Trib1 regulates mouse LDL metabolism through Cebpa-mediated regulation of the LDL receptor in hepatocytes.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA666639 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12747800.fastq.gz | Fastqsanger.gz | |||
| SRR12747801.fastq.gz | Fastqsanger.gz | |||
| SRR12747802.fastq.gz | Fastqsanger.gz | |||
| SRR12747803.fastq.gz | Fastqsanger.gz | |||
| SRR12747804.fastq.gz | Fastqsanger.gz |
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Project description:The Tribbles homolog 1 protein (TRIB1), encoded by the gene TRIB1, has been identified by genome-wide association studies (GWAS) as likely to be causal of a remarkable number of cardiometabolic traits, including plasma lipids, hepatic steatosis, adiponectin levels, and coronary artery disease. In its best-known function, Tribbles 1 interacts with the ubiquitin ligate COP1 protein to target the transcription factors CCAAT/enhancer-binding protein alpha and beta (CEBP a/b) for proteasomal degradation. We have previously published that specific Trib1 deletion in mice increased de novo lipogenesis, hepatic steatosis, and plasma triglycerides, attributable at least in part to increased protein levels of hepatic Cebpa. However, the mechanism by which Trib1 regulates plasma lipids and specifically LDL-C metabolism remained unknown. In this experiment our aim was to identify possible molecular interactions by which hepatic Trib1 regulates specifically LDL-C metabolism dependently of Cebpa expression. To do this, we compared total gene expression in livers of wild type mice, Trib1, Cebpa and Trib1;Cebpa hepatic deleted mice. Gene expression data was then used in Ingenuity Pathway analysis to identify upstream transcription factors that might be responsible for the gene expression changes observed.
2023-09-29 | GSE158815 | GEO
Project description:The TRIB1 locus has been associated with lipid dysfunction. The underlying mechanisms were investigated by examining the transcription landscape in response to TRIB1 suppression in human primary hepatocytes. Primary hepatocytes from 3 distinct donors were exposed for 48 h to an antisense nucleotide targeting TRIB1 or a control nucleotide. The resulting impacts on the transcription profile were assessed using Human Transcriptome 2.0 microarrays (Affymetrix).
2015-04-13 | E-GEOD-61473 | biostudies-arrayexpress
Project description:Genetic variants at the TRIB1 (Tribbles-homolog 1) gene locus are strongly associated with plasma lipid traits and the risk of coronary artery disease in humans. In this study, we analyzed the consequences of Trib1-deficiency (Trib1-/-) on hepatic gene expression in mice on the atherosclerosis-susceptible LDL-receptor deficient (Ldlr-/-) background. Therefore, Trib1-/- mice were crossed onto the Ldlr-/- background to generate double knockout mice (Trib1-/-Ldlr-/-) and fed a semisynthetic, modified AIN76 diet (0.02% cholesterol, 4.3% fat). At 20 weeks of age, Trib1-/-Ldlr-/- mice and Trib1+/+Ldlr-/- control mice were sacrificed and liver tissue was snap frozen in liquid nitrogen and stored at -80°C until further processing. Total RNA was isolated from liver tissue (n=8 mice per genotype) and subjected to microarray gene expression analysis.
2023-03-15 | E-MTAB-12669 | biostudies-arrayexpress
Project description:The TRIB1 locus has been associated with lipid dysfunction. The underlying mechanisms were investigated by examining the transcription landscape in response to TRIB1 suppression in human primary hepatocytes.
2015-04-13 | GSE61473 | GEO
Project description:Genetic variants near the TRIB1 gene are highly significantly associated with plasma lipid traits and coronary artery disease. While TRIB1 is likely causal of these associations, the molecular mechanisms are not well understood. Here we sought to investigate how TRIB1 influences low density lipoprotein cholesterol (LDL-C) levels in mice. Hepatocyte-specific deletion of Trib1 (Trib1Δhep) in mice increased plasma cholesterol and apoB and slowed the catabolism of LDL-apoB due to decreased levels of LDL receptor (LDLR) mRNA and protein. Simultaneous deletion of the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα) with TRIB1 eliminated the effects of TRIB1 on hepatic LDLR regulation and LDL catabolism. Using RNA-seq, we found that activating transcription factor 3 (Atf3) was highly upregulated in the livers of Trib1Δhep but not Trib1Δhep CebpaΔhep mice. ATF3 has been shown to directly bind to the CEBPα protein, and to repress the expression of LDLR by binding its promoter. Blunting the increase of ATF3 in Trib1Δhep mice reduced the levels of plasma cholesterol and partially attenuated the effects on LDLR. Based on these data, we conclude that deletion of Trib1 leads to a posttranslational increase in CEBPα, which increases ATF3 levels, thereby contributing to the downregulation of LDLR and increased plasma LDL-C.
| S-EPMC8592541 | biostudies-literature
Project description:Expression analysis of CEBPa knockout effects on gene expression in adult mouse liver. We used a conditional knock out strategy to delete CEBPa specifically in adult mouse hepatocytes and analysed the resulting changes in gene expression by means of microarrays.
