Impaired skeletal muscle hypertrophy signaling and amino acid deprivation response is seen in Apoe KO mice with an unhealthy lipoprotein distribution
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PROVIDER: PRJEB37530 | ENA |
REPOSITORIES: ENA
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Project description:This study explores if unhealthy lipoprotein distribution (LPD) impairs the anabolic and amino acid sensing responses to whey-protein feeding. Thus, if impairment of such anabolic response to protein consumption is seen by the LPD this may negatively affect the skeletal muscle mass. Muscle protein synthesis (MPS) was measured by puromycin labeling in Apolipoprotein E knockout (Apoe KO), characterized by an unhealthy LPD, and wild type mice post-absorptive at 10 and 20 weeks, and post-prandial after whey-protein feeding at 20 weeks. Hypertrophy signaling and amino acid sensing mechanisms were studied and gut microbiome diversity explored. Surprisingly, whey-protein feeding did not affect MPS. p-mTOR and p-4E-BP1 was increased 2 h after whey-protein feeding in both genotypes, but with general lower levels in Apoe KO compared to wild type. At 20 weeks of age, Apoe KO had a greater mRNA-expression for SNAT2, CD98, ATF4 and GCN2 compared to wild type. These responses were not associated with gut microbiota compositional differences. Regardless of LPD status, MPS was similar in Apoe KO and wild type. Surprisingly, whey-protein did not stimulate MPS. However, Apoe KO had lower levels of hypertrophy signaling, was amino acid deprived, and had impaired amino acid sensing mechanisms.
| S-EPMC8360952 | biostudies-literature
Project description:APOE is the strongest genetic risk factor for late-onset Alzheimer’s disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here we show that overexpressing a low-density lipoprotein receptor (LDLR) transgene in P301S tau transgenic mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. ApoE specifically interacts with a high-molecular-weight tau species, and highly correlates with phospho-tau and insoluble tau levels. Microglial expression of the LDLR transgene reduces intracellular apoE and is associated with less microglial activation. snRNA-seq analysis of apoE-deficient or LDLR-overexpressing brains reveals that apoE deficiency drives microglial catabolism and increases the oligodendrocyte progenitor cell population. LDLR overexpression shares overlapping mechanisms, but uniquely upregulates microglial expression of specific ion channels and neurotransmitter receptors in tauopathy. A subset of disease-associated astrocytes with both neuroprotective and neurotoxic gene signatures is also identified.
2021-02-06 | GSE166261 | GEO
Project description:The effect of perfluoroalkyl sulfonates on lipoprotein metabolism was investigated in APOE*3-Leiden.CETP mice with a humanized lipoprotein profile. Perfluorohexane sulfonate and perfluorooctane sulfonate markedly reduced both plasma TG and TC by decreasing nonHDL-C and HDL-C accompanied by a reduction in apoAI. Mechanistic studies showed that these effects were mainly caused by impaired lipoprotein production.
2011-01-01 | GSE22940 | GEO
Project description:The effect of perfluoroalkyl sulfonates on lipoprotein metabolism was investigated in APOE*3-Leiden.CETP mice with a humanized lipoprotein profile. Perfluorohexane sulfonate and perfluorooctane sulfonate markedly reduced both plasma TG and TC by decreasing nonHDL-C and HDL-C accompanied by a reduction in apoAI. Mechanistic studies showed that these effects were mainly caused by impaired lipoprotein production. Male E3L.CETP mice on a C57Bl/6 background were fed a Western-type diet, containing 0.25% (w/w) cholesterol, 1% (w/w) corn oil and 14% (w/w) bovine fat (Western-type diet) (Hope Farms, Woerden, The Netherlands) for 4 to 6 weeks in three independent experiments. Upon randomization according to total plasma cholesterol (TC) and TG levels, mice received the Western-type diet without or with PFBS (30 mg/kg/day), PFHxS (6 mg/kg/day) or PFOS (3 mg/kg/day) during 4-6 weeks. The effects of these PFAS on plasma lipids and lipoproteins were determined. In addition, PFAS levels were determined in plasma and livers were isolated for hepatic lipid analysis and hepatic gene expression analysis using an Affymetrix technology platform and Affymetrix GeneChip® mouse genome 430 2.0 arrays.
