Increased cardiac fatty acid oxidation in a mouse model with decreased malonyl-CoA sensitivity of CPT1B
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA724982 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14320672.fastq.gz | Fastqsanger.gz | |||
| SRR14320673.fastq.gz | Fastqsanger.gz | |||
| SRR14320674.fastq.gz | Fastqsanger.gz | |||
| SRR14320675.fastq.gz | Fastqsanger.gz | |||
| SRR14320676.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 13 |
Similar Datasets
Project description:Mitochondrial fatty acid oxidation (FAO) is an important energy provider for cardiac work and changes in cardiac substrate preference are associated with different heart diseases. Carnitine palmitoyltransferase 1B (CPT1B) is thought to perform the rate limiting enzyme step in FAO and is inhibited by malonyl-CoA. The role of CPT1B in cardiac metabolism has been addressed by inhibiting or decreasing CPT1B protein or after modulation of tissue malonyl-CoA metabolism. We assessed the role of CPT1B malonyl-CoA sensitivity in cardiac metabolism.
2021-04-26 | GSE173256 | GEO
Project description:Mlycd encodes malonyl-CoA decarboxylase (MCD), which is an enzyme that localizes in the cytosolic, mitochondrial, and peroxisomal compartments and catalyzes the conversion of malonyl-CoA into acetyl-CoA. Malonyl-CoA can be converted into malonylcarnitine (C3DC). Patients with an autosomal recessive defect of MCD and MCD KO mice have pronounced elevations of C3DC. Analysis of plasma C3DC levels in the BxD genetic reference population revealed increased levels in BxD strains that harbor the DBA/2J haplotype at the site of the Mlycd gene. RNA sequencing was performed on two samples of DBA/2J mouse livers and two C57BL/6J mouse livers. Decreased expression of Mlycd gene as well as intronic reads in intron 2 were observed in DBA/2J livers. Long-read sequecing of DBA/2J livers in the Mlycd region confirmed an intracisternal A-particle (IAP) retrotransposon in intron 2 of the DBA/2J Mlycd sequence. To confirm the causal nature of the variant, DBA/2J mice with and without the C57BL/6J variant of Mlycd spliced in were tested for products of MCD enzymatic activity, and the C57BL/6J variant was able to rescue the phenotype seen in the DBA/2J mice.
2024-10-26 | GSE186973 | GEO
Project description:In the heart, metabolic profile switches from glycolysis to fatty acid oxidation (FAO) rapidly after birth accompanied by chromatin reconfiguration, cell cycle exit and cardiomyocyte (CM) maturation, suggesting a synergistic rewiring of transcriptional networks regulated by epigenetic mechanisms in accordance with environmental and metabolic signals. To gain a better insight into the interconnection between epigenetic processes and metabolic pathways during cardiac development, maturation and heart regeneration, we induced a metabolic reprogramming by depleting CPT1b, a crucial enzyme for FAO, specifically in CM. Cpt1b inactivation led to cardiomegaly and attenuated cardiac damage in response to myocardial injury primarily attributed to augmented CM proliferation and enhanced resistance to ischemic injury.
2023-07-18 | GSE172412 | GEO
Project description:Malonyl-CoA, as a key metabolite, is not only the building block for lipogenesis, but also a critical metabolic switcher to mediates flux control over mitochondrial FAs β-oxidation in cellular. However, the levels and entire functions of malonyl-CoA in malignancy and drug resistance is still unclear, especially in those characterized by abnormal lipid metabolism, such as prostate cancer (PCa). Here, we showed the levels of malonyl CoA was increased in PCa, especially in castration-resistant prostate cancer (CRPC). Abnormal accumulation of malonyl-CoA promoted lipogenesis and reprogramed multiple metabolism (including lipid, glucose and amino acid metabolism), sustaining cellular homeostasis to contribute to PCa progression. Restoration of MLYCD expression activated PREK-mediated unfolded protein reaction (UPR) via consuming malonyl-CoA. Importantly, we also found that malonyl-CoA as a donor of malonylation, promoted lysine malonylation in PCa. We identified that malonyl-CoA promoted Ran K141 malonylation, increasing Ran activity and enhancing AR nuclear translocation and transcriptional activity, finally contributing to PCa development and resistance to antiandrogens. These findings highlighted the previously unrecognized role and function of MLYCD-mediated malonyl-CoA in PCa progression via the canonical pathway (metabolic reprogramming) and the non-canonical pathway (malonylated Ran K141), systematically revealing that might be a potentially reliable biomarker and therapy for PCa.
