Elisa Araldi
@unipr.it
Department of Medicine and Surgery
Università di Parma
RESEARCH, TEACHING, or OTHER INTERESTS
Biochemistry, Genetics and Molecular Biology, Physiology, Molecular Medicine, Endocrinology
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Uchenna Alex Anyaegbunam, Piyush More, Jean-Fred Fontaine, Vincent ten Cate, Katrin Bauer, Ute Distler, Elisa Araldi, Laura Bindila, Philipp Wild, and Miguel A. Andrade-Navarro
MDPI AG
Lipids are important modifiers of protein function, particularly as parts of lipoproteins, which transport lipophilic substances and mediate cellular uptake of circulating lipids. As such, lipids are of particular interest as blood biological markers for cardiovascular disease (CVD) as well as for conditions linked to CVD such as atherosclerosis, diabetes mellitus, obesity and dietary states. Notably, lipid research is particularly well developed in the context of CVD because of the relevance and multiple causes and risk factors of CVD. The advent of methods for high-throughput screening of biological molecules has recently resulted in the generation of lipidomic profiles that allow monitoring of lipid compositions in biological samples in an untargeted manner. These and other earlier advances in biomedical research have shaped the knowledge we have about lipids in CVD. To evaluate the knowledge acquired on the multiple biological functions of lipids in CVD and the trends in their research, we collected a dataset of references from the PubMed database of biomedical literature focused on plasma lipids and CVD in human and mouse. Using annotations from these records, we were able to categorize significant associations between lipids and particular types of research approaches, distinguish non-biological lipids used as markers, identify differential research between human and mouse models, and detect the increasingly mechanistic nature of the results in this field. Using known associations between lipids and proteins that metabolize or transport them, we constructed a comprehensive lipid–protein network, which we used to highlight proteins strongly connected to lipids found in the CVD-lipid literature. Our approach points to a series of proteins for which lipid-focused research would bring insights into CVD, including Prostaglandin G/H synthase 2 (PTGS2, a.k.a. COX2) and Acylglycerol kinase (AGK). In this review, we summarize our findings, putting them in a historical perspective of the evolution of lipid research in CVD.
Giampaolo Trivellin, Adrian F. Daly, Laura C. Hernández-Ramírez, Elisa Araldi, Christina Tatsi, Ryan K. Dale, Gus Fridell, Arjun Mittal, Fabio R. Faucz, James R. Iben,et al.
Frontiers Media SA
IntroductionPituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.MethodsFollowing the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis.ResultsIn germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction.ConclusionThe identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.
Elisa Araldi, Catherine R. Jutzeler, and Michael Ristow
Impact Journals, LLC
Lithium is a nutritional trace element that is also used pharmacologically for the management of bipolar and related psychiatric disorders. Recent studies have shown that lithium supplementation can extend health and lifespan in different animal models. Moreover, nutritional lithium uptake from drinking water was repeatedly found to be positively correlated with human longevity. By analyzing a large observational aging cohort (UK Biobank, n = 501,461 individuals) along with prescription data derived from the National Health Services (NHS), we here find therapeutic supplementation of lithium linked to decreased mortality (p = 0.0017) of individuals diagnosed with affective disorders. Subsequent multivariate survival analyses reveal lithium to be the strongest factor in regards to increased survival effects (hazard ratio = 0.274 [0.119–0.634 CI 95%, p = 0.0023]), corresponding to 3.641 times lower (95% CI 1.577–8.407) chances of dying at a given age for lithium users compared to users of other anti-psychotic drugs. While these results may further support the use of lithium as a geroprotective supplement, it should be noted that doses applied within the UK Biobank/NHS setting require close supervision by qualified medical professionals.
Giovanna Grigolon, Elisa Araldi, Reto Erni, Jia Yee Wu, Carolin Thomas, Marco La Fortezza, Beate Laube, Doris Pöhlmann, Markus Stoffel, Kim Zarse,et al.
