Abstract 403: Identification of CHROME as a Competing Endogenous RNA that Regulates Cholesterol Homeostasis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Coen van Solingen ◽  
Elizabeth J Hennessy ◽  
Mireille Ouimet ◽  
Kaitlyn Rinehold ◽  
Maryem Hussein ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Target Genes ◽  
Hdl Cholesterol ◽  
Cholesterol Homeostasis ◽  
Competing Endogenous Rna ◽  
Cellular Cholesterol ◽  
Expression Of Genes ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
X Receptors

The discovery of microRNAs (miRNA) targeting gene pathways involved in HDL and LDL metabolism illuminated the potent role of non-coding RNAs in the regulation of cholesterol homeostasis. Long non-coding RNAs (lncRNA) have also been identified as crucial regulators of gene expression; however, few have been fully characterized. Here we report a novel human lncRNA, CHROME (Cholesterol Homeostasis Regulator Of MicroRNA Expression), that functions as a competing endogenous RNA to regulate cellular cholesterol homeostasis. We show that CHROME has 7 broadly expressed variants that are transcriptionally regulated by the cholesterol-sensing liver X receptors. Computational analyses revealed that CHROME harbors binding sites for multiple (11) miRNAs involved in cholesterol homeostasis, including miR-27b and miR-33a/b, which function as hubs controlling the expression of genes involved in cholesterol efflux and HDL metabolism. Using CHROME knock-down and overexpression, we demonstrate that CHROME acts as a ‘miRNA sponge’ that sequesters these miRNAs, limiting their ability to repress target genes, including ABCA1, OSBPL6 and ANGPTL3. Consistent with this, we show that overexpression of CHROME increases cholesterol efflux, whereas its silencing reduces cholesterol efflux from primary human hepatocytes and macrophages. As hepatic cholesterol efflux via ABCA1 plays a central role in HDL biogenesis, we investigated the relationship of CHROME to its miRNA targets and plasma levels of HDL cholesterol in liver samples from a cohort of 200 healthy individuals. This analysis showed that CHROME is inversely correlated with miR-27b and miR-33a/b levels, and positively correlated with levels of their target genes and plasma HDL cholesterol. Collectively, these findings identify CHROME as a key regulatory component of the non-coding RNA circuitry that controls cellular cholesterol efflux and plasma HDL levels in humans.

scholarly journals Integrated Analysis of Long Non-Coding RNA and mRNA Expression Profiles in Testes of Calves and Sexually Mature Wandong Bulls (Bos taurus)

Animals ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 2006
Author(s):  
Hongyu Liu ◽  
Ibrar Muhammad Khan ◽  
Huiqun Yin ◽  
Xinqi Zhou ◽  
Muhammad Rizwan ◽  
...  
Keyword(s):  
Target Genes ◽  
Expression Profiles ◽  
Age Groups ◽  
Adherens Junction ◽  
Integrated Analysis ◽  
Sequencing Data ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Rna Interaction ◽  
Long Non Coding Rna

The mRNAs and long non-coding RNAs axes are playing a vital role in the regulating of post-transcriptional gene expression. Thereby, elucidating the expression pattern of mRNAs and long non-coding RNAs underlying testis development is crucial. In this study, mRNA and long non-coding RNAs expression profiles were investigated in 3-month-old calves and 3-year-old mature bulls’ testes by total RNA sequencing. Additionally, during the gene level analysis, 21,250 mRNAs and 20,533 long non-coding RNAs were identified. As a result, 7908 long non-coding RNAs (p-adjust < 0.05) and 5122 mRNAs (p-adjust < 0.05) were significantly differentially expressed between the distinct age groups. In addition, gene ontology and biological pathway analyses revealed that the predicted target genes are enriched in the lysine degradation, cell cycle, propanoate metabolism, adherens junction and cell adhesion molecules pathways. Correspondingly, the RT-qPCR validation results showed a strong consistency with the sequencing data. The source genes for the mRNAs (CCDC83, DMRTC2, HSPA2, IQCG, PACRG, SPO11, EHHADH, SPP1, NSD2 and ACTN4) and the long non-coding RNAs (COX7A2, COX6B2, TRIM37, PRM2, INHBA, ERBB4, SDHA, ATP6VOA2, FGF9 and TCF21) were found to be actively associated with bull sexual maturity and spermatogenesis. This study provided a comprehensive catalog of long non-coding RNAs in the bovine testes and also offered useful resources for understanding the differences in sexual development caused by the changes in the mRNA and long non-coding RNA interaction expressions between the immature and mature stages.

