Impact of liver-specific deletion of Dhcr24 gene on tissue gene expression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE146524 | GEO | 2020/09/04
REPOSITORIES: GEO
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Project description:Cholesterol biosynthetic intermediates such as lanosterol and desmosterol are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon (IFN) responses and attenuates the expression of anti-inflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/RXR activation and thus, macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mito-ROS production and NLRP3-dependent inflammasome activation. Deficiency of NLRP3 or ASC rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation, by integrating with macrophage cholesterol metabolism and inflammatory activation, and protecting from disease progression.
2021-12-31 | GSE172374 | GEO
Project description:Cholesterol biosynthetic intermediates such as lanosterol and desmosterol are emergent immune regulators of macrophages in response to inflammatory stimuli or lipid overloading, respectively. However, the participation of these sterols in regulating macrophage functions in the physiological context of atherosclerosis, an inflammatory disease driven by the accumulation of cholesterol-laden macrophages in the artery wall, has remained elusive. Here we report that desmosterol, the most abundant cholesterol biosynthetic intermediate in human coronary artery lesions, plays an essential role during atherogenesis, serving as a key molecule integrating cholesterol homeostasis and immune responses in macrophages. Depletion of desmosterol in myeloid cells by overexpression of 3β-hydroxysterol Δ24-reductase (DHCR24), the enzyme that catalyzes conversion of desmosterol to cholesterol, promotes the progression of atherosclerosis. Single cell transcriptomics in isolated CD45+CD11b+ cells from atherosclerotic plaques demonstrate that depletion of desmosterol increases interferon (IFN) responses and attenuates the expression of anti-inflammatory macrophage markers. Lipidomic and transcriptomic analysis of in vivo macrophage foam cells demonstrate that desmosterol is a major endogenous liver X receptor (LXR) ligand involved in LXR/RXR activation and thus, macrophage foam cell formation. Decreased desmosterol accumulation in mitochondria promotes macrophage mito-ROS production and NLRP3-dependent inflammasome activation. Deficiency of NLRP3 or ASC rescues the increased inflammasome activity and atherogenesis observed in desmosterol-depleted macrophages. Altogether, these findings underscore the critical function of desmosterol in the atherosclerotic plaque to dampen inflammation, by integrating with macrophage cholesterol metabolism and inflammatory activation, and protecting from disease progression.
2021-12-01 | GSE175312 | GEO
Project description:Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of SREBP1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the dominant LXR ligand in macrophage foam cells. Here, we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in liver that lead to hypertriglyceridemia.
2018-02-12 | GSE90815 | GEO
Project description:Here, we investigated changes of the VSMC transcriptome by utilizing 3D human vascular organoids organized as a core of VSMCs enclosed by a monolayer of ECs. Unbiased microarray-based analyses indicated that interaction with ECs for 48 hours down-regulates the VSMC expression of genes controlling rate-limiting steps of the cholesterol biosynthesis such as HMGCR, HMGCS1, DHCR24 and DHCR7. Protein analyses revealed a decrease in the abundance of 24-dehydrocholesterol reductase and lower cholesterol levels in VSMCs co-cultured with ECs. On the functional level, the blockade of the DHCR24 activity impaired spreading, migration and proliferation of VSMCs. Collectively, these findings indicate that ECs have the capacity to instruct VSMCs to shut down the expression of DHCR24 thereby limiting their capacity for cholesterol biosynthesis which may support their functional steady state.
2020-12-17 | GSE156274 | GEO
Project description:We studied how loss of the desmosome associated protein, desmoglein-2 (Dsg2), in the heart leads to Arrhythmogenic Cardiomyopathy with particular interest in the early stages of disease progression. Mice expressing the cardiac αMHC-Cre promoter were crossed with Dsg2 floxed mice in which exon 4-5 of the Dsg2 gene was flanked by loxP sites, resulting in Cre-mediated excision of Dsg2 in cardiac myocytes. Wild type Dsg2+/+ (Cre-, Dsg2flx/flx) and knockout Dsg2-/- (Cre+, Dsg2flx/flx) mice were generated. RNA-seq was performed on heart tissue obtained from wild-type and Dsg2-/- mice at 2-weeks and 10-weeks of age.
2021-07-22 | GSE153124 | GEO
Project description:Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, we showed that SOX9 is overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCL) harboring IGH-BCL2 translocations. SOX9 positivity in DLBCL correlates with advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole transcriptome analysis and CHIP-seq assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In DLBCL cell line xenograft models, SOX9 knockdown resulted in lower DHCR24 level, reduced cholesterol content and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell line with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrates that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol 3 biosynthesis axis may serve as a novel treatment target for DLBCL.
2022-01-12 | GSE179960 | GEO
Project description:Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, we showed that SOX9 is overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCL) harboring IGH-BCL2 translocations. SOX9 positivity in DLBCL correlates with advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole transcriptome analysis and CHIP-seq assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In DLBCL cell line xenograft models, SOX9 knockdown resulted in lower DHCR24 level, reduced cholesterol content and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell line with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrates that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol 3 biosynthesis axis may serve as a novel treatment target for DLBCL.
