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Hepatic phosphorylation of transcription factor SREBP-1a interferes with gene regulation and peroxisomal function

ABSTRACT: Hepatic phosphorylation of transcription factor SREBP-1a interferes with gene regulation and peroxisomal function

OTHER RELATED OMICS DATASETS IN: GSE110569

PROVIDER: PRJNA433992 | ENA |

REPOSITORIES: ENA

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Hepatic phosphorylation of transcription factor SREBP-1a interferes with gene regulation and peroxisomal function

Project description:The key lipid metabolism transcription factor sterol regulatory element-binding protein (SREBP)-1a integrates gene regulatory effects of hormones, cytokines, nutrition and metabolites as lipids, glucose or cholesterol via stimuli specific phosphorylation by different MAPK cascades. We have formerly reported the systemic impact of phosphorylation in transgenic mouse models with liver-specific overexpression of the N-terminal transcriptional active domain of SREBP-1a (alb-SREBP-1a) or a MAPK kinase phosphorylation sites deficient variant (alb-SREBP-1a∆P; (S63A, S117A, T426V)), respectively. Here we investigated the molecular basis of the systemic observation in holistic hepatic gene expression analyses and lipid degrading organelles involved in the pathogenesis of metabolic syndrome, i.e. peroxisomes, by 2D-DIGE and mass spectrometry analyses. Although alb-SREBP-1a mice develop a severe phenotype with visceral adipositas and hepatic lipid accumulation featuring a fatty liver, the hepatic differential gene expression and alterations in peroxisomal protein patterns compared to control mice were surprisingly relative low. In contrast, phosphorylation site deficient alb-SREBP-1a∆P mice, protected from hepatic lipid accumulation phenotype, showed gross alteration in hepatic gene expression and peroxisomal proteome. Further knowledge based analyzes revealed that overexpression of SREBP-1a favored mainly acceleration in lipid metabolism and indicated a regular insulin signaling, whereas disruption of SREBP-1a phosphorylation resulted in massive alteration of cellular processes including signs for loss of lipid metabolic targets. These results could be the link to a disturbed lipid metabolism that overall resembles a state of insulin resistance.

2018-03-30 | GSE110569 | GEO

Gene expression data from WT and SREBP-1a deficient macrophages

Project description:Gene expression from bone-marrow drived macrophages of WT and SREBP-1a deficient mice

2011-03-22 | GSE28037 | GEO

Gene expression data from WT and SREBP-1a deficient macrophages

Project description:Gene expression from bone-marrow drived macrophages of WT and SREBP-1a deficient mice RNAs were collected 6 different macropahges and pooled RNA for microarray

2011-03-22 | E-GEOD-28037 | biostudies-arrayexpress

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [MG_U74Cv2]

Project description:The synthesis of fatty acids and cholesterol is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs because of gene knockout of SREBP cleavage-activating protein (SCAP) required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. Application of stringent combinatorial criteria to the transgenic/knockout approach allows identification of genes whose activities are likely controlled directly by the SREBPs.

2017-08-05 | GSE102258 | GEO

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [MG_U74Bv2]

2017-08-05 | GSE102257 | GEO

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [MG_U74Av2]

2017-08-05 | GSE102256 | GEO

Peroxisomal retrograde signaling in C. elegans

Project description:Distinct retrograde signaling pathways have been identified for several cellular organelles. These pathways are important to maintain the function of these organelles in response to organelle-specific stress. Using Caenorhabditis elegans, we show for the first time that such a retrograde signaling also exists for peroxisomes. Analysis of the C. elegans transcriptome revealed that peroxisomal import stress caused by the knock-down of the peroxisomal matrix protein import receptor prx-5/PEX5 induces the compensatory up-regulation of genes involved in defense response and lipid metabolic processes, especially peroxisomal beta oxidation. We, therefore, propose that the peroxisomal retrograde signaling participates in the maintenance of peroxisomal function in response to peroxisomal import stress.

2020-12-19 | GSE156318 | GEO

HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation

Project description:HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation

| PRJNA1195349 | ENA

Enterococcus mundtii 1A strain:1A

Project description:Enterococcus mundtii 1A strain:1A Genome sequencing

| PRJNA172933 | ENA

HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation

Project description:Lipid accumulation in the renal tubules is a major determinant of diabetic kidney disease (DKD), and activation of SREBPs plays a central role in this process. Our study aimed to explore whether HSPA8, a molecular chaperone, is the master regulator of INSIG/SREBPs function in DKD. Here, we showed that tubular epithelial cell (TEC)-specific knockout of HSPA8 upregulated the phosphorylation of INSIG1 and INSIG2, which disrupted the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, and the activation of SREBPs. TEC-specific overexpression of HSPA8 restrained these changes. INSIG1 and INSIG2 can be phosphorylated by protein kinase R (PKR), while HSPA8 can recognize PKR and recruit the E3 ubiquitin ligase (CHIP) to promote PKR ubiquitination and degradation. SREBP1 transcriptionally activated HSPA8 expression under temporary hyperglycemic stimulation. However, persistent hyperglycemia reduced HSPA8 levels by promoting nuclear factor (NF)-κB-mediated transcriptional inhibition and reducing USP43-mediated deubiquitination of HSPA8. Collectively, these findings indicate that the molecular chaperone HSPA8 serves as a negative feedback regulator of SREBPs, lipogenesis, and DKD development.

2024-12-12 | GSE283754 | GEO

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