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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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A systems biology-based approach to deciphering the etiology of steatosis employing patient-derived dermal fibroblasts and iPS cells

ABSTRACT: We demonstrate how a multidisciplinary approach encompassing cellular reprogramming, transcriptomics, proteomics, metabolomics, modeling, network reconstruction and data management can be employed to unveil the mechanisms underlying the progression of steatosis. Proteomics revealed reduced AKT/mTOR signaling in fibroblasts derived from steatosis patients and further establishes that the insulin-resistant phenotype is present not only in insulin-metabolizing central organs, e.g. the liver, but is also manifested in skin fibroblasts. Transcriptome data enabled the generation of a regulatory network based on the transcription factor SREBF1, linked to a metabolic network of glycerolipid and fatty acid biosynthesis including the downstream transcriptional targets of SREBF1 which include LIPIN1 (LPIN) and low density lipoprotein receptor (LDLR). Glutathione metabolism was among the pathways enriched in steatosis patients in comparison to healthy controls. By using a model of the glutathione pathway we predict a significant increase in the flux through glutathione synthesis as both gamma-glutamylcysteine synthetase and glutathione synthetase have an increased flux. The transcriptomes of dermal fibroblasts derived from two patients with steatosis (60 yr, male BMI 45.7 (H0008) and 33 yr, female, BMI 51.3 (H0007)) and control fibroblasts (19 yr, female, BMI 21, (H0002)) were analyzed. Total RNA obtained from dermal fibroblasts derived from two patients with steatosis (60 yr, male BMI 45.7 (H0008) and 33 yr, female, BMI 51.3 (H0007)) and control fibroblasts (19 yr, female, BMI 21, (H0002)).

ORGANISM(S): Homo sapiens

SUBMITTER: Justyna Jozefczuk

PROVIDER: E-GEOD-37689 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A systems biology-based approach to deciphering the etiology of steatosis employing patient-derived dermal fibroblasts and iPS cells

Project description:We demonstrate how a multidisciplinary approach encompassing cellular reprogramming, transcriptomics, proteomics, metabolomics, modeling, network reconstruction and data management can be employed to unveil the mechanisms underlying the progression of steatosis. Proteomics revealed reduced AKT/mTOR signaling in fibroblasts derived from steatosis patients and further establishes that the insulin-resistant phenotype is present not only in insulin-metabolizing central organs, e.g. the liver, but is also manifested in skin fibroblasts. Transcriptome data enabled the generation of a regulatory network based on the transcription factor SREBF1, linked to a metabolic network of glycerolipid and fatty acid biosynthesis including the downstream transcriptional targets of SREBF1 which include LIPIN1 (LPIN) and low density lipoprotein receptor (LDLR). Glutathione metabolism was among the pathways enriched in steatosis patients in comparison to healthy controls. By using a model of the glutathione pathway we predict a significant increase in the flux through glutathione synthesis as both gamma-glutamylcysteine synthetase and glutathione synthetase have an increased flux. The transcriptomes of dermal fibroblasts derived from two patients with steatosis (60 yr, male BMI 45.7 (H0008) and 33 yr, female, BMI 51.3 (H0007)) and control fibroblasts (19 yr, female, BMI 21, (H0002)) were analyzed.

2013-12-31 | GSE37689 | GEO

Transcriptomic analysis of active form of Srebf1-overexpressed fibroblasts in bleomycin-induced lung fibrosis

Project description:Pulmonary fibrosis (PF) is an intractable disorder with a poor prognosis. Although lung fibroblasts play central roles in PF, their key regulatory molecules remain unclear. We performed transcriptome analysis of lung fibroblasts from bleomycin- and silica-treated murine lungs and identified 55 hub transcription factors highly connected to gene modules differentially expressed in PF. To elucidate whether fibroblast-specific intervention against the hub transcription factor Srebf1 modulates pathogenic activation of lung fibroblasts in vivo, we intratracheally-transferred active form of Srebf1-overexpressed fibroblasts into bleomycin-treated lungs and performed global transcriptome analysis.

2019-01-30 | GSE110533 | GEO

CREB regulated transcriptional coactivator 2 proteome landscape is plausibly modulated by SREBF1

Project description:CRTC2 is a critical transcription cofactor that induces the glucose homeostatic genes by activating CREB. However, energy homeostasis is maintained by multiple pathways, therefore, it is possible that CRTC2 may interact with other transcription factors, especially under metabolic stress. Thereby, CRTC2 liver-specific knockout mice were created and the global proteome, phosphoproteome and acetylome from liver tissue under the high fat diet conditions were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis. As expected, differentially expressed proteins (DEPs) are enriched in metabolic pathways that were subsequently corroborated by animal experiments. The consensus DEPs from these datasets were used as seed proteins to generate a protein-protein interaction (PPI) network using STRING and GeneMANIA identified fatty acid synthase (FASN) as the mutually relevant protein. Additional local-PPI (LPPI) analysis of CRTC2 and FASN with DEPs, SREBF1 was found to be a common mediator. CRTC2/CREB and SREBF1 are transcription factors, DNA-binding motif analysis showed multiple CRTC2/CREB regulated genes also possess SREBF1 binding motifs that unveil the possible induction by CRTC2/SREBF1 complex, which is reinforced by structural analysis. Thus, CRTC2/SREBF1 complex plausibly modulate the transcription of multiple proteins that fine-tune the cellular metabolism under metabolic stress.

