Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE125178 | GEO | 2019/01/17
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC7696670 | biostudies-literature
Project description:Probing the Global Cellular Responses to Lipotoxicity Caused by Saturated Fatty Acids
| PRJNA515481 | ENA
Project description: Not available
| S-EPMC4665795 | biostudies-other
Project description:To identify the genes induced by lipotoxicity and integrated stress response in pancreatic beta cells, we have employed whole genome microarray expression in panvreatic beta cell line MIN6m9 cells. First microarray analysis : Wild type MIN6m9 cells were treated with Palmitate, Oleate or negative control condition. Second microarray analysis : Wild type and Fv2E-PERK transgened MIN6m9 cells were treated with mock or artificial dimerizer AP20187(AP) in various time course.
2015-08-01 | E-GEOD-49647 | biostudies-arrayexpress
Project description:Pancreatic beta-cell dysfunction and death are central in the pathogenesis of type 2 diabetes. Saturated fatty acids cause beta-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA-sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling beta-cell phenotype including PAX4 and GATA6. 59 type 2 diabetes candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. DAVID analysis of transcription binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced beta-cell dysfunction and death. The data point to crosstalk between metabolic stress and candidate genes at the beta-cell level. 5 human islet of Langerhans preparations examined under 2 conditions (control and palmitate treatment)
2014-01-09 | E-GEOD-53949 | biostudies-arrayexpress
Project description:Pancreatic beta-cell dysfunction and death are central in the pathogenesis of type 2 diabetes. Saturated fatty acids cause beta-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA-sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling beta-cell phenotype including PAX4 and GATA6. 59 type 2 diabetes candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. DAVID analysis of transcription binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced beta-cell dysfunction and death. The data point to crosstalk between metabolic stress and candidate genes at the beta-cell level.
2014-01-09 | GSE53949 | GEO
Project description:The regulation of complex cellular activities in palmitate treated HepG2 cells, and the ensuing cytotoxic phenotype, involves cooperative interactions between genes. While previous approaches have largely focused on identifying individual target genes, elucidating interacting genes has thus far remained elusive. We applied the concept of information synergy to reconstruct a ?gene-cooperativity? network for palmititate-induced cytotoxicity in liver cells. Our approach integrated gene expression data with metabolic profiles to select a subset of genes for network reconstruction. Subsequent analysis of the network revealed insulin signaling as the most significantly enriched pathway, and desmoplakin (DSP) as its top neighbor. We determined that palmitate significantly reduces DSP expression, and treatment with insulin restores the lost expression of DSP. Insulin resistance is a common pathological feature of fatty liver and related ailments, whereas loss of DSP has been noted in liver carcinoma. Reduced DSP expression can lead to loss of cell-cell adhesion via desmosomes, and disrupt the keratin intermediate filament network. Our findings suggest that DSP expression may be perturbed by palmitate and, along with insulin resistance, may play a role in palmitate induced cytotoxicity, and serve as potential targets for further studies on non-alcoholic fatty liver disease (NAFLD). free fatty acids(palmitate, oleate, linoleate) 0.7mM and tnf-alpha (0 20,100 ng/ml) were subjected to HepG2 cell line to study the cytotoxicity induced by these two factors. control(Hepg2 medium and BSA medium) treatment(combinations of TNFa+FFAs) two biological replicates for each condition, color swap for each sample
2012-05-01 | E-GEOD-26885 | biostudies-arrayexpress
Project description:The regulation of complex cellular activities in palmitate treated HepG2 cells, and the ensuing cytotoxic phenotype, involves cooperative interactions between genes. While previous approaches have largely focused on identifying individual target genes, elucidating interacting genes has thus far remained elusive. We applied the concept of information synergy to reconstruct a ?gene-cooperativity? network for palmititate-induced cytotoxicity in liver cells. Our approach integrated gene expression data with metabolic profiles to select a subset of genes for network reconstruction. Subsequent analysis of the network revealed insulin signaling as the most significantly enriched pathway, and desmoplakin (DSP) as its top neighbor. We determined that palmitate significantly reduces DSP expression, and treatment with insulin restores the lost expression of DSP. Insulin resistance is a common pathological feature of fatty liver and related ailments, whereas loss of DSP has been noted in liver carcinoma. Reduced DSP expression can lead to loss of cell-cell adhesion via desmosomes, and disrupt the keratin intermediate filament network. Our findings suggest that DSP expression may be perturbed by palmitate and, along with insulin resistance, may play a role in palmitate induced cytotoxicity, and serve as potential targets for further studies on non-alcoholic fatty liver disease (NAFLD).
2012-05-02 | GSE26885 | GEO
Project description: Not available
| S-EPMC4553418 | biostudies-literature
Project description:Palm and coconut oils are linked to cardiovascular disease and diabetes because of their high saturated fatty acid (SFA) content but exactly how exogenous SFAs, but not unsaturated fatty acids (UFA), are toxic to cells remains unknown. In insulin-producing, β-cells of the Islets of Langerhans, loss of which exacerbates diabetes, we found that SFAs but not UFAs were toxic because they disable a highly conserved lipid droplet biogenesis machinery. We show that palmitate (a major SFA of these oils), but not palmitoleic or oleic, S-acylates the highly conserved ER-resident FITM2 protein, required for lipid coalescence and droplet budding from the ER. The S-acylation marks FITM2 for ubiquitination and proteosomal degradation, leaving SFAs within the ER instead safe sequestration within lipid droplets. ER-stress ensues with rapid induction of ER stress leading to β-cell apoptosis. Specific deletion of FITM2 in β-cells disrupts calcium signaling and key β-cell TFs and exacerbates high fat diet-induced ER stress and diabetes. Rescue by overexpression ameliorates ER-stress and β-cell apoptosis thus demonstrating an important link between lipid species and cell ability to sequester them away from the ER in the form of lipid droplets.
2021-07-08 | GSE133939 | GEO