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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Analysis of gene expression changes induced in wild-type or Atf6a-/- mice by treatment with tunicamycin for 8h

ABSTRACT: Protein misfolding stress in the endoplasmic reticulum (ER) leads to dysregulation of lipid metabolism in the liver, and ER stress is associated with human diseases that are accompanied by hepatic lipid accumulation, including obesity, alcoholism, and viral hepatitis; yet the pathways leading from ER stress to the regulation of lipid metabolism are poorly understood. Working exclusively in vivo, we used a “bottom-up” approach to infer pathways in the genetic regulation of lipid metabolism by the UPR. We used a functional genomics to link gene expression patterns taken from microarray data to the severity and persistence of ER stress, using mice lacking the UPR signaling molecule ATF6α. This approach revealed that functionally related genes clustered into a small number of distinct expression profiles, and that lipid oxidation and efflux were targets for coordinated transcriptional suppression during ER stress.Our results establish a framework for hepatic gene regulation during ER stress. Atf6a-/- or +/+ mice of variable age and gender were injected intraperitoneally with 2 mg/kg tunicamycin or vehicle. 3 separate mice were used in each group. 8h after injection, mice were sacrificed and total RNA was prepared from resected livers.

ORGANISM(S): Mus musculus

SUBMITTER: David Rutkowski

PROVIDER: E-GEOD-48932 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Analysis of gene expression changes induced in wild-type or Atf6a-/- mice by treatment with tunicamycin for 34h

Project description:Protein misfolding stress in the endoplasmic reticulum (ER) leads to dysregulation of lipid metabolism in the liver, and ER stress is associated with human diseases that are accompanied by hepatic lipid accumulation, including obesity, alcoholism, and viral hepatitis; yet the pathways leading from ER stress to the regulation of lipid metabolism are poorly understood. Working exclusively in vivo, we used a “bottom-up” approach to infer pathways in the genetic regulation of lipid metabolism by the UPR. We used a functional genomics to link gene expression patterns taken from microarray data to the severity and persistence of ER stress, using mice lacking the UPR signaling molecule ATF6α. This approach revealed that functionally related genes clustered into a small number of distinct expression profiles, and that lipid oxidation and efflux were targets for coordinated transcriptional suppression during ER stress.Our results establish a framework for hepatic gene regulation during ER stress. Atf6a-/- or +/+ mice of variable age and gender were injected intraperitoneally with 1 mg/kg tunicamycin or vehicle. 3 separate mice were used in each group. 34h after injection, mice were sacrificed and total RNA was prepared from resected livers.

2013-09-04 | E-GEOD-48935 | biostudies-arrayexpress

Analysis of gene expression changes induced in wild-type or Atf6a-/- mice by treatment with tunicamycin for 34h

2013-09-04 | GSE48935 | GEO

Analysis of gene expression changes induced in wild-type or Atf6a-/- mice by treatment with tunicamycin for 8h

2013-09-04 | GSE48932 | GEO

Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

Project description:Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation (ChIP) analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.

2020-04-24 | GSE131146 | GEO

Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

2015-05-12 | GSE68718 | GEO

ER stress inhibits liver fatty acid oxidation while unmitigated stress leads to anorexia-induced lipolysis and both liver and kidney steatosis

Project description:The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation are unclear, including which pathways contribute to the phenotype in each organ. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver, but not the kidney; while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.

2017-06-23 | MTBLS472 | MetaboLights

Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution.

Project description:Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress. 24 total samples. One sample represents one mouse. Three samples were analyzed from the following groups: Lrh-1 f/f (control littermates) treated with vehicle, Lrh-1 f/f treated with tunicamycin (TM; 1mg/kg BW for 24h), Lrh-1 f/f treated with tunicamycin and DLPC (100mg/kg BW 4x), Lrh-1 f/f treated with tunicamycin and vehicle for DLPC, Lrh-1 liver-specific KO mice (LKO) treated with vehicle, Lrh-1 LKO treated with tunicamycin, and Lrh-1 LKO treated with tunicamycin and DLPC, Lrh-1 LKO treated with tunicamycin and vehicle for DLPC

2015-05-12 | E-GEOD-68718 | biostudies-arrayexpress

ER in Liver - 2

Project description:Liver transcriptome was analyzed at proestrus (P) and metestrus (M) in liver IGF-1-/- or LID mice. In order to elucidate the mechanism underlying ER control of liver metabolic function, we investigated the genetic programs controlled by the hepatic receptor during the physiological fluctuation of circulating E2 in adult female mice. To this aim, we used Affymetrix GeneChip Arrays and compared the expression of hepatic genes in mice in two phases of the estrous cycle: Proestrus (P) and Metestrus (M), characterized by high and low circulating E2 respectively. Analysis of data demonstrated that the expression of genes involved in lipid and cholesterol metabolism changes during the reproductive cycle. To further elucidate ER transcriptional activity at M and P, we performed a whole genome ChIP experiment followed by tiling array. We observed that at M, but not at P, recruited ERs are mostly in proximity (20 kbp) of genes involved in energy metabolism, thus strengthening the hypothesis of ER playing a bridging role between metabolism and reproduction.

2012-07-04 | E-MEXP-3505 | biostudies-arrayexpress

ER in liver

Project description:In order to elucidate the mechanism underlying ER control of liver metabolic function, we investigated the genetic programs controlled by the hepatic receptor during the physiological fluctuation of circulating E2 in adult female mice. To this aim, we used Affymetrix GeneChip Arrays and compared the expression of hepatic genes in mice in two phases of the estrous cycle: Proestrus (P) and Metestrus (M), characterized by high and low circulating E2 respectively. Analysis of data demonstrated that the expression of genes involved in lipid and cholesterol metabolism changes during the reproductive cycle. To further elucidate ER transcriptional activity at M and P, we performed a whole genome ChIP experiment followed by tiling array. We observed that at M, but not at P, recruited ERs are mostly in proximity (20 kbp) of genes involved in energy metabolism, thus strengthening the hypothesis of ER playing a bridging role between metabolism and reproduction.

2012-07-04 | E-MEXP-3504 | biostudies-arrayexpress

The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

Project description:Disruptions of the endoplasmic reticulum (ER) that perturb protein folding cause ER stress and elicit an unfolded protein response (UPR) that involves translational and transcriptional changes in gene expression aimed at expanding the ER processing capacity and alleviating cellular injury. Three ER stress sensors PERK, ATF6, and IRE1 implement the UPR. PERK phosphorylation of eIF2 during ER stress represses protein synthesis, which prevents further influx of ER client proteins, along with preferential translation of ATF4, a transcription activator of the integrated stress response. In this study we show that the PERK/eIF2α~P/ATF4 pathway is required not only for translational control, but also activation of ATF6 and its target genes. The PERK pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6. As a consequence, liver-specific depletion of PERK significantly reduces both the translational and transcriptional phases of the UPR, leading to reduced protein chaperone expression, disruptions of lipid metabolism, and enhanced apoptosis. These findings show that the regulatory networks of the UPR are fully integrated, and helps explain the diverse pathologies associated with loss of PERK. 14 gene expression arrays, 3 WT control arrays; 3 lsPERK control arrays; 4 WT Treated arrays; 4 lsPERK treated arrays. Comparison of gene expression profiles for treated vs control in wildtype and knock-out.

2012-01-20 | E-GEOD-29929 | biostudies-arrayexpress

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