A dominant negative form of cJun affects genes that have opposing effects on lipid homeostasis in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE6850 | GEO | 2007/06/15
SECONDARY ACCESSION(S): PRJNA99091
REPOSITORIES: GEO
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Project description:The PPAR? activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. After 4 hours fasting, livers were isolated and individual gene arrays were performed.
2010-05-27 | E-GEOD-21211 | biostudies-arrayexpress
Project description:The PPARα activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced VLDL-TG clearance and decreased VLDL-TG production. However, since data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (-38%; P<0.001) and TG (-60%; P<0.001) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma half-life of intravenously injected glycerol tri[3H]oleate-labeled VLDL-like emulsion particles (-68%; P<0.01). This was associated with an increased post-heparin LPL activity (+110%; P<0.0001) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (+73%; P<0.0001) but not the VLDL-apoB production rate. Kinetic studies using [3H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma FA and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver.
2010-05-27 | GSE21211 | GEO
Project description:Apolipoprotein E-knock out (apoE-KO) mouse is known as a model animal for atherosclerosis accompanied by spontaneous hypercholesterolemia. When apoE-KO mice were fed a chow supplemented with 1.25% cholesterol (high-Chol diet), cholesterol and bile acids were highly increased in the liver within a week. However, the amount of triacylglycerol (TG) in very low-density lipoprotein (VLDL), but not in the liver, was reduced by 78%. The epididymal adipose tissue was almost diminished in the long term. Cholesterol metabolism is tightly regulated by both cholesterol and its metabolites in the mammalian liver, but the regulatory mechanism of TG synthesis remains to be elucidated. To evaluate the impact of high-Chol diet for 1 week on gene expression in the liver of apoE-KO mice, DNA microarray analysis was performed with comparison to apoE-KO mice fed a normal chow. We found that mRNA expression related to lipid metabolism was suppressed by the high-Chol diet in the liver of apoE-KO mice, which includes beta-oxidation and glycerol-3-phosphate (G3P) pathway for TG synthesis. In particular, the mRNA and protein expression of lipin-1 and lipin-2 was markedly decreased. PGC-1?, which up-regulates the transcription of lipin-1, was also suppressed. Lipin is reported to function as a coactivator of PGC-1? and is an inducible amplifier of PPAR?, indicating that the suppression of genes involved in beta-oxidation could be induced by suppression of the lipins. These data using apoE-KO mice indicate that cholesterol and its metabolites are involved in regulating TG metabolism through a suppression of lipin-1 and lipin-2 in the liver. This research provides evidence for the mechanism of lipin expression in the liver. Apo E-KO mice at 10 weeks of age were fed normal chow (control) or high-Chol diet containing 1.25% cholesterol for 1 week. Three independent experiments were performed at each diet.
2011-08-07 | E-GEOD-27457 | biostudies-arrayexpress
Project description:The goal of this study is to determine whether A1 adenosine receptor (ADORA1) plays a role in atherosclerosis development and its possible mechanisms. This dataset compares gene expression (aortas) of ADORA1 knockout mice to ADORA1+APOE double-knockout mice. Mice deficient in both ADORA1 and APOE (DKO) demonstrated reduced atherosclerotic lesions in aortic arch (en face), aortic root, and innominate arteries when compared to (APOE-KO) of the same age. Treating APOE-KO with the ADORA1 antagonist DPCPX also achieved concentration-dependent reduction in lesions. The total plasma cholesterol and triglyceride levels were not different between DKO and APOE-KO, however, higher triglyceride was observed in DKO fed a high-fat diet. DKO also were heavier than APOE-KO. Plasma cytokine levels (IL-5, IL-6, and IL-13) were significantly lower in DKO. Proliferating cell nuclear antigen (PCNA) expression was also significantly reduced in the aorta from DKO. Despite smaller lesions in DKO, the composition of the innominate artery lesions and cholesterol loading and effusion [export] from bone-marrow-derived macrophages from DKO were not different from APOE-KO.