2025-08-21 | PXD060607 | Pride
Project description:In the heart, metabolic profile switches from glycolysis to fatty acid oxidation (FAO) rapidly after birth accompanied by chromatin reconfiguration, cell cycle exit and cardiomyocyte (CM) maturation, suggesting a synergistic rewiring of transcriptional networks regulated by epigenetic mechanisms in accordance with environmental and metabolic signals. To gain a better insight into the interconnection between epigenetic processes and metabolic pathways during cardiac development, maturation and heart regeneration, we induced a metabolic reprogramming by depleting CPT1b, a crucial enzyme for FAO, specifically in CM. Cpt1b inactivation led to cardiomegaly and attenuated cardiac damage in response to myocardial injury primarily attributed to augmented CM proliferation and enhanced resistance to ischemic injury.
2023-07-18 | GSE172413 | GEO
Project description:In the heart, metabolic profile switches from glycolysis to fatty acid oxidation (FAO) rapidly after birth accompanied by chromatin reconfiguration, cell cycle exit and cardiomyocyte (CM) maturation, suggesting a synergistic rewiring of transcriptional networks regulated by epigenetic mechanisms in accordance with environmental and metabolic signals. To gain a better insight into the interconnection between epigenetic processes and metabolic pathways during cardiac development, maturation and heart regeneration, we induced a metabolic reprogramming by depleting CPT1b, a crucial enzyme for FAO, specifically in CM. Cpt1b inactivation led to cardiomegaly and attenuated cardiac damage in response to myocardial injury primarily attributed to augmented CM proliferation and enhanced resistance to ischemic injury.
2023-07-18 | GSE172414 | GEO
Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which induces diverse biological and toxic effects, including the reprograming of intermediate metabolism, mediated by the aryl hydrocarbon receptor (AHR). Targeted LC-MS analysis of hepatic extracts from mice gavaged with TCDD every 4 days for 28 days detected an increase in S-(2-carboxyethyl)-L-cysteine, a conjugate produced following the spontaneous reaction between the sulfhydryl group of cysteine and highly reactive acrylyl-CoA, an intermediate in the cobalamin (Cbl)-independent β–oxidation-like metabolism of propionyl-CoA. In addition to repressing genes in both the canonical Cbl-dependent carboxylase and the alternate Cbl-independent β–oxidation-like pathways at 30 µg/kg TCDD, methylmalonyl-CoA mutase (MUT) activity was inhibited at lower doses. Moreover, TCDD decreased serum Cbl levels and hepatic cobalt levels while eliciting negligible effects on gene expression associated with Cbl absorption, transport, trafficking, or the derivatization to 5’-deoxy-adenosylcobalamin (AdoCbl), the required MUT cofactor. In addition to inducing Acod1 that encodes for aconitate decarboxylase 1, the enzyme responsible for the decarboxylation cis-aconitate to itaconate, TCDD also dose-dependently increased itaconate levels in hepatic extracts. MUT inhibition is consistent with itaconate activation to itaconyl-CoA, a MUT suicide inactivator that adducts AdoCbl, that in turn, inhibits MUT activity and reduces Cbl levels. Collectively, these results suggest the decrease in MUT activity is due to Cbl depletion following TCDD treatment that redirected propionyl-CoA metabolism to the alternate Cbl-independent β–oxidation-like pathway. The resulting hepatic accumulation of acrylyl-CoA likely contributes to TCDD-elicited hepatotoxicity and the multi-hit progression of steatosis to steatohepatitis with fibrosis.
