Trib1 regulates mouse LDL metabolism through Cebpa-mediated regulation of the LDL receptor in hepatocytes.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE158815 | GEO | 2023/09/29
REPOSITORIES: GEO
Similar Datasets
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:Trib1 regulates mouse LDL metabolism through Cebpa-mediated regulation of the LDL receptor in hepatocytes.
| PRJNA666639 | ENA
Project description:The goal of this study is to understand the role of adipocyte-specific Trib1 in adiponectin and plasma lipid regulation. Here, we report that adipocyte-specific Trib1 knockout mice (Trib1_ASKO) have increased plasma adiponectin levels and decreased plasma cholesterol and triglycerides. We demonstrate that loss of Trib1 increases adipocyte production and secretion of adiponectin independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice suggests that alterations in adipocyte function underlie the plasma lipid changes observed in these mice. Secretomics and RNA-seq analysis revealed that Trib1_ASKO mice have increased production of Lpl and decreased production of Angptl4 in adipose tissue, and fluorescent substrate assays confirm an increase in adipose tissue Lpl activity, which likely underlies the observed triglyceride phenotype. In summary, we demonstrate here a novel role for adipocyte Trib1 in regulating plasma adiponectin, total cholesterol, and triglycerides in mice, confirming previous genetic associations observed in humans and providing a novel avenue through which Trib1 regulates plasma lipids and coronary artery disease.
2022-06-30 | GSE168596 | GEO
Project description:Objective - The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease (CAD) in humans. The lipid associated SNPs identified by genome-wide association studies (GWAS) are located ~ 30 kb downstream from TRIB1 suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. Methods & Results - Characterization of the risk locus reveals that it encompasses a gene, TRIB1 associated locus (TRIBAL) comprised of a well conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and re-sequencing identified a single nucleotide polymorphism (SNP), rs2001844, within the promoter region that associates with increased plasma triglycerides, reduced HDL-C and CAD risk. Furthermore, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs (lncRNA), including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. Conclusions - These studies demonstrate an interplay between a novel locus,TRIBAL, and TRIB1. TRIBAL is located in the GWAS identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression and associates with plasma triglyceride concentrations. HepG2 hepatoma cells were stably infected with TRIBAL1 or no insert carrying lentiviruses
2014-02-14 | E-GEOD-54937 | biostudies-arrayexpress
Project description:Objective - The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease (CAD) in humans. The lipid associated SNPs identified by genome-wide association studies (GWAS) are located ~ 30 kb downstream from TRIB1 suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. Methods & Results - Characterization of the risk locus reveals that it encompasses a gene, TRIB1 associated locus (TRIBAL) comprised of a well conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and re-sequencing identified a single nucleotide polymorphism (SNP), rs2001844, within the promoter region that associates with increased plasma triglycerides, reduced HDL-C and CAD risk. Furthermore, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs (lncRNA), including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. Conclusions - These studies demonstrate an interplay between a novel locus,TRIBAL, and TRIB1. TRIBAL is located in the GWAS identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression and associates with plasma triglyceride concentrations. Transcriptome changes to TRIBAL downregulation (48 h) Huh7 were exposed to non-target or TRIBAL-specific antisense oligonucleotides for 48 h in normal (low glucose DMEM, 10% serum, Pen-Strep)
2014-02-14 | E-GEOD-54956 | biostudies-arrayexpress
Project description:Objective - The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease (CAD) in humans. The lipid associated SNPs identified by genome-wide association studies (GWAS) are located ~ 30 kb downstream from TRIB1 suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. Methods & Results - Characterization of the risk locus reveals that it encompasses a gene, TRIB1 associated locus (TRIBAL) comprised of a well conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and re-sequencing identified a single nucleotide polymorphism (SNP), rs2001844, within the promoter region that associates with increased plasma triglycerides, reduced HDL-C and CAD risk. Furthermore, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs (lncRNA), including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. Conclusions - These studies demonstrate an interplay between a novel locus,TRIBAL, and TRIB1. TRIBAL is located in the GWAS identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression and associates with plasma triglyceride concentrations.
2014-02-14 | GSE54956 | GEO
Project description:Objective - The TRIB1 locus has been linked to hepatic triglyceride metabolism in mice and to plasma triglycerides and coronary artery disease (CAD) in humans. The lipid associated SNPs identified by genome-wide association studies (GWAS) are located ~ 30 kb downstream from TRIB1 suggesting complex regulatory effects on genes or pathways relevant to hepatic triglyceride metabolism. The goal of this study was to investigate the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits. Methods & Results - Characterization of the risk locus reveals that it encompasses a gene, TRIB1 associated locus (TRIBAL) comprised of a well conserved promoter region and an alternatively spliced transcript. Bioinformatic analysis and re-sequencing identified a single nucleotide polymorphism (SNP), rs2001844, within the promoter region that associates with increased plasma triglycerides, reduced HDL-C and CAD risk. Furthermore, we show that rs2001844 is an expression trait locus (eQTL) for TRIB1 expression in blood and alters TRIBAL promoter activity in a reporter assay model. The TRIBAL transcript has features typical of long noncoding RNAs (lncRNA), including poor sequence conservation. Modulation of TRIBAL expression had limited impact on either TRIB1 or lipid regulatory genes mRNA levels in human hepatocyte models. In contrast, TRIB1 knockdown markedly increased TRIBAL expression in HepG2 cells and primary human hepatocytes. Conclusions - These studies demonstrate an interplay between a novel locus,TRIBAL, and TRIB1. TRIBAL is located in the GWAS identified risk locus, responds to altered expression of TRIB1, harbors a risk SNP that is an eQTL for TRIB1 expression and associates with plasma triglyceride concentrations.
2014-02-14 | GSE54937 | GEO
Project description:The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR–IDOL axis are both tissue- and species-specific. In mice, LXR agonist induces Idol expression in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues but not in the liver and have minimal change in plasma LDL levels. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a strategy for LDL lowering in humans.
2014-12-31 | GSE61381 | 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
Project description:Electronegative LDL (LDL(-)) is a minor modified fraction of human plasma LDL with several atherogenic properties. Among them, LDL(-) has increased content of bioactive lipid mediators, such as lysophosphatidylcholine (LPC), non-esterified fatty acids (NEFA), ceramide (Cer), and sphingosine (Sph), which are related to the presence in LDL(-) of some phospholipolytic activities, including platelet-activating factor acetylhydrolase (PAF-AH), phospholipase C (PLC) and sphingomyelinase (SMase). However, the activity of these enzymes does not explain the increased content of Sph, which should derive from Cer degradation. In the present study we analyzed the putative presence of a ceramidase (CDase) activity that could explain the increased content of Sph. Thin layer chromatography (TLC) and lipidomic analysis showed that Cer, Sph and NEFA spon-taneously increased in LDL(-) incubated alone at 37ºC, in contrast with native LDL(+). An inhibitor of neutral CDase prevented the formation of Sph and, in contrast, increased the content of Cer in LDL(-). In addition, a fluorescently-labelled Cer (NBD-Cer) was efficiently degraded by LDL(-) to form Sph and NEFA. These observations point to the existence of a CDase activity associated to LDL(-). However, neither proteomic analysis nor western blot detected the presence of a known CDase enzyme. Further studies are warranted to define the origin of the CDase activity detected in LDL(-).
2023-01-09 | PXD036168 | Pride