Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA126105 | ENA |
REPOSITORIES: ENA
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Project description:Studies in vitro and in mice indicate a role for Coenzyme Q10 (CoQ10) in gene expression. To determine this function in relationship to physiological readouts, a 2-week supplementation study with the reduced form of CoQ10 (ubiquinol, Q10H2, 150 mg/d) was performed in 53 healthy males. Mean CoQ10 plasma levels increased 4.8-fold after supplementation. Transcriptomic and bioinformatic approaches identified a gene-gene interaction network in CD14-positive monocytes, which functions in inflammation, cell differentiation and PPAR-signaling. These Q10H2-induced gene expression signatures were also described previously in liver tissues of SAMP1 mice. Biochemical as well as NMR-based analyses showed a reduction of LDL cholesterol plasma levels after Q10H2 supplementation. This effect was especially pronounced in atherogenic small dense LDL particles (19-21 nm, 1.045 g/l). In agreement with gene expression signatures, Q10H2 reduces the number of erythrocytes but increases the concentration of reticulocytes. In conclusion, Q10H2 induces characteristic gene expression patterns, which are translated into reduced LDL cholesterol levels and erythropoiesis in humans. Whole genome expression profiles were analyzed in isolated monocytes of 3 Q10H2 supplemented subjects at the indicated time points (before (T0) and after (T14) Q10H2 supplementation. This results in a total of 6 microarrays.
2013-04-08 | E-GEOD-21351 | biostudies-arrayexpress
Project description:Studies in vitro and in mice indicate a role for Coenzyme Q10 (CoQ10) in gene expression. To determine this function in relationship to physiological readouts, a 2-week supplementation study with the reduced form of CoQ10 (ubiquinol, Q10H2, 150 mg/d) was performed in 53 healthy males. Mean CoQ10 plasma levels increased 4.8-fold after supplementation. Transcriptomic and bioinformatic approaches identified a gene-gene interaction network in CD14-positive monocytes, which functions in inflammation, cell differentiation and PPAR-signaling. These Q10H2-induced gene expression signatures were also described previously in liver tissues of SAMP1 mice. Biochemical as well as NMR-based analyses showed a reduction of LDL cholesterol plasma levels after Q10H2 supplementation. This effect was especially pronounced in atherogenic small dense LDL particles (19-21 nm, 1.045 g/l). In agreement with gene expression signatures, Q10H2 reduces the number of erythrocytes but increases the concentration of reticulocytes. In conclusion, Q10H2 induces characteristic gene expression patterns, which are translated into reduced LDL cholesterol levels and erythropoiesis in humans.
2013-04-08 | GSE21351 | GEO
Project description:The impact of a dual TLR7 and TLR9 antagonist on hypercholesteremia and atherosclerosis was evaluated in hyperlipidemic mice. Treatment with antagonist induced a dose dependent reduction of total cholesterol (TC) and LDL-cholesterol. Changes in Adiponectin, Leptin and free fatty acids levels were observed. Plaque formation was inhibited in ApoE-/- and LDL-R-/- mice fed high fat diet and treated with the antagonist. Hepatic and renal steatosis was reduced by the treatment. Induction of IL-10 expression was inversely correlated with TC levels. The antagonist induced decrease in hepatic IKKα protein level and enhancement of Akt and Gsk3β phosphorylation. Treatment of C57BL/6 mice caused increase in hepatic LXR, PPARγ and ABCG1 expression and in stool content of TC. Antagonist treatment resulted in altered expression of several genes and pathways related to immune system, cholesterol, fatty acid and glucose metabolism. Data obtained suggest involvement of TLR7 and TLR9 in diet induced hyperlipidemia and atherosclerosis and demonstrate therapeutic potential of TLR7/9 antagonist.
2021-11-01 | GSE28125 | GEO
Project description:Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect of finasteride on cardiovascular disease remains elusive. We evaluated the role of finasteride on atherosclerosis using low-density lipoprotein (LDL) receptor-deficient (Ldlr-/-) mice. Next, we examined the relevance to humans by analysing the data deposited between 2009 and 2016 in the National Health and Nutrition Examination Survey (NHANES). We show that finasteride reduces total plasma cholesterol and delays the development of atherosclerosis in Ldlr-/- mice. Finasteride reduced monocytosis, monocyte recruitment to the lesion, macrophage lesion content, and necrotic core area, the latter of which is an indicator of plaque vulnerability in humans. RNA sequencing analysis revealed a downregulation of inflammatory pathways and an upregulation of bile acid metabolism, oxidative phosphorylation, and cholesterol pathways in the liver of mice taking finasteride. Men reporting the use of finasteride showed lower plasma levels of cholesterol and LDL-cholesterol than those not taking the drug. Our data unveil finasteride as a potential treatment to delay cardiovascular disease in people by improving the plasma lipid profile.
