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GSE76172
Mus musculus
6 Downloadable Samples
Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
FNDC4 is a novel secreted factor sharing high homology with the exercise-associated myokine irisin (FNDC5). Here we report that Fndc4 is robustly upregulated in various mouse models of inflammation as well as in human inflammatory conditions. Specifically, subjects with inflammatory bowel disease show increased FNDC4 levels locally at inflamed sites of the intestine. Interestingly, administration of recombinant FNDC4 during colitis development in mice resulted in markedly reduced disease severity compared to mice injected with a control protein. Conversely, mice that lacked Fndc4 showed increased colitis severity. Analysis of binding of FNDC4 to different immune cell types revealed strong and specific binding to macrophages and monocytes. FNDC4 treatment of bone marrow-derived macrophages in vitro resulted in reduced phagocytosis, improved survival and reduced pro-inflammatory chemokine expression. Hence, treatment with FNDC4 resulted in a state of dampened macrophage activity, while enhancing their survival. Thus, we have characterized a novel factor with direct therapeutic potential in inflammatory bowel disease and possibly other inflammatory diseases.
Publication Title
FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice.
Sample Metadata Fields
Sex, Specimen part, Treatment
View Samples- Rattus norvegicus
- 3 Downloadable Samples
- Affymetrix Rat Gene 1.0 ST Array (ragene10st)
Description
Aims/hypothesis: While lipid deposition in skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like skeletal muscle. Here we investigated the effects of PLIN5 overexpression in comparison with effects of PLIN2 on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity. Methods: Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet. Eight days after electroporation, insulin-mediated glucose uptake in skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays. Results: TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function. Conclusions/interpretation: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PLIN5 in skeletal muscle promoted expression of a cluster of genes under control of PPAR and PGC1 involved in FA catabolism and mitochondrial oxidation.
Publication Title
Overexpression of PLIN5 in skeletal muscle promotes oxidative gene expression and intramyocellular lipid content without compromising insulin sensitivity.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Homo sapiens
- 13 Downloadable Samples
Illumina HiSeq 2500
Description
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance, which is frequently caused by reactivation of the Mitogen Activated Protein Kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor (HDACi) vorinostat represses SLC7A11 that leads to a lethal increase in the already elevated levels of ROS in drug-resistant cells, thereby causing selective apoptotic death of only the drug resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with HDACi in mice results in a dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor resistant melanoma, we find that HDACi can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here. Overall design: one replicate of RNA Seq data A375, A375R, A375DR vorinostat treated and patient samples pre- post- vorinostat treatment
Publication Title
An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Cell line, Treatment, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid storage exceeds intracellular needs and induces lipotoxic events ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/ADRP) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol storage, marginally increased FA oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase of OXPHOS protein content. Diacylglycerol levels were unchanged, while ceramide levels were increased. Despite the increased intramyocellular lipid accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs towards triacylglycerol storage in LDs thereby blunting lipotoxicity-associated insulin resistance.
Publication Title
Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 112 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Homo sapiens
- 54 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Samples were taken from surgically resected tumor specimens from patients with colorectal cancer. The expression profiles were determined using the Affymetrix GeneChip Human Exon 1.0 ST Array version 2. Gene mutation status was determined using Sanger sequencing.
Publication Title
BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Homo sapiens
- 58 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
mRNA from 59 primary colorectal tumour samples were extracted and hybridized to HG-U133Plus 2.0 expression arrays. Mutation status for several genes were determined using Sanger sequencing.
Publication Title
BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression.
Sample Metadata Fields
Sex, Age, Subject
View Samples- Mus musculus
- 35 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Background: The selective absorption of nutrients and other food constituents in the small intestine is mediated by a group of transport proteins and metabolic enzymes, often collectively called intestinal barrier proteins. An important receptor that mediates the effects of dietary lipids on gene expression is the peroxisome proliferator-activated receptor alpha (PPAR), which is abundantly expressed in enterocytes. In this study we examined the effects of acute nutritional activation of PPAR on expression of genes encoding intestinal barrier proteins. To this end we used triacylglycerols composed of identical fatty acids in combination with gene expression profiling in wild-type and PPAR-null mice. Treatment with the synthetic PPAR agonist WY14643 served as reference.
Publication Title
PPARalpha-mediated effects of dietary lipids on intestinal barrier gene expression.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We studied the effect of dietary fat type, varying in polyunsaturated/saturated fatty acid ratio's (P/S) on development of metabolic syndrome. C57Bl/6J mice were fed purified high-fat diets (45E% fat) containing palm oil (HF-PO; P/S 0.4), olive oil (HF-OO; P/S 1.1) or safflower oil (HF-SO; P/S 7.8) for 8 weeks. A low-fat palm oil diet (LF-PO; 10E% fat) was used as a reference. Additionally, we analyzed diet-induced changes in gut microbiota composition and mucosal gene expression. The HF-PO diet induced a higher body weight gain and liver triglyceride content compared to the HF-OO, HF-SO or LF-PO diet. In the intestine, the HF-PO diet reduced microbial diversity and increased the Firmicutes/Bacteroidetes ratio. Although this fits a typical obesity profile, our data clearly indicate that an overflow of the HF-PO diet to the distal intestine, rather than obesity itself, is the main trigger for these gut microbiota changes. A HF-PO diet-induced elevation of lipid metabolism-related genes in the distal small intestine confirmed the overflow of palm oil to the distal intestine. Some of these lipid metabolism-related genes were previously already associated with the metabolic syndrome. In conclusion, our data indicate that saturated fat (HF-PO) has a more stimulatory effect on weight gain and hepatic lipid accumulation than unsaturated fat (HF-OO and HF-SO). The overflow of fat to the distal intestine on the HF-PO diet induced changes in gut microbiota composition and mucosal gene expression. We speculate that both are directly or indirectly contributive to the saturated fat-induced development of obesity and hepatic steatosis.
Publication Title
Saturated fat stimulates obesity and hepatic steatosis and affects gut microbiota composition by an enhanced overflow of dietary fat to the distal intestine.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 30 Downloadable Samples
- Illumina HiSeq 2500
Description
The goal of this study is to compare gene expression profiles in quiescent RPE1 hTert cells treated with microtubule-stabilizing (paclitaxel) and microtubule-destabilizing poisons (combretastatin A4) Overall design: RPE 1 hTert cells were grown to full confluency, and maintained as such for 5 days to induce quiescence. Quiescent cells were treated with microtubule poisons combretastatin A4 and paclitaxel for 6 or 24 hours. Total RNA was collected and purified using the PureLink RNA Mini Kit (Invitrogen, Thermo Fisher Scientific, USA). RNA concentration and quality were determined using NanoDrop and Bioanalyzer respectively, and 500 ng of purified RNA was used as input for the Illumina TruSeq Stranded mRNA Library Prep Kit (Illumina, USA). Barcoded libraries were pooled and quantitated using KAPA, and single-end sequenced on an Illumina NextSeq (Illumina, USA). RNA-seq reads were mapped using STAR (version 2.1.0j) and processed using HTSeq-count (version 0.6.1). GRCh38 reference genome and transcript annotations were used for gene mapping; Entrez Gene identifiers and org.Hs.eg.db database were used for genome wide annotation. Differential gene expression and statistical analysis were performed using edgeR package. Genes with >50 reads per million and a fold change significantly different from zero in Wilcoxon signed-rank test (p< 0.05), were marked as differentially expressed genes, based on three biological replicates.
Publication Title
Tubulin mRNA stability is sensitive to change in microtubule dynamics caused by multiple physiological and toxic cues.
Sample Metadata Fields
Specimen part, Subject
View Samples