scholarly journals Regulation of Cholesterol Homeostasis by the Liver X Receptors in the Central Nervous System

2002 ◽  
Vol 16 (6) ◽  
pp. 1378-1385 ◽  
Author(s):  
Karl D. Whitney ◽  
Michael A. Watson ◽  
Jon L. Collins ◽  
William G. Benson ◽  
Tammy M. Stone ◽  
...  
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
Cholesterol Efflux ◽  
Target Genes ◽  
Cholesterol Homeostasis ◽  
Neuronal Cultures ◽  
Primary Neuronal Cultures ◽  
The Central Nervous System ◽  
Lxr Agonists

Abstract The nuclear oxysterol receptors liver X receptor-α [LXRα (NR1H3)] and LXRβ (NR1H2) coordinately regulate genes involved in cholesterol homeostasis. Although both LXR subtypes are expressed in the brain, their roles in this tissue remain largely unexplored. In this report, we show that LXR agonists have marked effects on gene expression in murine brain tissue both in vitro and in vivo. In primary astrocyte cultures, LXR agonists regulated several established LXR target genes, including ATP binding cassette transporter A1, and enhanced cholesterol efflux. In contrast, little or no effect on gene expression or cholesterol efflux was detected in primary neuronal cultures. Treatment of mice with a selective LXR agonist resulted in the induction of several LXR target genes related to cholesterol homeostasis in the cerebellum and hippocampus. These data provide the first evidence that the LXRs regulate cholesterol homeostasis in the central nervous system. Because dysregulation of cholesterol balance is implicated in central nervous system diseases such as Alzheimer’s and Niemann-Pick disease, pharmacological manipulation of the LXRs may prove beneficial in the treatment of these disorders.

scholarly journals Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol

2008 ◽  
Vol 158 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Robin P F Dullaart ◽  
Albert K Groen ◽  
Geesje M Dallinga-Thie ◽  
Rindert de Vries ◽  
Wim J Sluiter ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
High Density Lipoprotein ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Cholesterol Esterification ◽  
Cellular Cholesterol ◽  
Apo E ◽  
Pltp Activity ◽  
Cellular Cholesterol Efflux

ObjectiveWe tested whether in metabolic syndrome (MetS) subjects the ability of plasma to stimulate cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport pathway, is maintained despite low high-density lipoprotein (HDL) cholesterol.DesignIn 76 subjects with and 94 subjects without MetS based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, we determined plasma (apo)lipoproteins, pre-β-HDL formation, phospholipid transfer protein (PLTP) activity, cholesterol esterification (EST), cholesteryl ester transfer (CET), adiponectin, and the ability of plasma from each subject to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single donor.ResultsApo E, PLTP activity, EST, and CET were higher (P=0.04 to <0.001), whereas adiponectin was lower in MetS subjects (P<0.01). Pre-β-HDL and pre-β-HDL formation were not different between subjects with and without MetS. Cellular cholesterol efflux to plasma from MetS subjects was slightly higher versus plasma from subjects without MetS (8.8±1.0 vs 8.5±0.9%,P=0.05), but the difference was not significant after age, sex, and diabetes adjustment. Cellular cholesterol efflux was positively related to pre-β-HDL formation, EST, PLTP activity, and apo E (P<0.05 for all by multiple linear regression analysis), without an independent association with MetS and diabetes status.ConclusionsThe ability of plasma from MetS subjects to promote fibroblast cholesterol efflux is not defective, although HDL cholesterol is decreased. Higher cholesterol esterification, PLTP activity, and apo E levels may contribute to the maintenance of cholesterol efflux in MetS.

scholarly journals Promoter-Specific Roles for Liver X Receptor/Corepressor Complexes in the Regulation of ABCA1 and SREBP1 Gene Expression

