Mus musculus
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ABSTRACT:
PROVIDER: PRJNA126303 | ENA |
REPOSITORIES: ENA
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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:cJun is a transcription factor activated by phosphorylation by SAPK/JNK MAP kinase pathway that has been linked to atherosclerosis. Adenovirus mediated gene transfer of a dominant negative form of cJun in C57BL/6 mice increased greatly the apolipoprotein E (ApoE) mRNA and plasma apoE levels and induced dyslipidmia, characterized by increased plasma cholesterol, triglyceride and VLDL levels and accumulation of discoidal HDL particles. Unexpectedly, infection of ApoE-/- mice with adenovirus expressing dn-cJun reduced by 50% plasma cholesterol, suggesting that the dn-cJun affected other genes that control plamsa cholesterol. To determine the molecular pathways implicated in this process we performed whole genome expression profiling using total RNA from the liver of infected ApoE-/- mice. Keywords: disease
2007-06-15 | GSE6850 | 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:Elevated circulating triglycerides, which are considered a risk factor for cardiovascular disease, can be targeted by treatment with fenofibrate or fish oil. To gain insight into underlying mechanisms, we carried out a comparative transcriptomics and metabolomics analysis of the effect of 2 week treatment withfenofibrate and fish oil in mice. Plasma triglycerides were significantly decreased byfenofibrate (-49.1%) and fish oil (-21.8%), whereas plasma cholesterol was increased by fenofibrate (+29.9%) and decreased by fish oil (-32.8%). Levels of various phospholipid species were specifically decreased by fish oil, while levels of Krebs cycle intermediates were increased specifically by fenofibrate. Plasma levels of many amino acids were altered by fenofibrate and to a lesser extent by fish oil. Both fenofibrate and fish oil upregulated genes involved in fatty acid metabolism, and downregulated genes involved in blood coagulation and fibrinolysis. Significant overlap in gene regulation by fenofibrate and fish oil was observed, reflecting their property as high or low affinity agonist for PPARα, respectively. Fenofibrate specifically downregulated genes involved in complement cascade and inflammatory response. Fish oil specifically downregulated genes involved in cholesterol and fatty acid biosynthesis, and upregulated genes involved in amino acid and arachidonic acid metabolism. Taken together, the data indicate that despite being similarly potent towards modulating plasma free fatty acids, cholesterol and triglyceride levels, fish oil causes modest changes in gene expression likely via activation of multiple mechanistic pathways, whereas fenofibrate causes pronounced gene expression changes via a single pathway, reflecting the key difference between nutritional and pharmacological intervention. Expression profiling of liver from mice fed control diet, fish oil or fenofibrate for 2 weeks.
2011-10-07 | E-GEOD-32706 | biostudies-arrayexpress
Project description:Background: Non-alcoholic fatty liver disease (NAFLD) affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. Approach and results: To identify liver-regulated pathways linking intra-hepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic APOF (encoding apolipoprotein F) expression showed the 4th strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic VLDL-TG secretion and hepatic lipoprotein remnant clearance, associated a ~25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo, and reduced hepatocyte VLDL uptake by ~15% in vitro. Transcriptomic analysis of APOF-overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1, among others. Conclusion: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance.
2022-06-29 | GSE203290 | GEO
Project description:Elevated circulating triglycerides, which are considered a risk factor for cardiovascular disease, can be targeted by treatment with fenofibrate or fish oil. To gain insight into underlying mechanisms, we carried out a comparative transcriptomics and metabolomics analysis of the effect of 2 week treatment withfenofibrate and fish oil in mice. Plasma triglycerides were significantly decreased byfenofibrate (-49.1%) and fish oil (-21.8%), whereas plasma cholesterol was increased by fenofibrate (+29.9%) and decreased by fish oil (-32.8%). Levels of various phospholipid species were specifically decreased by fish oil, while levels of Krebs cycle intermediates were increased specifically by fenofibrate. Plasma levels of many amino acids were altered by fenofibrate and to a lesser extent by fish oil. Both fenofibrate and fish oil upregulated genes involved in fatty acid metabolism, and downregulated genes involved in blood coagulation and fibrinolysis. Significant overlap in gene regulation by fenofibrate and fish oil was observed, reflecting their property as high or low affinity agonist for PPARα, respectively. Fenofibrate specifically downregulated genes involved in complement cascade and inflammatory response. Fish oil specifically downregulated genes involved in cholesterol and fatty acid biosynthesis, and upregulated genes involved in amino acid and arachidonic acid metabolism. Taken together, the data indicate that despite being similarly potent towards modulating plasma free fatty acids, cholesterol and triglyceride levels, fish oil causes modest changes in gene expression likely via activation of multiple mechanistic pathways, whereas fenofibrate causes pronounced gene expression changes via a single pathway, reflecting the key difference between nutritional and pharmacological intervention.
