A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis (NASH) in mice via binding and relocating acetyl-coA carboxylase
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1029988 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26440767_1.fastq.gz | Fastqsanger.gz | |||
| SRR26440767_2.fastq.gz | Fastqsanger.gz | |||
| SRR26440768_1.fastq.gz | Fastqsanger.gz | |||
| SRR26440768_2.fastq.gz | Fastqsanger.gz | |||
| SRR26440769_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 16 |
Similar Datasets
Project description:Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drug targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, has been approved by FDA. Whether cytosolic ACC1 can be regulated spatially is unknown. Herein, we found that streptavidin, which is a bacterium derived tetrameric protein, forms cytosolic condensates and efficiently induce a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensates formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase (FASN). Notably, AAV mediated delivery of SA partially blocks mice liver DNL and ameliorate NASH without eliciting hypertriglyceridemia. In summary, our study demonstrates that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.
2023-10-25 | GSE245797 | GEO
Project description:Heteromeric acetyl-CoA carboxylase (ACCase) catalyzes the ATP-dependent carboxylation of acetyl-CoA to produce malonyl-CoA, the committed step for de novo fatty acid synthesis. In plants, ACCase activity is controlled at multiple levels, including negative regulation by biotin attachment domain-containing (BADC) proteins, of which the badc1/3 double mutant leads to increased seed triacylglycerol accumulation. Unexpectedly, the Arabidopsis badc1/3 mutant also accumulates more protein. The metabolic consequences from both higher oil and protein were investigated in developing badc1/3 seed using global transcriptomics, translatomics, proteomics, metabolomics and other biomass measurements. Changes included increased storage proteins and lipid-droplet packaging proteins, increased SDP1 lipase, altered organic acid metabolism, and reduced extracellular lipid synthesis perhaps offsetting the increase in TAG. We present a model of how Arabidopsis adapted to deregulated ACCase, resulting in more oil, and altered flux through pathways that partition carbon and propose targets for future bioengineering of seed storage reserves.
2025-02-28 | GSE278842 | GEO
Project description:In this study, we hypothesize that acetyl CoA carboxylase (ACC) is an important intermediate in Cystic fibrosis (CF) inflammatory signaling cascade. Here, we demonstrate that ACC inhibition mimics the cellular effects of ibuprofen promoting both redistribution of intracellular cholesterol and increased rates of microtubule reformation, while decreasing RhoA expression in CF epithelial cell models. Inhibiting ACC polymerization with citrate increases RhoA expression and decreases microtubule reformation rates in wild-type epithelial cells, suggesting pro-inflammatory signaling. Together, these findings demonstrate a novel mechanism of high-dose ibuprofen efficacy and point to a potential new therapeutic target for anti-inflammatory drugs in CF.
2019-03-18 | GSE118567 | GEO
Project description:Acetyl-CoA Carboxylase Obstructs CD8+ T-Cell Lipid Utilization in the Tumor Microenvironment
| PRJNA1068086 | ENA
Project description:The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control.However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, invoking lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell longevity, engendering T cells with increased survival and polyfunctionality, with the ability to control solid cancer.
2024-03-05 | GSE254000 | GEO
Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1M-NM-^T acs2M-NM-^T S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor. To investigate the impact of introduced changes in native pathway of cytosolic acetyl-CoA formation in S. cerevisiae, a DNA microarray-based transcriptome analysis was performed on aerobic or anaerobic, glucose-limited chemostat cultures.
2013-11-21 | E-GEOD-47983 | biostudies-arrayexpress
Project description:In plants the initiation of fatty acid synthesis is catalyzed by acetyl-CoA carboxylase (ACCase) which produces malonyl-CoA. The heteromeric form of ACCase (htACCase) is a holoenzyme consisting of biotin carboxylase and carboxyltransferase sub-complexes, both of which are subject to extensive regulation. Biotin carboxylase activity is controlled in part by the presence of the catalytic biotin carboxyl carrier proteins (BCCP1/2) and/or the non-catalytic, non-biotinylated, biotin/lipoyl attachment domain-containing proteins (BADC1/2/3) that associate with backbone biotin carboxylase (BC) protein. However, the mechanisms regulating BADC and BCCP interaction with BC and thus ACCase activity in planta are not clear. Here we demonstrate the Arabidopsis thaliana regulatory protein PII modulates htACCase activity through independent interactions with BADC and BCCP proteins in a selective manner. Analysis of badc1/2 and badc1/3 mutant lines and the respective pii triple mutants reveal that changes in seed oil and protein accumulation of badc double mutants are PII/nitrogen dependent. Absolute quantification of htACCase subunits and PII in developing seeds suggests that Arabidopsis exerts tight regulation over individual protein stoichiometry to balance oil and protein accumulation. The effects on vegetative and seed development indicate PII and BADC proteins have distinct but overlapping roles in the regulation of plant metabolism.
2025-12-16 | PXD057351 | Pride
Project description:Acetyl-CoA carboxylase inhibition regulates microtubule dynamics and intracellular transport in cystic fibrosis epithelial cells
| PRJNA486100 | ENA
Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
2023-03-05 | GSE226139 | GEO
Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1Δ acs2Δ S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor.
2013-11-21 | GSE47983 | GEO