Bone marrow TTP deficeincy significantly increased inflammation while reduced plasma lipid and hepatic steatosis in LDLR knockout mice
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PROVIDER: PRJNA522059 | ENA |
REPOSITORIES: ENA
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Project description:In order to examine the effects of bone marrow TTP deficiency on inflammation and lipid metabolism and determine the driving force during atherosclerosis, 8 week-old female LDLR−/− mice on C57BL/6J background were lethally irradiated and reconstituted with a wild type (TTP+/+) or TTP knockout (TTP−/−) bone marrow cells and fed a Western diet for 12 weeks. Then mice were sacrificed and tissues were collected for analysis. Liver tissues were collected and gene expression was analysed using a whole genome microarray. Bone marrow TTP−/− recipients displayed a significantly higher systemic and multi-organ inflammation compared to the BM-TTP+/+ recipients. BM-TTP−/− mice displayed a significant reduction of serum lipid levels, attenuated hepatic steatosis, and decreased lipid excretion than the control mice. microarray data showed that BM-TTP deficiency modulate liver genes involved in lipid metabolism and inflammatory response. RT-qPCR was used to confirm the results in several genes from microarray data. BM-TTP deficiency did not further accelerate atherorogenesis process in LDLR−/− mice after a Western diet feeding. TTP promoted VLDL to drive proinflammatory mechanism into proatherogenic mechanism.
2019-08-12 | GSE126481 | GEO
Project description:Abstract. Background and aims: Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic medication that has recently been approved for treatment of obesity as well. Semaglutide is also postulated to be a promising candidate for treatment of non-alcoholic steatohepatitis (NASH). Here, we evaluated the effects of semaglutide in a translational diet-induced model with advanced NASH and fibrosis. Methods: Ldlr-/-.Leiden mice received a fast food diet (FFD) for 25 weeks, followed by another 12 weeks on FFD with daily subcutaneously injections of semaglutide or vehicle (control). Plasma parameters were evaluated, livers and hearts were examined and hepatic transcriptome analysis was performed. Results: In the liver, semaglutide significantly reduced macrovesicular steatosis (-74%, p<0.001), inflammation (-73%, p<0.001) and completely abolished microvesicular steatosis (-100%, p<0.001). Histological and biochemical assessment of hepatic fibrosis showed no significant effects of semaglutide. However, digital pathology revealed significant improvements in the degree of collagen fiber reticulation (-12%, p<0.001). Semaglutide did not affect atherosclerosis relative to controls. Additionally, we compared the transcriptome profile of FFD-fed Ldlr-/-.Leiden mice with a human gene set that differentiates human NASH patients with severe fibrosis from those with mild fibrosis. In FFD-fed Ldlr-/-.Leiden control mice, this gene set was upregulated as well, while semaglutide predominantly reversed this gene expression. Conclusions: Using a translational model with advanced NASH, we demonstrated that semaglutide is a promising candidate with particular potential for treatment of hepatic steatosis and inflammation, while for reversal of advanced fibrosis, combinations with other NASH agents may be necessary.