Springer Science and Business Media LLC
AbstractAging is impacted by interventions across species, often converging on metabolic pathways. Transcription factors regulate longevity yet approaches for their pharmacological modulation to exert geroprotection remain sparse. We show that increased expression of the transcription factor Grainyhead 1 (GRH-1) promotes lifespan and pathogen resistance in Caenorhabditis elegans. A compound screen identifies FDA-approved drugs able to activate human GRHL1 and promote nematodal GRH-1-dependent longevity. GRHL1 activity is regulated by post-translational lysine methylation and the phosphoinositide (PI) 3-kinase C2A. Consistently, nematodal longevity following impairment of the PI 3-kinase or insulin/IGF-1 receptor requires grh-1. In BXD mice, Grhl1 expression is positively correlated with lifespan and insulin sensitivity. In humans, GRHL1 expression positively correlates with insulin receptor signaling and also with lifespan. Fasting blood glucose levels, including in individuals with type 2 diabetes, are negatively correlated with GRHL1 expression. Thereby, GRH-1/GRHL1 is identified as a pharmacologically malleable transcription factor impacting insulin signaling and lifespan.
Xinbo Zhang, Noemi Rotllan, Alberto Canfrán-Duque, Jonathan Sun, Jakub Toczek, Anna Moshnikova, Shipra Malik, Nathan L. Price, Elisa Araldi, Wen Zhong,et al.
Ovid Technologies (Wolters Kluwer Health)
Background: miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis. Methods: We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics. Results: The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes ( Col2a1, Col3a1, Col1a2, Fn1 , etc) and tissue inhibitor of metalloproteinase 3 ( Timp3 ) and downregulation of Mmp12 in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33. Conclusions: This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.
Xinbo Zhang, Jeffrey G. McDonald, Binod Aryal, Alberto Canfrán‐Duque, Emily L. Goldberg, Elisa Araldi, Wen Ding, Yuhua Fan, Bonne M. Thompson, Abhishek K. Singh,et al.
Proceedings of the National Academy of Sciences
Significance Previous work has shown that foamy macrophages accumulate desmosterol, a cholesterol biosynthetic intermediate. However, the participation of desmosterol in regulating the functions of cholesterol-laden macrophages in the physiological context of atherosclerosis has remained elusive. In this work, we selectively deplete desmosterol by overexpressing DHCR24, the enzyme that catalyzes the conversion of desmosterol into cholesterol, in myeloid cells and demonstrate that desmosterol content in atherosclerotic plaque macrophages controls their function and activation. Molecular analysis of macrophages isolated from lesions revealed that depletion of desmosterol increases the expression of interferon-regulated genes and genes associated with “classical” macrophage activation. Together, our work provides molecular insights into the intimate links between cholesterol metabolism and inflammatory responses of macrophages during atherogenesis.
Ahmad Kobiita, Svenja Godbersen, Elisa Araldi, Umesh Ghoshdastider, Marc W. Schmid, Giatgen Spinas, Holger Moch, and Markus Stoffel
Elsevier BV
Nathan L. Price, Abhishek K. Singh, Noemi Rotllan, Leigh Goedeke, Allison Wing, Alberto Canfrán-Duque, Alberto Diaz-Ruiz, Elisa Araldi, Ángel Baldán, Joao-Paulo Camporez,et al.
Elsevier BV
Alberto Canfrán‐Duque, Noemi Rotllan, Xinbo Zhang, Marta Fernández‐Fuertes, Cristina Ramírez‐Hidalgo, Elisa Araldi, Lidia Daimiel, Rebeca Busto, Carlos Fernández‐Hernando, and Yajaira Suárez
EMBO
AbstractAtherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR‐21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR‐21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR‐21 expression influences foam cell formation, sensitivity to ER‐stress‐induced apoptosis, and phagocytic clearance capacity. Mechanistically, we discovered that the absence of miR‐21 in macrophages increases the expression of the miR‐21 target gene, MKK3, promoting the induction of p38‐CHOP and JNK signaling. Both pathways enhance macrophage apoptosis and promote the post‐translational degradation of ABCG1, a transporter that regulates cholesterol efflux in macrophages. Altogether, these findings reveal a major role for hematopoietic miR‐21 in atherogenesis.
Elisa Araldi, Marta Fernández-Fuertes, Alberto Canfrán-Duque, Wenwen Tang, Gary W. Cline, Julio Madrigal-Matute, Jordan S. Pober, Miguel A. Lasunción, Dianqing Wu, Carlos Fernández-Hernando,et al.