2015-06-02 | GSE39888 | GEO
Project description:Apolipoprotein E-knock out (apoE-KO) mouse is known as a model animal for atherosclerosis accompanied by spontaneous hypercholesterolemia. When apoE-KO mice were fed a chow supplemented with 1.25% cholesterol (high-Chol diet), cholesterol and bile acids were highly increased in the liver within a week. However, the amount of triacylglycerol (TG) in very low-density lipoprotein (VLDL), but not in the liver, was reduced by 78%. The epididymal adipose tissue was almost diminished in the long term. Cholesterol metabolism is tightly regulated by both cholesterol and its metabolites in the mammalian liver, but the regulatory mechanism of TG synthesis remains to be elucidated. To evaluate the impact of high-Chol diet for 1 week on gene expression in the liver of apoE-KO mice, DNA microarray analysis was performed with comparison to apoE-KO mice fed a normal chow. We found that mRNA expression related to lipid metabolism was suppressed by the high-Chol diet in the liver of apoE-KO mice, which includes beta-oxidation and glycerol-3-phosphate (G3P) pathway for TG synthesis. In particular, the mRNA and protein expression of lipin-1 and lipin-2 was markedly decreased. PGC-1α, which up-regulates the transcription of lipin-1, was also suppressed. Lipin is reported to function as a coactivator of PGC-1α and is an inducible amplifier of PPARα, indicating that the suppression of genes involved in beta-oxidation could be induced by suppression of the lipins. These data using apoE-KO mice indicate that cholesterol and its metabolites are involved in regulating TG metabolism through a suppression of lipin-1 and lipin-2 in the liver. This research provides evidence for the mechanism of lipin expression in the liver.
2011-08-08 | GSE27457 | GEO
Project description:Hypertriglyceridemia results from accumulation of triglyceride (TG)-rich lipoproteins (TRLs) in the circulation and is associated with increased cardiovascular disease risk. ApoC-III is an apolipoprotein on TRLs and a prominent negative regulator of TG catabolism. We recently established that in vivo apoC-III predominantly inhibits LDLR and LRP1 mediated hepatic TRL clearance and that apoC-III enriched TRLs are preferentially cleared by syndecan-1 (SDC1). In this study, we determined the impact of apoE, a common ligand for all three receptors, on apoC-III metabolism using apoC-III antisense oligonucleotide (ASO) treatment in mice lacking apoE and functional SDC1 (Apoe(-/-) Ndst1(f/f) Alb-Cre+). ApoC-III ASO treatment significantly reduced plasma TG levels in Apoe(-/-) Ndst1(f/f) Alb-Cre+ mice without reducing hepatic VLDL production or improving hepatic TRL clearance. Further analysis revealed that apoC-III ASO treatment lowered plasma TGs in Apoe(-/-) Ndst1(f/f) Alb-Cre+ mice, which was associated with increased LPL activity in white adipose tissue (WAT) in the fed state. Finally, clinical data confirm that ASO-mediated lowering of apoC-III via volanesorsen can reduce plasma TG levels independent of the apoE isoform genotype. Our data indicate that apoE determines the metabolic impact of apoC-III as we establish that apoE is essential to mediate inhibition of TRL clearance by apoC-III and that in the absence of functional apoE apoC-III inhibits tissue LPL activity.
2019-05-24 | GSE131284 | GEO
Project description:Kyrtsos2011 - A systems biology model for
Alzheimer's disease (Cholesterol in AD)
Encoded non-curated model. Issues:
- Confusing HmgCoA differential equation
- Confusing d2 and t1 parameters
- Lack of initial values for several key species
This model is described in the article:
Of Mice and Math: A Systems
Biology Model for Alzheimer's disease
Kyrtsos, Christina Rose
UMD Theses and Dissertations
Abstract:
Alzheimer's disease (AD) is the most prevalent
neurodegenerative disorder in the US, affecting over 1 in 8
people over the age of 65. There are several well-known
pathological changes in the brains of AD patients, namely: the
presence of diffuse beta amyloid plaques derived from the
amyloid precursor protein (APP), hyper-phosphorylated tau
protein, neuroinflammation and mitochondrial dysfunction.
Recent studies have shown that cholesterol levels in both the
plasma and the brain may play a role in disease pathogenesis,
however, this exact role is not well understood. Additional
proteins of interest have also been identified (ApoE, LRP-1,
IL-1) as possible contributors to AD pathogenesis. To help
understand these roles better, a systems biology mathematical
model was developed. Basic principles from graph theory and
control analysis were used to study the effect of altered
cholesterol, ApoE, LRP and APP on the system as a whole.