2023-08-01 | GSE226496 | GEO
Project description:Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that was identified through its rapid induction by mitogens in fibroblasts. Studies of TTP-deficient mice, and cells derived from them, showed that TTP could bind to certain AU-rich elements in mRNAs, leading to increases in the rates of mRNA deadenylation and destruction. Known physiological target mRNAs for TTP include tumor necrosis factor alpha (TNF), granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin 2 beta (IL2 beta). Here we used microarray analysis of RNA from wild-type and TTP-deficient fibroblast cell lines to identify transcripts with different decay rates, after serum stimulation and actinomycin D treatment. Of 250 mRNAs apparently stabilized in the absence of TTP, 23 contained conserved TTP binding sites; 10 of these were shown by secondary analyses to be stabilized. The most dramatically affected transcript encoded the protein Ier3, recently implicated in the physiological control of blood pressure. The Ier3 transcript contained several conserved TTP binding sites that could bind TTP directly, and conferred TTP sensitivity to the mRNA in cell transfection studies. These studies have identified several new, physiologically relevant TTP target transcripts in fibroblasts; these target mRNAs encode proteins from a variety of functional classes. Keywords: mRNA degradation, time course, knockout experiment
2006-10-17 | GSE5324 | GEO
Project description:Basophils play crucial roles in type 2 immune responses, such as chronic allergic inflammation and protective immunity against parasites. However, the molecular mechanisms underlying the regulation of proinflammatory molecule production by basophils remain unclear. To investigate the role of RNA-binding proteins (RBPs), we first analyzed the gene expression of CCCH zinc finger proteins in antigen/IgE-stimulated basophils and identified that Zfp36, encoding tristetraprolin (TTP), was the most significantly upregulated gene encoding a CCCH zinc finger protein. To explore the functions of TTP in basophils, we generated TTP-knockout (TTP-KO) mice using the CRISPR-Cas9 method and conducted bulk RNA-seq analysis of antigen/IgE-stimulated basophils from wild-type (WT) and TTP-KO mice. TTP-KO basophils exhibited elevated mRNA expression of pro-inflammatory mediators, such as Il4, Il13, Areg, Ccl3, and Cxcl2, compared to WT basophils, suggesting the key role of TTP in the expression of mRNAs encoding proinflammatory mediators. Since TTP is known to regulate mRNA stability in other immune cell types, we evaluated the mRNA stability of WT and TTP-KO basophils under antigen/IgE stimulation using SLAM-seq [thiol (SH)-Linked Alkylation for the Metabolic sequencing of RNA] analysis. SLAM-seq analysis revealed that the mRNA half-lives of proinflammatory molecules, such as Il4, Il13, Areg, Ccl3, and Cxcl2, were prolonged by TTP deficiency, suggesting the importance of TTP in regulating the stability of mRNAs encoding inflammatory molecules in basophils.
2024-11-17 | GSE272531 | GEO
Project description:Controlled decay of cytokine and chemokine mRNAs restrains the time and amplitude of inflammatory responses. Tristetraprolin (TTP) binds to AU-rich elements in 3´ untranslated regions of mRNA and targets the bound mRNA for degradation. We have addressed here the function of TTP in balancing the macrophage activation state by a comprehensive analysis of TTP-dependent mRNA decay in LPS-stimulated macrophages from WT and TTP-deficient mice.
2011-12-15 | GSE28880 | GEO
Project description:Basophils play crucial roles in type 2 immune responses, such as chronic allergic inflammation and protective immunity against parasites. However, the molecular mechanisms regulating basophil activation and effector molecule production remain poorly understood. To investigate the role of RNA-binding proteins (RBPs), we first analyzed the gene expression of CCCH zinc finger proteins in antigen/IgE-stimulated basophils. Among these proteins, we identified that Zfp36, encoding tristetraprolin (TTP), was the most significantly upregulated gene. Therefore, we focused on the functions of TTP in basophils. We generated TTP-KO mice using the CRISPR-Cas9 method and conducted bulk RNA-seq analysis of antigen/IgE-stimulated basophils from wild-type (WT) and TTP-knockout (TTP-KO) mice. TTP-KO basophils exhibited elevated mRNA expression of pro-inflammatory mediators, such as Il4, Il13, Areg, Ccl3, and Cxcl2, compared to WT basophils. These data suggest that TTP is a key regulator of basophil activation, controlling the mRNA expression of inflammatory mediators.
2024-11-17 | GSE272532 | GEO
Project description:Tristetraprolin (TTP) binds to specific AU-rich elements in the 3'UTR of certain transcripts and regulates post-transcriptional gene expression by increasing the rate of mRNA turnover. Here, we generated a novel TTP mouse line (TTPΔARE) with a 136 base deletion in the 3'UTR AU-rich region of TTP mRNA, which resulted in a moderate increase in TTP protein expression in many tissues. In this study, we evaluated the effects of the moderate TTP overexpression on the overall pattern of gene expression in spleen, to investigate the effect of this mutation on mRNA targets of TTP under normal conditions. We utilized "TTPΔARE" (136 b deletion in the 3'UTR AU-rich region of Zfp36 mRNA) mice that overexpress TTP and compared the transcriptomic changes to the littermate "WT" mice. Spleen mRNA from four WT and four "TTPΔARE" mice were subjected to mRNA-Seq. All the animals used in this study were males between the ages of 8-12 weeks and were on a C57BL/6 background.