Elsevier BV
Elisa Araldi and Yajaira Suárez
Elsevier BV
Emilie Montenont, Christina Echagarruga, Nicole Allen, Elisa Araldi, Yajaira Suarez, and Jeffrey S. Berger
American Society of Hematology
Key PointsPlatelet transcription of WDR1 suppresses platelet activity. Reduced transcription of WDR1 in platelets may be a link between elevated platelet activity and increased risk of cardiovascular disease.
Binod Aryal, Noemi Rotllan, Elisa Araldi, Cristina M. Ramírez, Shun He, Benjamin G. Chousterman, Ashley M. Fenn, Amarylis Wanschel, Julio Madrigal-Matute, Nikhil Warrier,et al.
Springer Science and Business Media LLC
AbstractLipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and it’s absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.
Victoria Ulrich, Noemi Rotllan, Elisa Araldi, Amelia Luciano, Philipp Skroblin, Mélanie Abonnenc, Paola Perrotta, Xiaoke Yin, Ashley Bauer, Kristen L Leslie,et al.
EMBO
Abnormal remodeling of atherosclerotic plaques can lead to rupture, acute myocardial infarction, and death. Enhancement of plaque extracellular matrix (ECM) may improve plaque morphology and stabilize lesions. Here, we demonstrate that chronic administration of LNA‐miR‐29 into an atherosclerotic mouse model improves indices of plaque morphology. This occurs due to upregulation of miR‐29 target genes of the ECM (col1A and col3A) resulting in reduced lesion size, enhanced fibrous cap thickness, and reduced necrotic zones. Sustained LNA‐miR‐29 treatment did not affect circulating lipids, blood chemistry, or ECM of solid organs including liver, lung, kidney, spleen, or heart. Collectively, these data support the idea that antagonizing miR‐29 may promote beneficial plaque remodeling as an independent approach to stabilize vulnerable atherosclerotic lesions.
Aránzazu Chamorro-Jorganes, Monica Y. Lee, Elisa Araldi, Shira Landskroner-Eiger, Marta Fernández-Fuertes, Mahnaz Sahraei, Maria Quiles del Rey, Coen van Solingen, Jun Yu, Carlos Fernández-Hernando,et al.
Ovid Technologies (Wolters Kluwer Health)
Rationale: Several lines of evidence indicate that the regulation of microRNA (miRNA) levels by different stimuli may contribute to the modulation of stimulus-induced responses. The miR-17–92 cluster has been linked to tumor development and angiogenesis, but its role in vascular endothelial growth factor–induced endothelial cell (EC) functions is unclear and its regulation is unknown. Objective: The purpose of this study was to elucidate the mechanism by which VEGF regulates the expression of miR-17–92 cluster in ECs and determine its contribution to the regulation of endothelial angiogenic functions, both in vitro and in vivo. This was done by analyzing the effect of postnatal inactivation of miR-17–92 cluster in the endothelium (miR-17–92 iEC-KO mice) on developmental retinal angiogenesis, VEGF-induced ear angiogenesis, and tumor angiogenesis. Methods and Results: Here, we show that Erk/Elk1 activation on VEGF stimulation of ECs is responsible for Elk-1-mediated transcription activation (chromatin immunoprecipitation analysis) of the miR-17–92 cluster. Furthermore, we demonstrate that VEGF-mediated upregulation of the miR-17–92 cluster in vitro is necessary for EC proliferation and angiogenic sprouting. Finally, we provide genetic evidence that miR-17–92 iEC-KO mice have blunted physiological retinal angiogenesis during development and diminished VEGF-induced ear angiogenesis and tumor angiogenesis. Computational analysis and rescue experiments show that PTEN (phosphatase and tensin homolog) is a target of the miR-17–92 cluster and is a crucial mediator of miR-17-92–induced EC proliferation. However, the angiogenic transcriptional program is reduced when miR-17–92 is inhibited. Conclusions: Taken together, our results indicate that VEGF-induced miR-17–92 cluster expression contributes to the angiogenic switch of ECs and participates in the regulation of angiogenesis.
Leigh Goedeke, Noemi Rotllan, Cristina M. Ramírez, Juan F. Aranda, Alberto Canfrán-Duque, Elisa Araldi, Ana Fernández-Hernando, Cedric Langhi, Rafael de Cabo, Ángel Baldán,et al.
