Liver transcriptome of statin-treated patients
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PROVIDER: PRJNA542262 | ENA |
REPOSITORIES: ENA
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Project description:Background: Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown. Methods: An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Results: We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. Patients on statin treatment showed higher diabetes prevalence (OR=2.67; 95%CI, 1.60-4.45; P= 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein-1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism. Conclusions: DNL gene activation profile in response to statins was associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus suggest that statin treatment increases the risk for diabetes in humans at least in part via induction of DNL.
2019-05-15 | GSE130991 | GEO
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:Transcriptome (RNA-seq) of statin-treated human primary myotubes
| PRJNA422136 | ENA
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:We performed a genome-wide association study in pooled DNA samples from patients with severe statin myopathy and persistent symptoms post-therapy versus pooled DNAs from an age-adjusted statin-tolerant group. Affymetrix 100K SNP arrays were used according to the manufacturers instructions with two pools of 19 and 20 statin myopathy patients and two pools of 20 statin-tolerant controls.
2010-07-09 | E-GEOD-17574 | biostudies-arrayexpress
Project description:KLF2 and KLF4 are important transcriptional factors in endothelial cells, however their roles in statin treatment has not been elucidated. Here we report the comprehensive change of transcripts of statin treated HUVECs transfected with siRNA KLF2 or KLF4. We used repeated microarray analysis of HUVECs treated with pitavastatin for 4hours. Before statin treatment, cells were transfected with siRNA KLF2 or KLF4.
2013-01-01 | GSE32693 | GEO
Project description:We performed a genome-wide association study in pooled DNA samples from patients with severe statin myopathy and persistent symptoms post-therapy versus pooled DNAs from an age-adjusted statin-tolerant group.
2010-07-09 | GSE17574 | GEO
Project description:We investigated the role of statin treatment in adipocyte differentiation by using the in vitro pre-adipocyte SGBS cell line. We found that statins induced a reduction in adipogenesis by decreasing the mRNA expression of key transcriptional regulators, such as ADIPOQ and GLUT4. Therefore, we analysed the whole methylome of statin-treated cells, compared to DMSO-vehicle controls, using the 850K methylation arrays (Illumina) to identify putative effective genes.
2020-09-21 | GSE139211 | GEO
Project description:KLF2 and KLF4 are important transcriptional factors in endothelial cells, however their roles in statin treatment has not been elucidated. Here we report the comprehensive change of transcripts of statin treated HUVECs transfected with siRNA KLF2 or KLF4. We used repeated microarray analysis of HUVECs treated with pitavastatin for 4hours. Before statin treatment, cells were transfected with siRNA KLF2 or KLF4. HUVECs were used within the first 6 passages. For studies, HUVECs were cultivated in medium EGM2MV containing pitavastatin at a concentration of 1 micromolar.
2013-01-01 | E-GEOD-32693 | biostudies-arrayexpress
Project description:This study investigates miRNA expression profiles from peripheral blood specimens in patients with hypercholesterolemia. Our findings demonstrated that miRNA regulations could be involved in statin-induced inflammation modulation in immune cells, thereby providing an anti-inflammatory approach to reduce residual ASCVD risk in individuals with optimal lipid control.
2020-09-30 | GSE152016 | GEO