2019-01-19 | GSE65357 | GEO
Project description:Single-nucleus RNA-seq of aortas was performed in Ldlr-/- and Ldlr-/-Trem2-/- mice fed a high fat diet for 10 weeks
2024-01-12 | GSE243086 | GEO
Project description:Tristetraprolin (TTP) is a tandem CCCH zinc finger protein that was identified through its rapid induction by mitogens in fibroblasts. Studies of TTP-deficient mice, and cells derived from them, showed that TTP could bind to certain AU-rich elements in mRNAs, leading to increases in the rates of mRNA deadenylation and destruction. Known physiological target; mRNAs for TTP include tumor necrosis factor alpha (TNF), granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin 2 beta (IL2 beta). Here we used microarray analysis of RNA from wild-type and TTP-deficient fibroblast cell lines to identify transcripts with different decay rates, after serum stimulation and actinomycin D treatment. Of 250 mRNAs apparently stabilized in the absence of TTP, 23 contained conserved TTP binding sites; 10 of these were shown by secondary analyses to be stabilized. The most dramatically affected transcript encoded the protein Ier3, recently implicated in the physiological control of blood pressure. The Ier3 transcript contained several conserved TTP binding sites that could bind TTP directly, and conferred TTP sensitivity to the mRNA in cell transfection studies. These studies have identified several new, physiologically relevant TTP target transcripts in fibroblasts; these target mRNAs encode proteins from a variety of functional classes. Experiment Overall Design: Cell lines were derived from mouse embryonic fibroblast (MEF) cultures from littermate E14.5 embryos (for Zfp36 +/+ and -/- cells). MEFs were maintained at 37o C (5% CO2) in DMEM containing 10% FBS, 100 Experiment Overall Design: U/ml penicillin, 100 μg/ml streptomycin and 2 mM L-glutamine. When the cells had reached approximately 70-90 % confluence, they were trypsinized and diluted 2-50 fold in the same medium, based on morphology and growth rate, such that they would reach near confluence in 3-4 days when subcultured. Experiment Overall Design: Five identical experiments involving sequential serum deprivation, serum stimulation and actinomycin D treatment were performed on five different days; each experiment involved simultaneous identical experiments with the WT and KO cell lines. In each experiment, the cells were serum deprived for 16h, and a sample was taken at that point as a serum-deprived control. The cells were then stimulated by 10% FBS for Experiment Overall Design: 90 min and another sample taken, after which 5μg/ml actinomycin D was added; samples for RNA analysis were then removed at 30, 60, 90 and 120 min after actinomycin D treatment. In all experiments, each sample represented three combined 100 mm dishes of cells.
2008-11-22 | E-GEOD-5324 | biostudies-arrayexpress
Project description:Controlled decay of cytokine and chemokine mRNAs restrains the time and amplitude of inflammatory responses. Tristetraprolin (TTP) binds to AU-rich elements in 3´ untranslated regions of mRNA and targets the bound mRNA for degradation. We have addressed here the function of TTP in balancing the macrophage activation state by a comprehensive analysis of TTP-dependent mRNA decay in LPS-stimulated macrophages from WT and TTP-deficient mice. We compared mRNA stability in LPS-treated BMDMs from WT and TTP-/- mice by microarray-based measurement of the remnant mRNA after transcriptional blockade with actinomycin D (act D). To increase the sensitivity of the mRNA decay profiling we inhibited the LPS-activated p38 MAPK with the specific inhibitor SB203580 since p38 MAPK negatively regulates the mRNA-destabilizing activity of TTP. LPS stimulation was for 3h before addition of act D. RNA was harvested at 0', 45' and 90' thereafter.
2011-12-15 | E-GEOD-28880 | biostudies-arrayexpress