Negative feedback regulation and the rate of cholesterol
transfer between astrocytes and neurons were identified as key
modulators in the level of beta amyloid. Experiments were run
concurrently to test whether decreasing plasma and brain
cholesterol levels with simvastatin altered the expression
levels of beta amyloid, ApoE, and LRP-1, to ascertain the edge
directions in the network model and to better understand
whether statin treatment served as a viable treatment option
for AD patients. The work completed herein represents the first
attempt to create a systems-level mathematical model to study
AD that looks at intercellular interactions, as well as
interactions between metabolic and inflammatory pathways.
This model is hosted on
BioModels Database
and identified by:
MODEL1504240000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2016-05-09 | MODEL1504240000 | BioModels
Project description:Objective: Although relationships between smoking and cardiovascular diseases (CVD), and CVD and lipids are established, direct impact of cigarette smoke (CS) on lipidomes remains elusive. We investigated the effect of 6 month smoke exposure on a well-established mouse model for human atherogenesis, Apoe mouse plasma, liver, and aorta molecular lipid profiles and liver transcriptome. // Methods: Plasma, liver, and aorta samples from Apoe mice exposed to CS or fresh air for 6 months were extracted for lipids using robotic-assisted method and analyzed by mass spectrometry. Gene expression of samples from the same livers was obtained on microarrays. Development of atherosclerosis in aorta was further assessed by plaque size measurement in the aortic arch and lipoprotein measurements in plasma and in the plaque. // Results: CS increased most lipid classes and molecular lipid species in tissues evaluated. In plasma, free cholesterol, ceramides, cerebrosides, and majority of phospholipids were increased in CS-exposed mice. In liver, CS elevated several lipid species including free and esterified cholesterol, triacylglycerols, phospholipids, sphingomyelins, and ceramides. In aorta, more than 2-fold higher cholesteryl ester (CE), lysophosphatidylcholine, and glucosyl/galactosylceramide levels were recorded in mice exposed to CS compared to mice exposed to fresh air. Moreover, CS exposure induced a significant decrease in several plasma CE and phosphatidylcholine species that contained polyunsaturated fatty acids. Genes involved in amino acid and lipid metabolism showed perturbed transcription profiles in liver. // Conclusion: These data reveal molecular details accompanying the increase in plaque size, sign of atherogenesis in Apoe mice, which is accelerated by CS exposure.
2013-10-03 | E-MTAB-1195 | biostudies-arrayexpress
Project description:Hyperlipidemia is a well-established risk factor for cardiovascular diseases. Trillions of people worldwide display mildly elevated levels of plasma lipids and cholesterol due to diet and life-style. The relationship between severe hyperlipidemia and thrombosis has been extensively investigated, but the effects of the preliminary stages of hyperlipidemia on platelet function are unclear. Therefore, we investigated how moderate elevation of different plasma lipid profiles influence platelet activation and thrombus formation, as compared to higher plasma lipid concentrations. Hyperlipidemic Apoe-/- and Ldlr-/- and wild-type mice were fed a normal chow diet, resulting in mildly increased plasma cholesterol. Blood from both knockout mice was used in comparison to wild-type mice, for multiparameter ex vivo measurements of thrombus formation under flow. Whole blood (fibrin-)thrombus formation on collagen in the absence or presence of coagulation (with(out) tissue factor), indicated enhancement of the thrombotic process in both knockout mice. These effects were not further aggravated in aged mice, as well as in Apoe-/- mice on high fat diet with very high plasma cholesterol levels. Bone marrow chimeras of wild-type or Ldlr-/- platelets into irradiated Ldlr-/- recipient mice showed similar thrombus formation patterns. This suggested that hyperlipidemia itself, not the platelet LDL receptor deficiency is responsible for the altered platelet activation status in Ldlr-/- mice. Exploration of the platelet proteome revealed high similarity between the three genotypes, although some proteins showed significantly changed expression in Apoe-/- mice. Finally, platelet lipidomic analysis showed an increased lipid profile in mildly hyperlipidemic mice, which may further contribute to the observed prothrombotic phenotype
2021-01-08 | PXD020276 | Pride
Project description:Fenofibrate increases VLDL-triglyceride production despite reducing plasma triglyceride levels in APOE*3-Leiden.CETP mice
| PRJNA126303 | ENA