2003 ◽  
Vol 23 (16) ◽  
pp. 5780-5789 ◽  
Author(s):  
Brandee L. Wagner ◽  
Annabel F. Valledor ◽  
Gang Shao ◽  
Chris L. Daige ◽  
Eric D. Bischoff ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hormone Receptors ◽  
Target Genes ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Whole Body ◽  
Abca1 Gene ◽  
Element Binding Protein ◽  
X Receptors

ABSTRACT Liver X receptors (LXRs) regulate the expression of genes involved in cholesterol and fatty acid homeostasis, including the genes for ATP-binding cassette transporter A1 (ABCA1) and sterol response element binding protein 1 (SREBP1). Loss of LXR leads to derepression of the ABCA1 gene in macrophages and the intestine, while the SREBP1c gene remains transcriptionally silent. Here we report that high-density-lipoprotein (HDL) cholesterol levels are increased in LXR-deficient mice, suggesting that derepression of ABCA1 and possibly other LXR target genes in selected tissues is sufficient to result in enhanced HDL biogenesis at the whole-body level. We provide several independent lines of evidence indicating that the repressive actions of LXRs are dependent on interactions with the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT). While dissociation of NCoR and SMRT results in derepression of the ABCA1 gene in macrophages, it is not sufficient for derepression of the SREBP1c gene. These findings reveal differential requirements for corepressors in the regulation of genes involved in cholesterol and fatty acid homeostasis and raise the possibility that these interactions may be exploited to develop synthetic ligands that selectively modulate LXR actions in vivo.

scholarly journals Identification of Non-coding RNA Biomarkers in Stress-induced Depression via Comprehensive Analysis of Competing Endogenous RNA Network

2020 ◽  
Author(s):  
xuanjun liu ◽  
Lan Yan ◽  
Chun Lin ◽  
Yiliang Zhang ◽  
Haofei Miao ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Comprehensive Analysis ◽  
Differentially Expressed ◽  
Psychiatric Disease ◽  
Circular Rnas ◽  
Messenger Rnas ◽  
Competing Endogenous Rna ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Promising Perspective

Abstract BackgroundDepression is one of the most common psychiatric disease worldwide. Although the research about the pathogenesis of depression have achieved progress, the detailed effect of non-coding RNAs (ncRNAs) in depression are still not clearly elucidated. This study was aimed to identify non-coding RNA biomarkers in stress-induced depression via comprehensive analysis of competing endogenous RNA networkMethodsIn this present study, we acquired RNA expression from RNA seq expression profile in three mice with depressive-like behaviors using chronic restraint stress paradigm and three C57BL/6J wild-type mice as control mice. ResultsA total of 41 differentially expressed circular RNAs (circRNAs) and 181 differentially expressed messenger RNAs (mRNAs) were up-regulated, and 65 differentially expressed circRNAs and 289 differentially expressed mRNAs were down-regulated, which were selected by a threshold of fold change ≥2 and a p-value < 0.05. Gene Ontology was performed to analyze the biological functions, and we predicted potential signaling pathways based on Kyoto Encyclopedia of Genes and Genomes pathway database. In addition, we constructed a circRNA-microRNA (miRNA)-mRNA regulatory network to further identify non-coding RNAs biomarkers. ConclusionsOur findings provide a promising perspective for further research into molecular mechanisms of depression, and targeting circRNA -mediated competing endogenous RNA (ceRNA) network is a useful strategy to early recognize the depression.

scholarly journals Identification of Long Non-Coding RNAs Involved in Porcine Fat Deposition Using Two High-Throughput Sequencing Methods

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1374
Author(s):  
Yibing Liu ◽  
Ying Yu ◽  
Hong Ao ◽  
Fengxia Zhang ◽  
Xitong Zhao ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Target Genes ◽  
Gene Prediction ◽  
Fat Deposition ◽  
Acid Oxidation ◽  
Rna Seq ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Rate Limiting ◽  
Long Non Coding Rna

