Transcriptomic sterol response in the HepG2 human hepatoma cell line
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190736 | GEO | 2024/12/10
REPOSITORIES: GEO
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Project description:Lovastatin and other statins inhibit HMG-CoA reductase, which carries out an early step in the sterol biosynthesis pathway. Statins lower cholesterol and are widely prescribed to prevent heart disease, but like many drugs, they can interact with nutritionally acquired metabolites. To probe these interactions, we explored the effect of a diverse library of metabolites on statin effectiveness using a Saccharomyces cerevisiae model. In yeast, treatment with lovastatin results in reduced growth. We combined lovastatin with the library of metabolites and found that copper and zinc ions impaired the ability of the statin to inhibit yeast growth. Using an integrated genomic and metabolomic approach, we found that lovastatin plus metal synergistically upregulated some sterol biosynthesis genes. This altered pattern of gene expression resulted in greater flux through the sterol biosynthesis pathway and an increase in ergosterol levels. Each sterol intermediate level was correlated with expression of the upstream gene. Thus, the ergosterol biosynthetic response induced by statin is enhanced by copper and zinc. In cultured mammalian cells, these metals also rescued statin growth inhibition. Because copper and zinc impair the ability of statin to reduce sterol biosynthesis, dietary intake of these metals could have clinical relevance for statin treatment in humans.
2010-10-29 | GSE25004 | GEO
Project description:Lovastatin and other statins inhibit HMG-CoA reductase, which carries out an early step in the sterol biosynthesis pathway. Statins lower cholesterol and are widely prescribed to prevent heart disease, but like many drugs, they can interact with nutritionally acquired metabolites. To probe these interactions, we explored the effect of a diverse library of metabolites on statin effectiveness using a Saccharomyces cerevisiae model. In yeast, treatment with lovastatin results in reduced growth. We combined lovastatin with the library of metabolites and found that copper and zinc ions impaired the ability of the statin to inhibit yeast growth. Using an integrated genomic and metabolomic approach, we found that lovastatin plus metal synergistically upregulated some sterol biosynthesis genes. This altered pattern of gene expression resulted in greater flux through the sterol biosynthesis pathway and an increase in ergosterol levels. Each sterol intermediate level was correlated with expression of the upstream gene. Thus, the ergosterol biosynthetic response induced by statin is enhanced by copper and zinc. In cultured mammalian cells, these metals also rescued statin growth inhibition. Because copper and zinc impair the ability of statin to reduce sterol biosynthesis, dietary intake of these metals could have clinical relevance for statin treatment in humans. There are 23 total samples comprising replicates of combinations of statin (5 ug/mL), CuSO4 (1mM), and ZnSO4 (2mM) treatments. There are three biological replicates. Within each biological replicate set, there are two conditions that were randomly chosen to be duplicated (i.e., technical replicates). An RNA sample consisting of a mix of RNA from all 6 experimental conditions was used as the reference.
2010-10-29 | E-GEOD-25004 | biostudies-arrayexpress
Project description:Transcriptomic sterol response in the HepG2 human hepatoma cell line
| PRJNA788285 | ENA
Project description:Statin-induced myopathy is a common side-effect but its mechanisms in human skeletal muscle have never been explained satisfyingly. We exposed 25 different primary human muscle cell lines to either a lipophilic or a hydrophilic statin, quantified cholesterol, mevalonate, proliferation, differentiation, and performed a comprehensive transcriptome and proteome analysis. We found reduced mevalonic acid (MVA) and cholesterol levels demonstrating incorporation of statins into the cells. Statins also significantly impaired proliferation and differentiation. Using an integrated pathway analysis approach with transcriptome and proteome data from statin-treated human primary myotubes, we modelled a novel statin-induced metabolism network for human muscle cells. This analysis confirmed the effect of statins on cholesterol biosynthesis but also uncovered alterations of acetyl CoA-dependent lipid and fatty acid metabolism
2020-02-24 | GSE107998 | GEO
Project description:There is emerging evidence that, beyond their cholesterol lowering properties, statins exhibit important antileukemic effects in vitro and in vivo, but the precise mechanisms by which they generate such responses remain to be determined. We have previously shown that statins promote differentiation of acute promyelocytic leukemia (APL) cells and enhance generation of all-trans-retinoic acid (ATRA)-dependent antileukemic responses. We now provide evidence that statin-dependent leukemic cell differentiation requires engagement and activation of the JNK kinase pathway. In addition, in experiments to define the molecular targets and mediators of statin-induced differentiation we found a remarkable effect of statins on ATRA-dependent gene transcription, evidenced by the selective induction of over 400 genes by the combination of atorvastatin and ATRA. Altogether, our studies identify novel statin molecular targets linked to differentiation, establish that statins modulate ATRA-dependent transcription, and suggest that combined use of statins with retinoids may provide a novel approach to enhance antileukemic responses in APL and possibly other leukemias.