2022-01-12 | GSE180051 | GEO
Project description:To explore how Mier1 affects liver regeneration, we specifically knocked out Mier1 in mouse liver through adeno-associated virus (AAV). The mice we used were knocked in a Cre-induced Cas9 expression cassette. Through tail vein injection, we delivered the AAV expressing Cre-recombinase under TBG promoter, and sgRNA targeting Mier1 (AAV-Mier1 sgRNA), into the adult Cas9 knockin mice to knock out the Mier1 gene in liver. AAV vectors with no sgRNA inserted (AAV-Cre) were used in control animals. To assess the role of MIER1 in liver regeneration, we performed 70% partial hepatectomy, 3 weeks after AAV injection. We then performed ATAC-seq in Control and Mier1 liver-sepcific knockout mice liver tissues at 0 h and 24 h after PHx to explore the influence of Mier1 on the chromation opening during liver regeneration.
2022-12-31 | GSE212626 | GEO
Project description:Feeding animals with either concentrates or alfalfa grazing has been proven to reduce the oxidative process that occurs in meat products. Indoor-kept lambs were fed a standard concentrate (n=7, C) before slaughtering all animals at 22–24 kg of live weight. Simultaneously, 7 unweaned lambs grazed in alfalfa paddocks (ALF) with their dams. Global transcriptomic data of liver with the Affymetrix® Ovine Gene 1.1 microarray was used. When ALF group was compared with C group, were identified 96 genes differentially expressed. Among these genes 92 were down- regulated and 4 were up- regulated. The clusters corresponding to gene expression profiles from treatments were clearly separated from each other. These differentially expressed genes were selected for a functional analysis by using DAVID. Three major gene clusters associated with “sterol biosynthesis (EBP, MVD, HMGCR, CYP51A1, HMGCS1, NR0B2, C14ORF1, FDFT1, SQLE, DHCR7, SC5DL, DHCR24, NSDHL) , “lipid biosynthetic process (ACACA, CYP51A1, FADS1, FADS2, SCD y SC5DL)”, “cholesterol metabolic process (EBP, MVD, HMGCR, CYP51A1, SQLE, DHCR7, HMGCS1, NR0B2, DHCR24, FDFT1, NSDHL)” were found.
2019-02-05 | GSE125661 | GEO
Project description:Breakdown products of some glucosinolates M-bM-^@M-^S defense chemicals of Brassicales M-bM-^@M-^S induce detoxifying enzymes and demonstrate preventive activities against chemically induced tumorigenesis in animal models. However, other breakdown products are genotoxic. 1-Methoxy-3-indolylmethyl alcohol (1-MIM-OH) is mutagenic in bacterial and mammalian cells upon activation by sulphotransferases and forms DNA adducts in mouse tissues. This effect was enhanced in mice transgenic for human sulphotransferases 1A1/2 (FVB/N-hSULT1A1/2). In this study we explored gene expression changes induced by 1-MIM-OH in mouse liver. FVB/N-hSULT1A1/2 mice were orally treated with 1-MIM-OH for 21 or 90 days, leading to high levels of hepatic 1-MIM-DNA adducts. Genome-wide expression analyzes in this tissue demonstrated no influence on detoxifying enzymes, but up-regulation of many mediators of the tumour suppressor p53 and down-regulation of Fhit and other long genes. In conclusion, 1-MIM-OH did not induce protective enzymes, but formed high levels of DNA adducts, which were recognized by affected cells as reflected by p53 activation. While this p53 response might aim to protection, it was unable to prevent the accumulation of DNA adducts. However, various epdemiological studies reported inverse associations between the intake of cruciferous vegetables and cancer. This association might be due to the presence of other glucosinolates with tumour-preventing influences possibly outweighing adverse effects of some metabolites. Nevertheless, 1-MIM-OH is a genotoxic substance inducing a gene expression profile similar to the expression signature caused by known genotoxic hepatocarcinogens. Male FVB/N-SULT1A1/2 mice were orally treated with 1-MIM-OH, trice per week, 26 mg/kg body mass per treatment. Control animals only received the vehicle (glyceryl trioctanoate) over the same period. Animals were killed after 10 and 40 treatments (over a period of 21 and 90 d, respectively), always 24 h after the last treatment (6 treated and 6 control mice, respectively). Organs were weighed, shock-frozen in liquid nitrogen and stored for a few days at -80M-BM-0C until further processing. Liver organs were ground in a Tissuelyser ball mill (Qiagen, Hilden, Germany) under cooling with liquid nitrogen. The frozen liver tissue was crushed and total RNA was isolated using the RNeasy Mini Kit (Qiagen, Hilden, Germany) according to the manufacturerM-bM-^@M-^Ys instructions. For genome-wide microarray analysis quality of RNA was controlled using the BioAnalyzer (Agilent, Santa Clara, CA, USA). Affymetrix GeneChip hybridization (GeneChip MouseGenome 430 2.0) was performed with 1 M-BM-5g total RNA according to the manufacturerM-bM-^@M-^Ys recommendations. RNA from six individual animals per group (21-day and 90-day treatments with 1-MIM-OH or the vehicle only) was analyzed. For the analysis one hybridized GeneChip (mouse 6 [treated for 21 days with 1-MIM-OH]) was excluded due to hybridization artefacts.
2015-02-18 | E-GEOD-61494 | biostudies-arrayexpress