Elsevier BV
Leigh Goedeke, Noemi Rotllan, Alberto Canfrán-Duque, Juan F Aranda, Cristina M Ramírez, Elisa Araldi, Chin-Sheng Lin, Norma N Anderson, Alexandre Wagschal, Rafael de Cabo,et al.
Springer Science and Business Media LLC
Laura Mangiavini, Christophe Merceron, Elisa Araldi, Richa Khatri, Rita Gerard-O'Riley, Tremika L. Wilson, George Sandusky, Jerome Abadie, Karen M. Lyons, Amato J. Giaccia,et al.
Elsevier BV
Elisa Araldi, Aranzazu Chamorro-Jorganes, Coen Solingen, Carlos Fernandez-Hernando, and Yajaira Suarez
Bentham Science Publishers Ltd.
Atherosclerosis (also known as arteriosclerotic vascular disease) is a chronic inflammatory disease of the arterial wall, characterized by the formation of lipid-laden lesions. The activation of endothelial cells at atherosclerotic lesion-prone sites in the arterial tree results in the up-regulation of cell adhesion molecules and chemokines, which mediate the recruitment of circulating monocytes. Accumulation of monocytes and monocyte-derived phagocytes in the wall of large arteries leads to chronic inflammation and the development and progression of atherosclerosis. The lesion experiences the following steps: foam cell formation, fatty streak accumulation, migration and proliferation of vascular smooth muscle cells, and fibrous cap formation. Finally, the rupture of the unstable fibrous cap causes thrombosis in complications of advanced lesions that lead to unstable coronary syndromes, myocardial infarction and stroke. MicroRNAs have recently emerged as a novel class of gene regulators at the post-transcriptional level. Several functions of vascular cells, such as cell differentiation, contraction, migration, proliferation and inflammation that are involved in angiogenesis, neointimal formation and lipid metabolism underlying various vascular diseases, have been found to be regulated by microRNAs and are described in the present review as well as their potential therapeutic application.
Noemi Rodlan, Aránzazu Chamorro‐Jorganes, Elisa Araldi, Amarylis C. Wanschel, Binod Aryal, Juan F. Aranda, Leigh Goedeke, Alessandro G. Salerno, Cristina M. Ramírez, William C. Sessa,et al.
Wiley
Atherosclerosis is the major cause of death and disability in diabetic and obese subjects with insulin resistance. Akt2, a phosphoinositide‐dependent serine‐threonine protein kinase, is highly express in insulin‐responsive tissues; however, its role during the progression of atherosclerosis remains unknown. Thus, we aimed to investigate the contribution of Akt2 during the progression of atherosclerosis. We found that germ‐line Akt2‐deficient mice develop similar atherosclerotic plaques as wild‐type mice despite higher plasma lipids and glucose levels. It is noteworthy that transplantation of bone marrow cells isolated from Akt2‐/‐ mice to Ldlr‐/‐ mice results in marked reduction of the progression of atherosclerosis compared with Ldlr‐/‐ mice transplanted with wild‐type bone marrow cells. In vitro studies indicate that Akt2 is required for macrophage migration in response to proatherogenic cytokines (monocyte chemotactic protein‐1 and macrophage colony‐stimulating factor). Moreover, Akt2‐/‐ macrophages accumulate less cholesterol and have an alternative activated or M2‐type phenotype when stimulated with proinflammatory cytokines. Together, these results provide evidence that macrophage Akt2 regulates migration, the inflammatory response and cholesterol metabolism and suggest that targeting Akt2 in macrophages might be beneficial for treating atherosclerosis.—Rodlan, N., Chamorro‐Jorganes, A., Araldi, E., Wanschel, A. C., Aryal, B., Aranda, J. F., Goedeke, L., Salerno, A. G., Ramírez, C. M., Sessa, W. C., Suárez, Y., Fernández‐Hernando, C. Hematopoietic Akt2 deficiency attenuates the progression of atherosclerosis. FASEB J. 29, 597‐610 (2015). www.fasebj.org
Laura Mangiavini, Christophe Merceron, Elisa Araldi, Richa Khatri, Rita Gerard-O’Riley, Tremika LeShan Wilson, Erinn B. Rankin, Amato J. Giaccia, and Ernestina Schipani
Elsevier BV
Aránzazu Chamorro-Jorganes, Elisa Araldi, Noemi Rotllan, Daniel Cirera-Salinas, and Yajaira Suárez
The Company of Biologists
MiR-149 is located within the first intron of glypican-1 (GPC1) gene. GPC1 is low affinity receptor for fibroblast growth factor (FGF2) that favors FGF2- binding to its receptor (FGFR1), subsequently promoting FGF2-FGFR1 activation and signaling. Using bioinformatic approaches, both GPC1 and FGFR1 were identified and subsequently validated as targets for miR-149 (both mature and passenger strands) in endothelial cells (ECs). ?As a consequence of their targeting activity towards GPC1 and FGFR1, both miR-149 and miR-149* regulated FGF2 signaling and FGF2-induced responses in ECs, namely proliferation, migration and cord formation. Moreover, lentiviral overexpression of miR-149 reduced in vivo tumor-induced neovascularization. Importantly, FGF2 transcriptionally stimulated the expression of miR-149 independently of its host gene, therefore assuring the steady state of FGF2-induced responses through the regulation of the GPC1-FGFR1 binary complex in ECs.
