Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA107219 | ENA |
REPOSITORIES: ENA
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Project description:The synthesis of fatty acids and cholesterol is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs because of gene knockout of SREBP cleavage-activating protein (SCAP) required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. Application of stringent combinatorial criteria to the transgenic/knockout approach allows identification of genes whose activities are likely controlled directly by the SREBPs.
2017-08-05 | GSE102257 | GEO
Project description:The synthesis of fatty acids and cholesterol is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs because of gene knockout of SREBP cleavage-activating protein (SCAP) required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. Application of stringent combinatorial criteria to the transgenic/knockout approach allows identification of genes whose activities are likely controlled directly by the SREBPs.
2017-08-05 | GSE102256 | GEO
Project description:The synthesis of fatty acids and cholesterol is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs because of gene knockout of SREBP cleavage-activating protein (SCAP) required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. Application of stringent combinatorial criteria to the transgenic/knockout approach allows identification of genes whose activities are likely controlled directly by the SREBPs.
2017-08-05 | GSE102258 | GEO
Project description:Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.https://pubmed.ncbi.nlm.nih.gov/35743314/
2022-08-02 | PXD032211 | Pride
Project description:Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.https://pubmed.ncbi.nlm.nih.gov/35743314/
2022-08-02 | PXD032214 | Pride
Project description:The key lipid metabolism transcription factor sterol regulatory element-binding protein (SREBP)-1a integrates gene regulatory effects of hormones, cytokines, nutrition and metabolites as lipids, glucose or cholesterol via stimuli specific phosphorylation by different MAPK cascades. We have formerly reported the systemic impact of phosphorylation in transgenic mouse models with liver-specific overexpression of the N-terminal transcriptional active domain of SREBP-1a (alb-SREBP-1a) or a MAPK kinase phosphorylation sites deficient variant (alb-SREBP-1a∆P; (S63A, S117A, T426V)), respectively. Here we investigated the molecular basis of the systemic observation in holistic hepatic gene expression analyses and lipid degrading organelles involved in the pathogenesis of metabolic syndrome, i.e. peroxisomes, by 2D-DIGE and mass spectrometry analyses. Although alb-SREBP-1a mice develop a severe phenotype with visceral adipositas and hepatic lipid accumulation featuring a fatty liver, the hepatic differential gene expression and alterations in peroxisomal protein patterns compared to control mice were surprisingly relative low. In contrast, phosphorylation site deficient alb-SREBP-1a∆P mice, protected from hepatic lipid accumulation phenotype, showed gross alteration in hepatic gene expression and peroxisomal proteome. Further knowledge based analyzes revealed that overexpression of SREBP-1a favored mainly acceleration in lipid metabolism and indicated a regular insulin signaling, whereas disruption of SREBP-1a phosphorylation resulted in massive alteration of cellular processes including signs for loss of lipid metabolic targets. These results could be the link to a disturbed lipid metabolism that overall resembles a state of insulin resistance.
2018-03-30 | GSE110569 | GEO
Project description:Mitochondrial function is an important control variable in the progression of metabolic dysfunction associated fatty liver disease (MAFLD). We hypothesize that organization and function of mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. Paradoxically, in MAFLD increased de novo lipogenesis (DNL) occurs despite hepatic insulin resistance. Therefore, we addressed this question using our animal model alb-SREBP-1c, which exhibits increased DNL by constitutively active SREBP-1c. Using an omics approach, we show that the abundance of ETC complex subunits and metabolic pathways are altered in liver of these animals. Analyses of cellular metabolic status by functional assays revealed that SREBP-1c-forced DNL induces a limitation of substrates for oxidative phosphorylation that is rescued by enhanced complex II activity. Furthermore, energy metabolism associated gene regulation indicates the counteracting to increase expression of mitochondrial genes and features cell communication by miRNA and exosomal RNA transfer. In conclusion, substrate availability fuels mainly complex II electron flows as a consequence of activated DNL with impact on whole body by liver-specific exosomal RNAs in early stages of MAFLD.