Adipose is an important body tissue in pigs, and fatty traits are critical in pig production. The function of long non-coding RNA (lncRNA) in fat deposition and metabolism has been found in previous studies. In this study, we collected the adipose tissue of six Landrace pigs with contrast backfat thickness (nhigh = 3, nlow = 3), after which we performed strand-specific RNA sequencing (RNA-seq) based on pooling and biological replicate methods. Biological replicate and pooling RNA-seq revealed 1870 and 1618 lncRNAs, respectively. Using edgeR, we determined that 1512 genes and 220 lncRNAs, 2240 genes and 127 lncRNAs were differentially expressed in biological replicate and pooling RNA-seq, respectively. After target gene prediction, we found that ACSL3 was cis-targeted by lncRNA TCONS-00052400 and could activate the conversion of long-chain fatty acids. In addition, lncRNA TCONS_00041740 cis-regulated gene ACACB regulated the rate-limiting enzyme in fatty acid oxidation. Since these genes have necessary functions in fat metabolism, the results imply that the lncRNAs detected in our study may affect backfat deposition in swine through regulation of their target genes. Our study explored the regulation of lncRNA and their target genes in porcine backfat deposition and provided new insights for further investigation of the biological functions of lncRNA.

scholarly journals Comprehensive analysis of micro RNAs in recurrent implantation failures patients and construction of prediction models based on circulating micro RNAs

2021 ◽  
Author(s):  
Peigen Chen ◽  
Yingchun Guo ◽  
Tingting Li ◽  
Lei Jia ◽  
Yanfang Wang ◽  
...  
Keyword(s):  
Target Genes ◽  
Prediction Models ◽  
Reproductive Technology ◽  
Control Group ◽  
Circulating Mirnas ◽  
Competing Endogenous Rna ◽  
Micro Rnas ◽  
Non Coding Rnas ◽  
Analytical Tools ◽  
The Relationship

Abstract BackgroundRecurrent implantation failure (RIF) is an obstacle in the process of assisted reproductive technology (ART). At present, there was limited research on its pathogenesis, diagnosis and treatment methods.ResultsIn this study, a series of analytical tools were used to analyze differences in miRNAs, mRNAs and lncRNAs in the endometrium of patients in the RIF group and the control group. At the same time, multiple databases are used to predict the target genes of non-coding RNAs. Then the competing endogenous RNA (ceRNA) network was built to describe the relationship between gene regulation in the endometrium of the RIF.ConcludesBased on the results of the logistic regression of co-expression miRNAs between serum and endometrial samples, we built a predictive model based on circulating miRNAs.

Sensing Nuclear Glucose

2007 ◽  
Vol 2007 (369) ◽  
pp. tw20-tw20
Author(s):  
Elizabeth M. Adler
Keyword(s):  
Lipid Metabolism ◽  
Transcriptional Activation ◽  
Hepg2 Cells ◽  
Target Genes ◽  
Glucose Sensor ◽  
Acid Synthesis ◽  
Cholesterol Homeostasis ◽  
Binding Domains ◽  
Glucose And Lipid Metabolism ◽  
X Receptors

The liver X receptors (LXR-α and -β) are nuclear transcription factors that have been implicated in both glucose and lipid metabolism; their activation by oxysterol ligands elicits both a decrease in atherosclerosis and antidiabetic effects. Although synthetic LXR ligands decrease hepatic gluconeogenesis and increase lipogenesis in rodent models, the normal rodent diet lacks cholesterol, which led Mitro et al. to search for other ligands. They found that glucose and glucose derivatives stimulated the transcriptional activation of a Gal4-responsive gene reporter in human HepG2 cells expressing constructs in which LXR ligand-binding domains (LBDs) were fused to the Gal4 DNA binding domain and transcriptionally activated LXR-RXR (retinoid X receptor) targets. Cell-free coactivator recruitment assays and scintillation proximity assays indicated that glucose and glucose-6-phosphate were direct LXR agonists that bound to the LXR LBD. Furthermore, glucose protected LXR-α from proteolytic attack and increased the LXR-β melting temperature. Glucose had effects on the transcription of LXR target genes in HEPG2 cells similar to those of known ligands, stimulating the expression of genes involved in fatty acid synthesis and cholesterol homeostasis and inhibiting expression of gluconeogenic genes; moreover, it potentiated the effects of LXR ligands. Similarly, glucose- or sucrose-feeding stimulated the expression of LXR target genes in the livers of fasted mice, even mice that were insulin deficient. Thus, glucose itself appears to act as a ligand for LXR, leading the authors to propose that LXR acts as a "transcriptional switch" to coordinate carbohydrate and lipid metabolism. N. Mitro, P. A. Mak, L. Vargas, C. Godio, E. Hampton, V. Molteni, A. Kreusch, E. Saez, The nuclear receptor LXR is a glucose sensor. Nature445, 219-223 (2007). [PubMed]

