Insights from long non-coding RNAs profiling of beta cells undergoing high glucose/palmitate -induced glucolipotoxicity
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE124833 | GEO | 2019/12/01
REPOSITORIES: GEO
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Project description:Obesity-induced insulin resistance of the liver is characterised by increased gluconeogenesis, which contributes to elevated blood glucose levels in individuals with type 2 diabetes. Research into how fatty acids induce insulin resistance has commonly focused on the induction of insulin resistance. We hypothesise that by shifting focus to the reversal of an insulin resistant phenotype, novel insights can be made into the mechanisms by which insulin resistance can be overcome. Using global gene and lipid expression profiling, we aimed to identify biological pathways altered in parallel with restoration of palmitate-induced deregulation of glucose production using metformin and sodium salicylate. FAO hepatoma cells were treated with palmitate (0.075mM, 48h) with or without metformin (0.25mM) and sodium salicylate (2mM) in the final 24h of palmitate treatment, and effects on glucose production were determined. Microarray followed by gene set enrichment analysis was performed to investigate pathway regulation. A lipidomic analysis (HPLC-MS/MS) and measurement of secreted bile acids and cholesterol were performed. Reversal of palmitate-induced impairment of glucose production by metformin and sodium salicylate was characterised by down-regulated expression of metabolic pathways regulating acetyl-CoA to cholesterol and bile acid biosynthesis. Total levels of intracellular and secreted cholesterol and bile acids were not different between impaired and restored glucose production. Total intracellular levels of diacylgycerol, triacylglycerol and cholesterol esters increased with palmitate (impaired glucose production), however, these were not further altered with metformin and sodium salicylate (restored glucose production). Six individual lipid species containing 18:0 and 18:1 side-chains were reduced by metformin and sodium salicylate. Widespread lipid metabolism changes induced by the reversal of palmitate-induced deregulation of glucose production with metformin and sodium salicylate were identified. While cholesterol and bile acid levels remained unchanged, the flux through these pathways may in part explain these findings. The identification of lipid species containing 18:0 and 18:1 side chains being regulated alongside changes to glucose production may indicate potential mediators of glucose production and insulin resistance. Three-condition experiment, Vehicle, Palmitate (PA) and Palmitate (PA) + Metformin (Met) + Sodium Sailcylate (NaS) with biological replicates: 8 Vehicle, 20 PA and 20 PA+Met+NaS , independently grown and harvested. One replicate per array.
2013-11-08 | E-GEOD-52204 | biostudies-arrayexpress
Project description:Time course treatment with 0.4 mM Palmitate and 200 nM thapsigargin of insulinoma INS-1E cells. Timepoints; 0, 4, 16 and 24h in biological duplicates within an iTRAQ 8 set for palmitate and thapsigargin, respectively.
2020-08-18 | PXD020851 | JPOST Repository
Project description:Background: Prolonged exposure to elevated free fatty acids induces β-cell failure (lipotoxicity) and contributes to the pathogenesis of type 2 diabetes. In vitro exposure of β-cells to the saturated free fatty acid palmitate is a valuable model of lipotoxicity, reproducing features of β-cell failure observed in type 2 diabetes. In order to map the β-cell response to lipotoxicity, we combined RNA-sequencing of palmitate-treated human islets with iTRAQ proteomics of insulin-secreting INS-1E cells following a time course exposure to palmitate. Results: Crossing transcriptome and proteome of palmitate-treated β-cells revealed 85 upregulated and 122 downregulated genes at both transcript and protein level. Pathway analysis identified lipid metabolism, oxidative stress, amino-acid metabolism and cell cycle pathways among the most enriched palmitate-modified pathways. Palmitate induced gene expression changes compatible with increased free fatty acid mitochondrial import and β-oxidation, decreased lipogenesis and modified cholesterol transport. Palmitate modified genes regulating endoplasmic reticulum (ER) function, ER-to-Golgi transport and ER stress pathways. Furthermore, palmitate modulated cAMP/protein kinase A (PKA) signaling, inhibiting expression of PKA anchoring proteins and downregulating the GLP-1 receptor. SLC7 family amino-acid transporters were upregulated in response to palmitate but this induction did not contribute to β-cell demise. To unravel critical mediators of lipotoxicity upstream of the palmitate-modified genes, we identified overrepresented transcription factor binding sites and performed network inference analysis. These identified LXR, PPARα, FOXO1 and BACH1 as key transcription factors orchestrating the metabolic and oxidative stress responses to palmitate. Conclusions: This is the first study to combine transcriptomic and sensitive time course proteomic profiling of palmitate-exposed β-cells. Our results provide comprehensive insight into gene and protein expression changes, corroborating and expanding beyond previous findings. The identification of critical drivers and pathways of the β-cell lipotoxic response points to novel therapeutic targets for type 2 diabetes.
