolated from the miR-92a pool demonstrated 114% increase in qP and 88% increase in titer. However, the mechanisms by which miR-92a enhances qP in CHO cells are still uninvestigated. Materials and methodsTo understand possible pathways via which miR-92a enhances productivity in CHO cells, we carried out transcriptomics study on 2 high-producing miR-92a clones (~33pg/cell-day) and blank-transfected pool (16pg/cell-day) using microarray. Genes identified to be differentially expressed in both clones relative to the blank-transfected pool were analyzed for pathway/gene ontology enrichment. Differential expression levels of Insig1 were confirmed using qPCR. Validation of insig1 as a direct target of miR-92a was done using a vector construct comprising of the 3' UTR sequence of insig1 downstream of luciferase reporter gene. Cholesterol assays were carried out on the cellular lipid extracts and the supernatant harvested from the miR-92a clones and blank-transfected pool. The clones were also stained with wheat germ agglutinin (WGA) conjugate for the visualization of the Golgi apparatus by confocal microscopy. The relative surface area of Golgi was calculated by normalizing surface area of Golgi compartment to that of the cell ResultsGenes involved in cholesterol synthesis and metabolism were found to be enriched among the differentially expressed genes identified by microarray. Using qPCR, decreased expression levels of insig1 were found in transient pools and stable clones over-expressing miR-92a. Co-transfection of miR-92a mimic with the (luciferaseinsig1 3'UTR) vector reduced luciferase expression bỹ 19% whereas miR-92a inhibitor significantly increased luciferase expression by 120%. INSIG1 inhibits cholesterol biosynthesis by preventing the activation of the SREBP transcription factor. The intracellular cholesterol concentration of both miR-92a clones were significantly increased by~30% compared to the blank-transfected pool. The extracellular cholesterol concentrations for the miR-92a clones were also~2-3-fold higher than that of the blank-transfected pool. Knock-out of miR-92a has been reported to reduce systemic cholesterol levels in mice [2], concurring with our observations that miR-92a overexpression increases cholesterol biosynthesis/secretion. Cholesterol is known to be essential for vesicular transport from the ER [3] and Golgi [4], and constitutes about 20% of th...

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MicroRNA-758 Regulates Cholesterol Efflux Through Posttranscriptional Repression of ATP-Binding Cassette Transporter A1

Cited by 225 publications

References 39 publications

A big role for small RNAs in HDL homeostasis

A big role for small RNAs in HDL homeostasis

RNA binding protein HuR regulates the expression of ABCA1

miR‐92a enhances recombinant protein productivity in CHO cells by increasing intracellular cholesterol levels

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