2009-01-20 | GSE12870 | GEO
Project description:Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of patients taking statins experience muscle related adverse events. Myalgia, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels, is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin-associated myalgia are not clearly understood. To elucidate changes in gene expression associated with statin-induced myalgia, we compared profiles of gene expression in the biopsied skeletal muscle from statin-intolerant patients undergoing statin re-challenge versus those of statin-tolerant controls. A robust separation of statin-intolerant and statin-tolerant cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of statin intolerant patients, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals are genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myopathy were observed with increased frequency among statin-intolerant study subjects.
2017-08-18 | GSE97254 | GEO
Project description:Background: COPD is currently the fourth leading cause of death worldwide and predicted to rank third by 2020. Statins are commonly used lipid lowering agents with documented benefits on cardiovascular morbidity and mortality, and have also been shown to have pleiotropic effects including anti-inflammatory and anti-oxidant activity. Objective: Identify a gene signature associated with statin use in the blood of COPD patients, and identify molecular mechanisms and pathways underpinning this signature that could explain any potential benefits in COPD. Methods: Whole blood gene expression was measured on 168 statin users and 452 non-users from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study. Gene expression was measured using the Affymetrix Human Gene 1.1 ST microarray chips. Factor Analysis for Robust Microarray Summarization (FARMS) was used to process the expression data and to filter out non-informative probe sets. Differential gene expression analysis was undertaken using the Linear Models for Microarray data (Limma) package adjusting for propensity score and employing a surrogate variable analysis. Similarity of the expression signal with published gene expression profiles was performed in ProfileChaser. Results: 18 genes were differentially expressed between statin users and non-users at a false discovery rate of 10%. Top genes included LDLR, ABCA1, ABCG1, MYLIP, SC4MOL, and DHCR24. The 18 genes were significantly enriched in pathways and biological processes related to cholesterol homeostasis and metabolism, and were enriched for transcription factor binding sites for sterol regulatory element binding protein 2 (SREBP-2). The resulting gene signature showed correlation with Huntington disease, Parkinson’s disease and acute myeloid leukemia. Conclusion: Statins gene signature was not enriched in any pathways related to respiratory diseases, beyond the drug’s effect on cholesterol homeostasis. Study subjects were a subset of those with COPD from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study (Vestbo et al.), funded by GlaxoSmithKline (GSK Study No. SCO104960, NCT00292552). ECLIPSE is a non-interventional, observational, multicentre, three-year study in people with COPD. Blood was collected in PAXGene tubes and frozen at -80oC. In this work we have looked at the effect of statins on gene expression in 620 subjects of whom 168 were statin users. ECLIPSE study was described in: Vestbo J, Anderson W, Coxson HO, et al.: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). Eur Respir J. 2008;31(4):869-73
2015-07-23 | E-GEOD-71220 | biostudies-arrayexpress
Project description:Statins are competitive inhibitors of (3-hydroxy-3-methylglutaryl coenzyme A) HMG-CoA reductase. The primary mechanism of statins is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis. Statins exert pleiotropic vasoprotective and atheroprotective effects in the vasculature, with its mechanism of action being incompletely understood.To depict the statin-regulated mRNA,long non-coding RNA (lncRNA) and circular RNA (circRNA) in human endothelial cells, we performed transcriptomic profiling of human umbilical vein endothelial cells (HUVECs) with atorvastatin treatment.Differentially expressed mRNA, lncRNA and circRNA may represent novel therapeutic targets against cardiovascular diseases.
2023-05-31 | GSE176531 | GEO
Project description:ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Association between genotyed SNPs and APOC3 response to therapy was conducted We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Genomic DNA extracted from peripheral blood was genotyped using a custom GoldenGate bead array encompassing 384 SNPs (Illumina). Multivariate linear regression and 2-way ANOVA for percent change in apoC-III level were performed between the groups receiving FA alone compared with FA+statin compared with statin alone.
2012-01-11 | E-GEOD-34945 | biostudies-arrayexpress
Project description:Oncogenic transformation alters the metabolism of cellular lipids to sustain tumor growth. We define a reciprocal mechanism by which cholesterol metabolism controls the formation and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of Nsdhl, or treatment with cholesterol-lowering statins caused murine pancreatic carcinomas induced by KrasG12D expression and homozygous Trp53 loss to undergo a differentiation switch from a glandular to basal (mesenchymal) phenotype. In parallel, PDACs from patients receiving statins had enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induced sterol response element binding protein 1 (SREBP1), promoting autocrine transforming growth factor beta (TGF) signaling, inducing epithelial-mesenchymal transition. Activation of promesenchymal TGFβ effectors by cholesterol-lowering statins may select for poorly differentiated carcinomas.
2020-08-14 | GSE156210 | GEO