2020-08-13 | GSE156109 | GEO
Project description:Palmitate or vehicle control-treated breast cancer cells
2014-07-16 | E-MTAB-2601 | biostudies-arrayexpress
Project description:High-fat diet or exposure to saturated fatty acids affects skeletal muscle growth and function. The aim of the present study was to investigate the effect of palmitate on the transcriptomic profile of mouse C2C12 myoblasts. Global gene expression was evaluated using whole mouse genome oligonucleotide microarrays, and the results were validated through real-time PCR. A total of 4047genes were identified as differentially expressed, including 3492 down-regulated and 555 up-regulated genes during 48-h-exposure to palmitate (0.1 mmol/l). Functional classification showed the involvement of PA-regulated genes in several processes which regulate cell growth. In conclusion, palmitate modifies the expression of genes associated with: i) myoblast responsiveness to hormones and growth factors, ii) cytokine and growth factor expression, and iii) regulation of cell-cell cell-matrix communication. Such alterations can affect myoblast growth and differentiation, however further studies in this field are required. To whom the correspondence should be addressed: Dr K. Grzelkowska-Kowalczyk; e-mail: k_grzel_kow@poczta.fm, tel/fax: (48 22) 847 24 52 After scanning of hybridized microarrays, quantitation of slide images was performed using Feature Extraction Software (Agilent) using default parameters and the raw data were exported to GeneSpring GX 12 (Agilent, Santa Clara, CA) and log2 transformed. For identification of genes significantly altered in cell compared with the control normal gene set. Total detected entities were filtered by flags (detected, non detected) and error (coefficient of variation: CV < 50.0 percent) to remove very low signal entities and to select reproducible signal values of entities among the replicated experiments, respectively. In statistical analysis, separated for experiment with myoblasts treated with palmitate acid was used t-test unpaired (p < 0.05) with multiple testing correction: Benjamini-Hochberg <0.05, all significant changes over fold change 1.6 were selected.
2015-11-25 | E-GEOD-75378 | biostudies-arrayexpress
Project description:High-fat diet or exposure to saturated fatty acids affects skeletal muscle growth and function. The aim of the present study was to investigate the effect of palmitate on the transcriptomic profile of mouse C2C12 myoblasts. Global gene expression was evaluated using whole mouse genome oligonucleotide microarrays, and the results were validated through real-time PCR. A total of 4047genes were identified as differentially expressed, including 3492 down-regulated and 555 up-regulated genes during 48-h-exposure to palmitate (0.1 mmol/l). Functional classification showed the involvement of PA-regulated genes in several processes which regulate cell growth. In conclusion, palmitate modifies the expression of genes associated with: i) myoblast responsiveness to hormones and growth factors, ii) cytokine and growth factor expression, and iii) regulation of cell-cell cell-matrix communication. Such alterations can affect myoblast growth and differentiation, however further studies in this field are required. To whom the correspondence should be addressed: Dr K. Grzelkowska-Kowalczyk; e-mail: k_grzel_kow@poczta.fm, tel/fax: (48 22) 847 24 52
2015-11-25 | GSE75378 | GEO
Project description:DNA microarray analysis was performed to investigate the expression of genes in HGF stimulated with palmitate Type 2 diabetes (T2D) is characterized by decreased insulin sensitivity and higher concentrations of free fatty acids (FFAs) in plasma. Among FFAs, saturated fatty acids (SFAs), such as palmitate, have been proposed to promote inflammatory responses. Although many epidemiological studies have shown a link between periodontitis and T2D, little is known about the clinical significance of SFAs in periodontitis. The goal of this study is to demonstrate a potential link between the pathogenesis of periodontitis and SFAs in plasma. HGF were treated with either with 0 (1% Bovine serum albumin) or 100 µM Palmitate for 36 hours (n=2 each).
2015-12-31 | E-GEOD-62761 | 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:T6PNE human pancreatic cells were treated by DMSO or N-trans caffeoyltyramine (NCT) for 2 days with palmitate, followed by harvesting for RNA isolation.
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