2011-01-01 | E-GEOD-22940 | biostudies-arrayexpress
Project description:Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration via apoE-dependent and independent mechanisms
| PRJNA699869 | ENA
Project description:Some people with obesity are resistant to the adverse metabolic effects of excess adiposity and are considered to have “metabolically healthy obesity” (MHO). However, the mechanisms responsible for MHO are not clear. We performed comprehensive cardiometabolic profiling in 20 adults with MHO (defined by features of normal insulin sensitivity), 20 age-, sex-, and BMI-matched adults with metabolically unhealthy obesity (MUO), and 15 adults who were metabolically healthy and lean (MHL). More than 120 variables were evaluated, including body composition, beta-cell function, 24-hour plasma metabolic profile, rates of de novo lipogenesis and cholesterol synthesis, plasma adipokine concentrations, oxidative stress, plasma lipoprotein profiles, cardiovascular structure/function, skeletal muscle bioactive lipids, and both adipose tissue and skeletal muscle transcriptomics. Using dimensionality reduction approaches, measures of insulinemia and skeletal muscle ceramides were the strongest discriminators of MHO and MUO status. These data clarify the characteristics associated with preserved metabolic health in response to obesity.
2024-03-06 | GSE244120 | GEO
Project description:Some people with obesity are resistant to the adverse metabolic effects of excess adiposity and are considered to have “metabolically healthy obesity” (MHO). However, the mechanisms responsible for MHO are not clear. We performed comprehensive cardiometabolic profiling in 20 adults with MHO (defined by features of normal insulin sensitivity), 20 age-, sex-, and BMI-matched adults with metabolically unhealthy obesity (MUO), and 15 adults who were metabolically healthy and lean (MHL). More than 120 variables were evaluated, including body composition, beta-cell function, 24-hour plasma metabolic profile, rates of de novo lipogenesis and cholesterol synthesis, plasma adipokine concentrations, oxidative stress, plasma lipoprotein profiles, cardiovascular structure/function, skeletal muscle bioactive lipids, and both adipose tissue and skeletal muscle transcriptomics. Using dimensionality reduction approaches, measures of insulinemia and skeletal muscle ceramides were the strongest discriminators of MHO and MUO status. These data clarify the characteristics associated with preserved metabolic health in response to obesity.
2024-03-06 | GSE244118 | GEO
Project description:The role of endothelial miR-92a-3p and miR-489-3p in CKD-associated atherosclerosis was examined by mRNA expression analysis in Apoe-/- mice with 5/6 nephrectomy treated with locked-nucleic acid (LNA) inhibitors complexed with high-density lipoprotein (HDL).
2019-03-01 | GSE120038 | GEO
Project description:Circulating microRNAs (miRNA) are relatively stable in plasma and are a new class of disease biomarkers. Here we present evidence that human high-density lipoprotein (HDL) transports endogenous miRNAs and delivers them to recipient cells with functional targeting capabilities. Highly-purified fractions of human HDL contain small RNAs, and the HDL-miRNA profile from normal subjects is significantly different than familial hypercholesterolemia subjects. miRNAs were demonstrated to associate with both native and reconstituted HDL particles, and reconstituted HDL injected into mice retrieved distinct miRNA profiles from normal and atherogenic models. Cellular export of miRNAs to HDL was demonstrated to be regulated by neutral sphingomyelinase. HDL-mediated delivery of miRNAs to recipient cells was demonstrated to be scavenger receptor BI-dependent. Furthermore, HDL delivery of both exogenous and endogenous miRNAs resulted in the direct targeting of mRNA reporters. Notably, HDL-miRNA from atherosclerotic subjects induced differential gene expression, with significant loss of conserved mRNA targets in cultured hepatocytes. Collectively, these observations suggest that HDL participates in a novel mechanism of intercellular communication involving the transport and delivery of miRNAs. microRNA signatures retrieved from rHDL injected into WT, ApoE-/- chow, ApoE-/-high fat diet Profiled rHDL miRNA signatures from n=3 WT; n=3 ApoE-/- chow, n=4 ApoE-/- high fat mice
2011-03-23 | E-GEOD-25424 | biostudies-arrayexpress
