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| Status |
Public on May 15, 2019 |
| Title |
Liver transcriptome of statin-treated patients |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
Total RNA from liver samples of 910 patients was extracted for Affymetrix microarray analysis from 30 mg frozen liver biopsies using Trizol reagent (Thermo Fisher Scientific) followed by a purification step on RNeasy columns (Qiagen). RNA purity and quantity was assessed using a Nanodrop spectrometer (Thermo Fisher Scientific). RNA integrity was quantified using the Agilent RNA6000 Nano assay and an Agilent 2100 BioAnalyzer. Nine hundred and ten samples complying with Affymetrix QC standards and a RNA integrity number (RIN) value of 5 to 7 were randomized for further processing and 300 ng RNA per sample was amplified using the Affymetrix WT amplification kit. Fragmented sscDNA was labelled using the Affymetrix WT Terminal Labeling Kit. Labeled DNA was then hybridized to Human Transcriptome Arrays 2.0 (Affymetrix) for 16 to 18 hours at 45°C and 60 rpm in a rotating hybridization oven (Hybridization Oven 640, Affymetrix). These high-resolution arrays contain >6 million distinct oligonucleotide probes (25-mers) covering coding and non-coding transcripts, enabling the identification and analysis of differential expression at the gene and exon level. After washing, arrays were scanned with the GeneChip Scanner 3000 7G (Affymetrix), controlled by the Affymetrix software GeneChip Operating System (GCOS) v1.4. Quality controls (pm_mean / background_mean, pos_vs_neg_auc, all_probeset_mad_residual_mean), hybridization controls (bioB, bioC, bioD and cre) and polyA controls (lys, phe, thr and dap) were performed according to the Affymetrix quality criteria using the Expression Console software (Affymetrix).
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| Contributor(s) |
Margerie D, Lefebvre P, Gheeraert C, Derudas B |
| Citation(s) |
31159817 |
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| Submission date |
May 09, 2019 |
| Last update date |
Jun 21, 2019 |
| Contact name |
Lefebvre Philippe |
| Organization name |
Inserm
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| Lab |
JK
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| Street address |
Bld Pr Jules Leclerc
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| City |
Lille |
| ZIP/Postal code |
59000 |
| Country |
France |
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| Platforms (1) |
| GPL20265 |
[HTA-2_0] Affymetrix Human Transcriptome Array 2.0 [transcript (gene) version] |
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| Samples (910)
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| Relations |
| BioProject |
PRJNA542262 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE130991_RAW.tar |
20.4 Gb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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