Coen van Solingen, Elisa Araldi, Aranzazu Chamorro‐Jorganes, Carlos Fernández‐Hernando, and Yajaira Suárez
Wiley
AbstractWound healing is a well‐regulated but complex process that involves haemostasis, inflammation, proliferation and maturation. Recent reports suggest that microRNAs (miRs) play important roles in dermal wound healing. In fact, miR deregulation has been linked with impaired wound repair. miR‐155 has been shown to be induced by inflammatory mediators and plays a central regulatory role in immune responses. We have investigated the potential role of miR‐155 in wound healing. By creating punch wounds in the skin of mice, we found an increased expression of miR‐155 in wound tissue when compared with healthy skin. Interestingly, analysis of wounds of mice lacking the expression of miR‐155 (miR‐155−/−) revealed an increased wound closure when compared with wild‐type animals. Also, the accelerated wound closing correlated with elevated numbers of macrophages in wounded tissue. Gene expression analysis of wounds tissue and macrophages isolated from miR‐155−/− mice that were treated with interleukin‐4 demonstrated an increased expression of miR‐155 targets (BCL6, RhoA and SHIP1) as well as, the finding in inflammatory zone‐1 (FIZZ1) gene, when compared with WT mice. Moreover, the up‐regulated levels of FIZZ1 in the wound tissue of miR‐155−/− mice correlated with an increased deposition of type‐1 collagens, a phenomenon known to be beneficial in wound closure. Our data indicate that the absence of miR‐155 has beneficial effects in the wound healing process.
Ashley M. Miller, Derek S. Gilchrist, Jagtar Nijjar, Elisa Araldi, Cristina M. Ramirez, Christopher A. Lavery, Carlos Fernández-Hernando, Iain B. McInnes, and Mariola Kurowska-Stolarska
Public Library of Science (PLoS)
Hepatic steatosis is a global epidemic that is thought to contribute to the pathogenesis of type 2 diabetes. MicroRNAs (miRs) are regulators that can functionally integrate a range of metabolic and inflammatory pathways in liver. We aimed to investigate the functional role of miR-155 in hepatic steatosis. Male C57BL/6 wild-type (WT) and miR-155−/− mice were fed either normal chow or high fat diet (HFD) for 6 months then lipid levels, metabolic and inflammatory parameters were assessed in livers and serum of the mice. Mice lacking endogenous miR-155 that were fed HFD for 6 months developed increased hepatic steatosis compared to WT controls. This was associated with increased liver weight and serum VLDL/LDL cholesterol and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1, Cebpa), fatty acid uptake (Cd36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2, Pla2g7). Using miRNA target prediction algorithms and the microarray transcriptomic profile of miR-155−/− livers, we identified and validated that Nr1h3 (LXRα) as a direct miR-155 target gene that is potentially responsible for the liver phenotype of miR-155−/− mice. Together these data indicate that miR-155 plays a pivotal role regulating lipid metabolism in liver and that its deregulation may lead to hepatic steatosis in patients with diabetes.
Cristina M. Ramírez, Noemi Rotllan, Alexander V. Vlassov, Alberto Dávalos, Mu Li, Leigh Goedeke, Juan F. Aranda, Daniel Cirera-Salinas, Elisa Araldi, Alessandro Salerno,et al.
Ovid Technologies (Wolters Kluwer Health)
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.