2024-03-06 | GSE255708 | GEO
Project description:We found that global heterozygous midnolin knockout attenuated the severity of nonalnonalcoholic fatty liver disease (NAFLD) in mice fed a Western-style diet, high in fat, cholesterol, and fructose. This attenuation in disease was associated with significantly reduced levels of large lipid droplets, hepatic free cholesterol, and serum LDL, with significantly differential gene expression involved in cholesterol/lipid metabolism.
2023-05-03 | GSE226810 | GEO
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: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 | GSE136797 | GEO
Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked with altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity, hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
2021-09-10 | GSE183790 | GEO
Project description:Intricate regulatory networks govern the net balance of cholesterol biosynthesis, uptake and efflux; however, the mechanisms surrounding cholesterol homeostasis remain incompletely understood. Here, we develop an integrative genomic strategy to detect regulators of LDLR activity and identify 250 genes whose knockdown affects LDL-cholesterol uptake and whose expression is modulated by intracellular cholesterol levels in human hepatic cells. From these hits, we focus on MMAB, an enzyme which catalyzes the conversion of vitamin B12 to adenosylcobalamin, and whose expression has previously been linked to altered levels of circulating cholesterol in humans. We demonstrate that hepatic levels of MMAB are modulated by dietary and cellular cholesterol levels through SREBP2, the master transcriptional regulator of cholesterol homeostasis. Knockdown of MMAB decreases intracellular cholesterol levels and augments SREBP2-mediated gene expression and LDL-cholesterol uptake in human and mouse hepatic cell lines. Reductions in total sterol content were attributed to increased intracellular levels of propionic and methylmalonic acid and subsequent inhibition of HMGCR activity and cholesterol biosynthesis. Moreover, mice treated with antisense inhibitors of MMAB display a significant reduction in hepatic HMGCR activity and hepatic sterol content and increased expression of SREBP2-mediated genes. Collectively, these findings reveal an unexpected role for the adenosylcobalamin pathway in regulating LDLR expression and identify MMAB as an additional control point by which cholesterol biosynthesis is regulated by its end product.
2021-06-01 | GSE169712 | GEO
Project description:LRP1 and, in particular the region that spans the C-terminal half of domain CR9 (from Gly1127 to Cys1140), named LP3, is essential for aggregated LDL internalization and human coronary vascular smooth muscle cells (hcVSMC)-cholesterol loading. Here, we investigated whether LP3 and its retro-enantio version (DP3) are protective against sphingomyelinase (SMase) and phospholipase 2 (PLA2)-induced LDL aggregation, the structural basis underlying this protection and the impact that LRP1-derived peptides might have on hcVSMC-cholesterol loading and cholesterol-modulated signaling pathways. For this purpose, biochemical, biophysical, molecular, proteomic, and cellular experiments were performed. Turbidimetry measurements show that LP3 and DP3 inhibit LDL aggregation induced by SMase and PLA2 in a dose-dependent manner, although the efficacy of DP3 is higher. Gel filtration chromatography (GFC) and transmission electron microscopy (TEM) show that LP3, and more efficiently DP3, almost completely counteract the increased percentage of aggregated LDL induced by both SMase and PLA2, respectively. Native polyacrilamide gradient gel electrophoresis (GGE), agarose gel electrophoresis (AGE) and high-performance thin layer chromatography (HPTLC) partitioning of LDL phospholipids indicated that LP3 and DP3 prevent SMase-induced alterations in LDL size, electric charge and phospholipid content but not those induced by PLA2. In contrast, LP3 and DP3 show high efficacy to counteract changes in ApoB-100 conformation induced by both SMase and PLA2. Together, these results indicate that LRP1-derived peptides protect LDL against aggregation induced by SMase and PLA2 through a common mechanism based on their capacity to prevent ApoB-100 conformational changes. Proteomics and computational modeling methods suggest that LRP1 derived peptides are able to establish strong electrostatic interactions with a specific ApoB-100 basic region. TLC and confocal microscopy show that DP3 with higher efficacy than LP3 significantly reduce intracellular cholesteryl ester accumulation induced by SMase-LDL in hcVSMC. Moreover, proteomics studies evidence several signaling pathways modulated by SMase-LDL that are counteracted specifically by DP3. These findings demonstrate that LRP1 derivative peptides protect against LDL aggregation and preserve vascular cells against cholesterol loading and associated alterations in critical signal pathways
2019-06-26 | PXD011246 | Pride