2022-08-05 | GSE203302 | GEO
Project description:CPT1B, as the major rate-limiting enzyme for fatty acid β-oxidation, involved in the regulation of adipose tissue lipid deposition, but its role in the regulation of goat intramuscular fat (IMF) remains unclear. Here, we conducted knockdown experiments targeting the CPT1B gene in goat intramuscular preadipocytes, resulting in a significant increase in intracellular triglyceride (TAG) content and lipid droplet accumulation. Conversely, the overexpression of CPT1B led to a significant decrease in intracellular TAG content and lipid droplet accumulation. Mechanistically, through RNA-seq analysis of CPT1B knockdown samples, we identified 285 differentially expressed genes (DEGs), including 71 up-regulated and 214 down-regulated genes. Notably, these DEGs were significantly enriched in various KEGG signaling pathways, such as fatty acid metabolism, focal adhesion, FoxO signaling, PI3K-Akt signaling, and MAPK signaling pathways. Gene Set Enrichment Analysis (GSEA) further confirmed the upregulation of the MAPK signaling pathway upon CPT1B knockdown in adipocytes. In rescue experiments, we demonstrated that the addition of a p38MAPK inhibitor (PD169316) to CPT1B-knockdown adipocytes counteracted the increase in lipid deposition caused by the loss of CPT1B function. These findings suggest that CPT1B inhibits lipid deposition in goat intramuscular preadipocytes via the p38MAPK signaling pathway. In addition, we observed a potential interaction between CPT1B and CPT1A through Protein-Protein Interaction Networks (PPIs). Interestingly, CPT1A exhibited a similar regulatory function to CPT1B, and they both were able to partially restore the changes in lipid deposition induced by each other. This observation supports the hypothesis of synergistic effects between CPT1B and CPT1A. Collectively, our results elucidate the role of CPT1B in the regulation of lipid deposition in goat intramuscular adipocytes through the p38MAPK signaling pathway, providing valuable insights for enhancing the quality of goat intramuscular fat.
2023-08-03 | GSE239570 | GEO
Project description:Short chain enoyl-CoA hydratase 1 (ECHS1) is involved in the second step of mitochondrial fatty acid β-oxidation (FAO), catalysing the hydration of short chain enoyl-CoA esters to short chain 3-hyroxyl-CoA esters. Genetic deficiency in ECHS1 (ECHS1D) is associated with a specific subset of Leigh Syndrome, a disease typically caused by defects in oxidative phosphorylation (OXPHOS). Here, we examined the molecular pathogenesis of ECHS1D using a CRISPR/Cas9 edited human cell ‘knockout’ model and fibroblasts from ECHS1D patients. Transcriptome analysis of ECHS1 ‘knockout’ cells showed reductions in key mitochondrial pathways, including the TCA cycle, receptor mediated mitophagy and nucleotide biosynthesis. Subsequent proteomic analyses confirmed these reductions and revealed additional defects in mitochondrial oxidoreductase activity and fatty acid β-oxidation. Functional analysis of ECHS1 ‘knockout’ cells showed reduced mitochondrial oxygen consumption rates when metabolising glucose or OXPHOS complex I-linked substrates, as well as decreased complex I and complex IV enzyme activities. ECHS1 ‘knockout’ cells also exhibited decreased OXPHOS protein complex steady-state levels (complex I, complex III2, complex IV, complex V and supercomplexes CIII2/CIV and CI/CIII2/CIV). Patient fibroblasts exhibit varied reduction of mature OXPHOS complex steady-state levels, with defects detected in CIII2, CIV, CV and the CI/CIII2/CIV supercomplex. Overall, these findings highlight the contribution of defective OXPHOS function, in particular complex I deficiency, to the molecular pathogenesis of ECHS1D.
2022-04-10 | GSE200252 | GEO
Project description:Fatty acid beta-oxidation (FAO), the breakdown of lipids, is a metabolic pathway used by various stem cells. FAO levels are generally high during quiescence and downregulated with proliferation. The endogenous metabolite malonyl-CoA modulates lipid metabolism as a reversible FAO inhibitor and as a substrate for de novo lipogenesis. Here we assessed whether malonyl-CoA can be exploited to steer the behavior of hematopoietic stem/progenitor cells (HSPCs), quiescent stem cells of clinical relevance. Treatment of mouse HSPCs in vitro with malonyl-CoA increases HSPC numbers compared to non-treated controls and ameliorates blood reconstitution capacity when transplanted in vivo, mainly through enhanced lymphoid reconstitution. Similarly, human HSPC numbers also increase upon malonyl-CoA treatment in vitro. These data corroborate that lipid metabolism can be targeted to direct cell fate and stem cell proliferation. Physiological modulation of metabolic pathways, rather than genetic or pharmacological inhibition, provides unique perspectives for stem cell manipulations in health and disease.
2020-08-25 | GSE153201 | GEO