2010-04-08 | E-MTAB-178 | biostudies-arrayexpress
Project description:In familial hypercholesterolemia (FH), mutations in the low-density lipoprotein (LDL) receptor (LDLr) gene result in increased plasma LDL cholesterol. Clinical and preclinical studies revealed an association between FH and hippocampus-related memory and mood impairment. We here asked whether hippocampal pathology in FH might be a consequence of compromised adult hippocampal neurogenesis. We evaluated hippocampus-dependent behaviour and neurogenesis in adult C57BL/6JRj and LDLr-/- mice. Behavioural tests revealed that adult LDLr-/- mice showed reduced performance in a dentate gyrus (DG)-dependent metric change task. This phenotype was accompanied by a reduction in cell proliferation and adult neurogenesis in the DG of LDLr-/- mice, suggesting a potential direct impact of LDLr mutation on NPC. We thus investigated the effects of elevated cholesterol and the function of LDLr in neural precursor cells (NPC) isolated from adult C57BL/6JRj mice in vitro. Exposure of NPC to LDL as well as LDLr gene knockdown reduced proliferation and disrupted transcriptional activity of genes involved in endogenous cholesterol synthesis and metabolism. The LDL treatment also induced an increase in intracellular lipid storage. Functional analysis of differentially expressed genes revealed parallel modulation of distinct regulatory networks upon LDL treatment and LDLr knockdown. Together, these results suggest that high LDL levels and a loss of LDLr function, which are characteristic to individuals with FH, might contribute to a disease-related impairment in adult hippocampal neurogenesis and, consequently, cognitive functions.
2019-09-04 | GSE136792 | GEO
Project description:The pseudokinase Trib1 functions as a myeloid oncogene that recruits E3 ubiquitin ligase COP1 to C/EBPa, and interacts with MEK1 to enhance ERK phosphorylation. Close genetic interaction between Trib1 and Hoxa9 has been observed in myeloid leukemogenesis as Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. Yet the mechanism how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Here we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analyses identified increased Histone H3K27Ac signals at the super-enhancers such as Erg, Aff3, Spns2 and Coro2 loci, as well as increased mRNA expression of these genes. The modification of super-enhancer activities is mostly achieved by degradation of C/EBPa by Trib1 and the MEK/ERK pathway only slightly contributes to the activities. Silencing of Erg abrogates the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of AML cells with the BRD4 inhibitor JQ1 showed growth inhibition in the Trib1/Erg-dependent manner. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential target of Hoxa9-associated AML. We used microarrays to detail the global program of gene expression in mouse AML
2020-10-21 | GSE139641 | GEO
Project description:The pseudokinase Trib1 functions as a myeloid oncogene that recruits E3 ubiquitin ligase COP1 to C/EBP, and interacts with MEK1 to enhance ERK phosphorylation. Close genetic interaction between Trib1 and Hoxa9 has been observed in myeloid leukemogenesis as Trib1 overexpression significantly accelerates Hoxa9-induced leukemia onset. Yet the mechanism how Trib1 functionally modulates Hoxa9 transcription activity is unclear. Here we provide evidence that Trib1 modulates Hoxa9-associated super-enhancers. ChIP-seq analyses identified increased Histone H3K27Ac signals at the super-enhancers such as Erg, Aff3, Spns2 and Coro2 loci, as well as increased mRNA expression of these genes. The modification of super-enhancer activities is mostly achieved by degradation of C/EBP by Trib1 and the MEK/ERK pathway only slightly contributes to the activities. Silencing of Erg abrogates the growth advantage acquired by Trib1 overexpression, indicating that Erg is a critical downstream target of the Trib1/Hoxa9 axis. Moreover, treatment of AML cells with the BRD4 inhibitor JQ1 showed growth inhibition in the Trib1/Erg-dependent manner. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential target of Hoxa9-associated AML.
2020-10-21 | GSE140313 | GEO
Project description:LDL or Ox-LDL 200ug/ml, which showed no loss of viability after a 48 hour exposure, induced a physiological and pathological transcriptional response, respectively. LDL induced a downregulation of genes associated with cholesterol biosynthesis while ox-LDL induced transcriptional alterations in genes related to inflammation, matrix expansion, lipid metabolism and processing, and apoptosis. Pentraxin-3 was secreted into the culture medium after RPE cells were stimulated with ox-LDL, and immunohistochemically evident in Bruchs membrane of human macular samples with age-related macular degeneration. ARPE-19 cells exposed to 200ug/ml ox-LDL had a 38% apoptosis rate compared to less than 1% when exposed to LDL or untreated controls (p<0.0001). While LDL induced a physiologic response by RPE cells, a pathological phenotypic response was seen after treatment with oxidatively modified LDL. The transcriptional, biochemical, and functional data provide initial support of a role for the hypothesis that modified LDLs are one trigger for initiating events that contribute to the development of age-related macular degeneration. Keywords: treatment with non-treatment control Human ARPE-19 cells were exposed to LDL or oxidatively modified LDL (ox-LDL) for 48 hours for RNA extraction and hybridization on Affymetrix microarrays. We sought to determine whether retina, pigment epithelial cells develop a pathologic phenotype after exposure to low density lipoproteins (LDL) that are oxidatively modified.We have made two comparsions: LDL treatment versus non-treatment; ox-LDL treatment versus non-treatment.
2006-09-01 | E-GEOD-5741 | biostudies-arrayexpress