Project description:The multi-ligand Receptor for AGE (RAGE) contributes to atherosclerosis in apolipoprotein (ApoE) null mice in both the non-diabetic and diabetic states. Previous studies using soluble RAGE, the extracellular ligand-binding domain of RAGE, or homozygous RAGE null mice showed that blockade or deletion of RAGE resulted in marked reduction in atherosclerotic lesion area and complexity compared to control animals. In parallel, significant down-regulation of inflammatory mediators and matrix metalloproteinases was evident in ApoE null mice aortas devoid of RAGE compared to those of ApoE null RAGE-expressing mice. Although these findings suggested that RAGE triggered pro-atherogenic mechanisms via regulation of inflammatory gene expression, these studies did not reveal the broader pathways by which RAGE contributed to atherosclerosis in ApoE null mice. Therefore, we performed Affymetrix gene expression arrays on aortas of non-diabetic and diabetic ApoE null mice expressing RAGE or devoid of RAGE at nine weeks of age, as this reflected a time point at which frank atherosclerotic lesions were not yet present, but, that we would be able to identify the genes likely involved in diabetes- and RAGE-dependent atherogenesis. The comparisons were as follows: 1. diabetic ApoE null relative to non-diabetic ApoE null; 2. non-diabetic ApoE null / RAGE null relative to non-diabetic ApoE null; 3. diabetic ApoE null / RAGE null relative to non-diabetic ApoE null / RAGE null; and 4. diabetic ApoE null / RAGE null relative to diabetic ApoE null aorta. Our data reveal that there is very little overlap of the genes which are differentially expressed both in the onset of diabetes in ApoE null mice, and in the effect of RAGE deletion in diabetic ApoE null mice. We next performed a Pathway-Express analysis to determine the pathways that were most associated with the onset of diabetes in ApoE null mice and the effect of RAGE gene deletion in diabetic ApoE null mice. Rigorous statistical analysis was undertaken and revealed that the transforming growth factor-beta pathway (tgf-beta) and focal adhesion pathways might be expected to play a significant role in both the mechanism by which diabetes facilitates the formation of atherosclerotic plaques in ApoE null mice, and the mechanism by which deletion of RAGE ameliorates this effect. We focused on three genes of the tgf-betafamily which were found to be up-regulated in diabetic vs. non-diabetic ApoE null aorta, and which were reduced by deletion of RAGE. These included: thrombospondin1 (Thbs1), transforming growth factor-beta (tgf-beta) and rho-associated kinase (ROCK1). Real-time quantitative polymerase chain reaction and Western blotting experiments were performed, as well as ROCK1 activity assays in mouse aorta, and validated the findings of the Affymetrix gene array. Further, confocal microscopy revealed that a principal cell type in the ApoE null aorta expressing these factors was the vascular smooth muscle cell. Our data suggest the novel finding that the observed reduction of accelerated atherosclerosis in diabetic ApoE null / RAGE null vs. diabetic ApoE null mice occurs, all or in part, through the ROCK1 branch of the TGF-betapathway. We have inferred a detailed mechanism for this process. Taken together, these data suggest that suppression of ROCK1 activity in the atherosclerosis-vulnerable vessel wall, especially in diabetes, but in non-diabetes as well, may underlie the beneficial effects of RAGE antagonism and genetic deletion in murine models. These findings highlight logical and novel targets for therapeutic intervention in cardiovascular disease and diabetes. 1. diabetic ApoE null relative to non-diabetic ApoE null; 2. non-diabetic ApoE null / RAGE null relative to non-diabetic ApoE null; 3. diabetic ApoE null / RAGE null relative to non-diabetic ApoE null / RAGE null; and 4. diabetic ApoE null / RAGE null relative to diabetic ApoE null aorta. There were 4 mice in each group initially. However there are only 3 non-diabetic ApoE null / RAGE null mice in the final experimental sample in group 3 due to a failure to generate cRNA from that sample. All samples were normalized to remove chip-dependent regularities using the RMA method. Chips and controls at each combination of genotype and disease sate were normalized together. The statistical significance of differential expression was calculated using the empirical Bayesian LIMMA (LInear Model for MicroArrays) method A cut-off B>0 was used for the statistical significance of gene expression.
2010-03-07 | E-GEOD-15729 | biostudies-arrayexpress