2011-10-08 | GSE32706 | GEO
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:Background and Aims: Inflammasome-mediated caspase-1 activity regulates the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1M-CM-^_ and IL-18. Recently, we showed that caspase-1 deficiency strongly reduces high fat diet-induced adiposity although the mechanism is still unclear. We now aimed to elucidate the mechanism by which caspase-1 deficiency reduces modulates resistance to high fat diet-feeding fat accumulation in adipose tissue by focusing on the role of caspase-1 in the regulation of triglyceride (TG)-rich lipoprotein metabolism. Methods: Caspase-1 deficient and wild-type mice (both C57Bl/6 background) were used to determine postprandial TG kinetics, intestinal TG absorption, VLDL-TG production as well as TG clearance, all of which strongly contribute to the supply of TG for storage in adipose tissue. Micro-array and qPCR analysis were used to unravel intestinal and hepatic metabolic pathways involved. Results: Caspase-1 deficiency reduced the postprandial response to an oral lipid load, while tissue specific clearance of TG-rich lipoproteins was not changed. Indeed, an oral olive oil gavage containing [3H]TG revealed that caspase-1 deficiency significantly decreased intestinal chylomicron-TG production and reduced the uptake of [3H]TG-derived FA by liver, muscle, and adipose tissue. Similarly, caspase-1 deficiency reduced the hepatic VLDL-TG production without reducing VLDL-apoB production, despite an elevated hepatic TG content. Pathway analysis revealed that caspase-1 deficiency reduces intestinal and hepatic expression of genes involved in lipogenesis. Conclusions: Absence of caspase-1 reduces assembly and secretion of TG-rich lipoproteins, thereby reducing the availability of TG-derived FA for uptake by peripheral organs including adipose tissue. We anticipate that caspase-1 represents a novel link between innate immunity and lipid metabolism. Keywords: Expression profiling by array Wild-type (WT) and Casp1-null mice were maintained at lab chow. Animals, aged between 14 and 16 weeks (n=3 per genotype), were killed and liver and intestinal segments were removed. Livers were isolated from mice that were fasted over night, whereas intesines were removed from mice 2 hrs after they received an oral lipid load.Total RNA was isolated and subjected to gene expression profiling.
2013-09-15 | E-GEOD-32515 | biostudies-arrayexpress
Project description:Liver-specific Knockdown of JNK1 Up-regulates Proliferator-activated Receptor Coactivator 1 and Increases Plasma Triglyceride despite Reduced Glucose and Insulin Levels in Diet-induced Obese Mice. The c-Jun N-terminal kinases (JNKs) have been implicated in the development of insulin resistance, diabetes, and obesity. Genetic disruption of JNK1, but not JNK2, improves insulin sensitivity in diet-induced obese (DIO) mice. We applied RNA interference to investigate the specific role of hepatic JNK1 in contributing to insulin resistance in DIO mice. Adenovirus-mediated delivery of JNK1 short-hairpin RNA (Ad-shJNK1) resulted in almost complete knockdown of hepatic JNK1 protein without affecting JNK1 protein in other tissues. Liver-specific knockdown of JNK1 resulted in significant reductions in circulating insulin and glucose levels, by 57 and 16%, respectively. At the molecular level, JNK1 knockdown mice had sustained and significant increase of hepatic Akt phosphorylation. Furthermore, knockdown of JNK1 enhanced insulin signaling in vitro. Unexpectedly, plasma triglyceride levels were robustly elevated upon hepatic JNK1 knockdown. Concomitantly, expression of proliferator-activated receptor coactivator 1, glucokinase, and microsomal triacylglycerol transfer protein was increased. Further gene expression analysis demonstrated that knockdown of JNK1 up-regulates the hepatic expression of clusters of genes in glycolysis and several genes in triglyceride synthesis pathways. Our results demonstrate that liver-specific knockdown of JNK1 lowers circulating glucose and insulin levels but increases triglyceride levels in DIO mice. Experiment Overall Design: Liver sample from vehicle, GFP Adv-shRNA, or Jnk1 Adv-shRNA treated DIO mice with 5, 4, and 5 replicates, respectively
2008-06-15 | E-GEOD-7648 | biostudies-arrayexpress