2022-06-21 | GSE198173 | GEO
Project description:Nrf/NFE2L family transcription factors regulate redox balance, metabolism, proteostasis, and aging. Nrf1/NFE2L1 is responsible for stress-responsive upregulation of proteasome subunit genes and is essential for adaptation to proteotoxic stress. The closely related Nrf2/NFE2L2 is responsible for activation of oxidative stress responses and xenobiotic detoxification. Although regulated by different mechanisms, Nrf1 and Nrf2 contain very similar DNA binding domains and can drive similar transcriptional responses. However, the extent to which functions of Nrf1/2 are distinct or overlapping has been unclear. In C. elegans, a single gene, skn-1, encodes distinct protein isoforms, SKN-1A and SKN-1C, that function analogously to mammalian Nrf1 and Nrf2, respectively. We previously showed that regulation of the proteasome by SKN-1A/Nrf1 requires post-translational conversion of N-glycosylated asparagine residues to aspartate by the PNG-1/NGLY1 peptide:N-glycanase, a process we term ‘sequence editing’. Here, we reveal the consequences of sequence editing for the transcriptomic output of activated SKN-1A. We show that whilst activation of proteasome subunit genes is strictly dependent on sequence editing, sequence edited SKN-1A also activate genes linked to redox homeostasis and xenobiotic detoxification that are also activated by non-sequence edited forms of SKN-1. Using mutant alleles that selectively inactivate either SKN-1A or SKN-1C, we show that SKN-1A/Nrf1 and SKN-1C/Nrf2 function coordinately to promote optimal oxidative stress resistance and confirm that they are regulated by discrete genetic pathways. This work demonstrates that sequence editing plays a critical role in tailoring SKN-1/Nrf functions by tuning the SKN-1A/Nrf1 regulated transcriptome.
2025-06-17 | GSE279082 | GEO
Project description:We find that selective inhibition of one arm of mTORC1 signaling, via deletion of FLCN, promotes activation of the transcription factor TFE3 and profoundly protects against NAFLD and NASH in mice. (1) We performed genome-wide RNA-seq on livers from Control, liver-specific Flcn-null mice (LiFKO), and Flcn/Tfe3 double knock-out (DKO) mice fed either normal chow (NC) or a NAFLD-inducing diet (AMLN). We find TFE3-mediated induction of lysosomal and mitochondrial gene programs, and also suppression of de novo lipogenesis genes. (2) To understand whether TFE3 directly affects gene expression, we performed TFE3 ChIP-seq on livers from Control and LiFKO mice on normal chow. We find TFE3 occupancy on the chromatin at lysosomal genes, Ppargc1a (a driver of mitochondrial genes), and at de novo lipogenesis genes. (3) Finally, we wanted to test whether TFE3 antagonistically competes with the pro-lipogenic transcription factor SREBP-1c on chromatin. We therefore injected HA-tagged constitutively nuclear (active) SREBP-1c (nSREBP-1c), or a control virus, into control and LiFKO mice, treated them with a NAFLD-inducing diet (FPC diet), and collected liver tissue. We consequently performed HA-nSREBP-1c and TFE3 ChIP-seq experiments and observed no evidence of antagonistic competition.
2022-04-15 | GSE160292 | GEO
Project description:<p>Background & Aims:</p><p>Intestinal dysbiosis contributes to the pathogenesis of metabolic-associated fatty liver disease (MAFLD), though precise bacterial targets and mechanisms remain incompletely elucidated. This study investigated whether the depletion of Alistipes putredinis (AP) in adolescents obesity-associated MAFLD is causally linked to disease progression and aimed to delineate its downstream signaling pathway.</p><p>Methods:</p><p>Fecal samples from 29 obese adolescents with MAFLD and 17 healthy controls in Hainan Province were analyzed by metagenomic sequencing. A high-fat diet–induced MAFLD mouse model was established and randomized into control, MAFLD, and AP-gavaged groups (12 weeks). Untargeted metabolomics and targeted short-chain fatty acid profiling were performed on fecal, hepatic, and AP culture supernatant samples. Liver transcriptomics, Western blot, and co-immunoprecipitation were employed to identify and validate involved molecular pathways.</p><p>Results:</p><p>AP abundance was significantly lower in MAFLD patients compared with controls. AP supplementation ameliorated hepatic lipid accumulation in MAFLD mice. Metabolomic analysis identified acetate as the principal mediator of AP’s protective effects. Acetate derived from AP activated the GPR43 receptor on hepatic neutrophils, inhibiting intracellular Ca²⁺ flux and NADPH oxidase 2 (NOX2) activity, thereby reducing reactive oxygen species (ROS) generation. Reduced ROS levels attenuated JNK phosphorylation, decreased LXRα binding to the SREBP-1c promoter, and suppressed proteolytic activation of SREBP-1c, leading to downregulation of key lipogenic enzymes ACC1 and FASN.</p><p>Conclusion:</p><p>Alistipes putredinis ameliorates MAFLD via acetate-mediated activation of the GPR43 receptor on hepatic neutrophils, which suppresses the Ca²⁺-NOX2-ROS signaling cascade and inhibits ROS-dependent SREBP-1c activation and lipogenic gene expression. These findings reveal a previously unrecognized gut microbiota–neutrophil signaling axis as a potential therapeutic target in MAFLD.</p>
2026-01-15 | MTBLS13691 | MetaboLights