2023-10-24 | PXD039817 | Pride

Hypoxia-induced cysteine metabolism reprogramming are crucial for the tumorigenesis of colorectal cancer [tissue pair]

Project description:Metabolic reprogramming is a hallmark of human cancer and cancer-specific metabolism provide opportunities for cancer diagnosis, prognosis, and treatment. However, how metabolic pathways affect the initiation and progression of colorectal cancer remain largely unknown. Here, we showed cysteine is highly enriched in colorectal tumors compared with adjacent non-tumor tissues to promote tumorigenesis of CRC. Both cystine and cysteine imports are essential to maintain intracellular cysteine level and promote tumor growth and survival. Transporter genes of cystine and cysteine are all upregulated in colorectal cancer by tumor microenvironment induced ROS through transcription factor ATF4. Glutathione synthetase GSS is upregulated and increases cysteine to reduced glutathione flux to support tumor growth and survival in colorectal cancer. Depletion of cystine and cysteine by a recombinant cyst(e)inase effectively reduced the growth of colorectal tumors. Moreover, scavenging cystine and cysteine induces autophagy of colorectal cancer cells through mTOR-ULK signaling axis. With this study, we demonstrate that cysteine metabolism is a key signature of CRC metabolic reprogramming and targeting cysteine metabolism might be an effective approach to treat colon cancer.

2023-01-21 | GSE223119 | GEO

Hypoxia-induced cysteine metabolism reprogramming are crucial for the tumorigenesis of colorectal cancer [HCT116]

2023-01-21 | GSE223118 | GEO

Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors

Project description:ATF4-dependent differential transcription in response to tRNA synthetase inhibitor treatment in mouse embryonic fibroblasts We performed RNAseq on wild type and ATF4 KO mouse embryonic fibroblasts with and without tRNA synthetase inhibitor as our block design described in JAAA-D-23-00283R1 by Geroscience

2023-09-05 | GSE217634 | GEO

Pre- and post-sexual maturity liver-specific ERα knockout does not impact hepatic mitochondrial function or steatosis but does alter gene expression

Project description:Compared to males, premenopausal women and female rodents are protected against hepatic steatosis and present with higher functioning mitochondria (greater hepatic mitochondrial respiration and reduced H2O2 emission). Despite evidence that estrogen action mediates female protection against steatosis, mechanisms remain unknown. Here we validated a mouse model with inducible reduction of liver ERα (LERKO) via AAV Cre. We phenotyped the liver health and mitochondrial function of LERKO mice (n=10-12 per group) on a short-term high-fat diet (HFD), and then tested if timing of LERKO induction at 2 timepoints (sexually immature: 4 wks old (n=11 per group) vs. sexually mature: 8-10 wks old (n=8 per group)) would impact HFD-induced outcomes. We opted for an inducible LERKO model due to known estrogen-mediated developmental programming, and report both receptor and tissue specificity with our model. Control mice were ERαfl/fl receiving AAV with GFP only. Results show that there were no differences in body weight/composition or hepatic steatosis in LERKO mice with either short-term (4 wk) or chronic (8 wk) high-fat feeding. Similarly, LERKO genotype nor timing of LERKO induction (pre vs post sexual maturity) did not alter hepatic mitochondrial O2 and H2O2 flux, coupling, or OXPHOS protein. Transcriptomic analysis showed that hepatic gene expression in LERKO was significantly influenced by developmental stage. Together, these studies suggest that hepatic ERα is not required in female protection against HFD-induced hepatic steatosis nor does it mediate sexual dimorphism in liver mitochondria function.

2023-05-24 | GSE228773 | GEO

Raw data for manuscript : "Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD"

Project description:Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one third of the global population. Understanding metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.

2023-12-12 | MSV000093653 | MassIVE

Murine MTHFD1-synthetase deficiency, a model for the human MTHFD1 R653Q polymorphism, decreases tumor growth in males

Project description:[Abstract] The R653Q variant in the synthetase domain of the folate-metabolizing enzyme MTHFD1 has been shown to increase risk for birth defects, but it does not affect risk for development of colorectal cancer (CRC). However, since we have shown that this variant reduces purine synthesis, the goal of this study was to determine whether it could affect tumor growth. Using our mouse model for MTHFD1-synthetase deficiency (Mthfd1S+/-), we induced tumor formation with azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild-type and Mthfd1S+/- mice. Tumor size was significantly smaller due to mutant genotype, particularly in males. Tumor size was increased in female mice compared with males, regardless of genotype. Tumor number was not influenced by genotype and was lower in females. Inflammation within tumors of male Mthfd1S+/- mice was lower than in wild-type mice. Proliferation of mouse embryonic fibroblasts from mutant lines was slower than that in wild-type fibroblasts. Gene expression analysis in tumor adjacent normal (preneoplastic) tissue identified several genes involved in proliferation (Fosb, Fos, Ptk6, Esr2, Atf3) or inflammation (Atf3, Saa1, TNF-α) that were downregulated in mutant male mice. Female mutants did not have changes in expression for those genes, nor in tumor inflammation levels, compared with wild-type, suggesting a different mechanism directing tumor growth in females. We suggest that restriction of purine synthesis and reduced expression of critical tumor-promoting genes leads to slower tumor growth in MTHFD1-synthetase deficiency. These findings may have implications for CRC tumor growth and prognosis in individuals with the R653Q variant.

2017-03-01 | GSE77931 | GEO

Profiling Glutathionylome in CD38-mediated Epithelial-Mesenchymal Transition

Project description:We engineered a cell system in which the glutathione synthetase (GS) mutant was expressed that catalyzed the formation of a glutathione analogy from azido-alanine to profile changes of glutathionylome in CD38-overexpressing cells.

2022-05-31 | PXD032233 | Pride

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