scholarly journals Long Non-Coding RNA Associated with Cholesterol Homeostasis and Its Involvement in Metabolic Diseases

2020 ◽  
Vol 21 (21) ◽  
pp. 8337
Author(s):  
Kang-Hoon Lee ◽  
Hyeon-Ji Hwang ◽  
Je-Yoel Cho
Keyword(s):  
Metabolic Diseases ◽  
Disease Process ◽  
Cholesterol Homeostasis ◽  
Cell Component ◽  
Non Coding Rna ◽  
Systemic Level ◽  
Development Processes ◽  
Non Coding Rnas ◽  
Long Non Coding Rna

Cholesterol is an essential cell component that functions to create and maintain all kinds of cell membranes and lipoprotein particles. It is crucial to maintain the proper amount of cholesterol at both the cellular and systemic level. Recently, the importance of cholesterol has been reported not only in various cell development processes but also in the development of diseases. Furthermore, the involvement of long non-coding RNAs (lncRNAs), which are regarded as important epigenetic regulators in gene expression, has also been reported in cholesterol homeostasis. It is thus necessary to summarize the research on lncRNAs related to cholesterol with increased interest. This review organized the role of lncRNAs according to the major issues in cholesterol homeostasis: efflux, metabolism and synthesis, and disease process.

scholarly journals Construction of asthma related competing endogenous RNA network revealed novel long non-coding RNAs and potential new drugs

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Yifang Liao ◽  
Ping Li ◽  
Yanxia Wang ◽  
Hong Chen ◽  
Shangwei Ning ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Repositioning ◽  
New Drugs ◽  
Differentially Expressed ◽  
Interaction Data ◽  
Competing Endogenous Rna ◽  
Non Coding Rna ◽  
Competing Endogenous Rna Network ◽  
Non Coding Rnas ◽  
Long Non Coding Rna

Abstract Background Asthma is a heterogeneous disease characterized by chronic airway inflammation. Long non-coding RNA can act as competing endogenous RNA to mRNA, and play significant role in many diseases. However, there is little known about the profiles of long non-coding RNA and the long non-coding RNA related competing endogenous RNA network in asthma. In current study, we aimed to explore the long non-coding RNA-microRNA-mRNA competing endogenous RNA network in asthma and their potential implications for therapy and prognosis. Methods Asthma-related gene expression profiles were downloaded from the Gene Expression Omnibus database, re-annotated with these genes and identified for asthma-associated differentially expressed mRNAs and long non-coding RNAs. The long non-coding RNA-miRNA interaction data and mRNA-miRNA interaction data were downloaded using the starBase database to construct a long non-coding RNA-miRNA-mRNA global competing endogenous RNA network and extract asthma-related differentially expressed competing endogenous RNA network. Finally, functional enrichment analysis and drug repositioning of asthma-associated differentially expressed competing endogenous RNA networks were performed to further identify key long non-coding RNAs and potential therapeutics associated with asthma. Results This study constructed an asthma-associated competing endogenous RNA network, determined 5 key long non-coding RNAs (MALAT1, MIR17HG, CASC2, MAGI2-AS3, DAPK1-IT1) and identified 8 potential new drugs (Tamoxifen, Ruxolitinib, Tretinoin, Quercetin, Dasatinib, Levocarnitine, Niflumic Acid, Glyburide). Conclusions The results suggested that long non-coding RNA played an important role in asthma, and these novel long non-coding RNAs could be potential therapeutic target and prognostic biomarkers. At the same time, potential new drugs for asthma treatment have been discovered through drug repositioning techniques, providing a new direction for the treatment of asthma.

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