Loss of CPT1a Modulates Phosphatidylethanolamine Levels Leading to Microvesicular Steatosis in Female Mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA937380 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To investigate the impact of liver-specific deletion of Cpt1a in hepatic lipid metabolism.
2025-02-26 | GSE225769 | GEO
Project description:One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Irg1 knockout mice that are deficient in synthesizing itaconate, we aimed at understanding the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Irg1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveal enhanced expression of enzymes involved in fatty acid oxidation in following 4-ocytl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Irg1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.
2024-01-29 | PXD047706 | Pride
Project description:Background: Alveolar rhabdomyosarcoma (ARMS) has a high propensity to metastasize, leading to its aggressiveness and a poor survival rate among those with the disease. More than 80% of aggressive ARMSs harbor a PAX3-FKHR fusion transcription factor, which regulates cell migration and promotes metastasis, most likely by regulating the fusion protein's transcriptional targets. Therefore, identifying druggable transcription targets of PAX3-FKHR that are also downstream effectors of PAX3-FKHR-mediated cell migration and metastasis may lead to novel therapeutic approaches for treating ARMS. Methods: To identify genes whose expression is directly affected by the level of PAX3-FKHR in an ARMS cellular-context, we first developed an ARMS cell line in which PAX3-FKHR is stably down-regulated, and showed that stably downregulating PAX3-FKHR in ARMS cells significantly decreased the cells' motility. We used microarrays analysis to identify genes whose expression level decreased when PAX3-FKHR was downregulated. We used mutational analysis, promoter reporter assays, and electrophoretic mobility shift assays to determine whether PAX3-FKHR binds directly and specifically to the promoter region of the target gene. We used siRNA and pharmacologic inhibitor to downregulate the target gene of PAX3-FKHR and investigated the effect of such downregulation on cell motility, Results: We found that When PAX3-FKHR was downregulated, the expression of carnitine palmitoyltransferase 1A (CPT1A) decreased. We showed that PAX3-FKHR binds directly and specifically to a paired-domain binding-site in the CPT1A promoter region, indicating that CPT1A is a novel direct transcriptional target of PAX3-FKHR. Furthermore, downregulating CPT1Adecreased cell motility in ARMS cells, indicating that CPT1A is a downstream effector of PAX3-FKHR-mediated cell migration and metastasis. Conclusions: Taken together, we have identified CPT1A as a novel direct transcriptional target of PAX3-FKHR and revealed the novel function of CPT1A in promoting cell motility. CPT1A may represent a novel therapeutic target for the treatment of ARMS. Identification of transcription targets of PAX3-FKHR in human alveolar rhabdomyosarcoma: By stably knocking down PAX3-FKHR in human alveolar rhabdomyosarcoma cell line Rh30 and comparing the gene expression profile of the knockdown clone (KD) to the parental Rh30, transcription targets of PAX3-FKHR have been identified. Gene expression in parental Rh30 cells was compared to that in either Rh30 cells stably expressing shRNA targeting PAX3-FKHR (KD) or control non-targeting shRNA (CON), in duplicate.
2012-05-15 | E-GEOD-35862 | biostudies-arrayexpress
Project description:Tafazzin Regulates Cell State by Modulating Phosphatidylethanolamine and Phosphatidylserine levels
| PRJNA418909 | ENA
Project description:To compare the transcriptional profile in aged kidneys lacking tubular Cpt1a with floxed littermate controls.
2024-03-01 | GSE205497 | GEO
Project description:To compare the transcriptional profile in renal tubules conditional deletion of Cpt1a, to floxed littermate controls.
2024-03-01 | GSE246150 | GEO
Project description:Endothelial cells (ECs) line the inner wall of blood vessels and maintain vascular stability. Vascular stability alteration is a hallmark of pathologies such as cancer and thrombosis. A role for fatty acid oxidation (FAO) in this process is unknown. Integrating MS-proteomics and metabolic modeling revealed that FAO increases when ECs cultured on matrigel are assembled into a fully formed network. Inhibition of CPT1A in ECs, a limiting enzyme in FAO, results in disruption of this network. Acute CPT1A inhibition reduces cellular ATP levels and oxygen consumption, which can be restored replenishing the tricarboxylic acid cycle (TCAc). Phosphoproteomic changes upon acute CPT1A inhibition evoked those triggered by thrombin, a potent inducer of EC permeability through calcium signaling. Indeed, CPT1A inhibition increased EC permeability and vascular leakage, which were restored replenishing the TCAc or, partially, inhibiting calcium influx. Our study shows the possibility of altering FAO to interfere with ECs in diseases.
2015-01-28 | PXD001186 | Pride
Project description:Carnitine palmitoyltransferase 1a (CPT1a) is the key regulator of mitochondrial long-chain fatty acid beta-oxidation (LCFAO). However, the functional significance of AT2 cell-specific LCFAO at baseline and during acute lung injury (ALI) is not fully understood. In this study, Murine models of AT2 cell-specific Cpt1a deletion were generated for investigating the role of CPT1a in regulating AT2 cell function and the severity of lipopolysaccharide-induced murine ALI models.
2024-07-05 | GSE255949 | GEO
Project description:argeting epigenetic regulators to potentiate anti-PD-1 immunotherapy converges on the activation of type I interferon (IFN-I) response, mimicking cellular response to viral infection, but how its strength and duration are regulated to impact combination therapy efficacy remains largely unknown. Here, we show that mitochondrial CPT1A downregulation following viral infection restrains, while its induction by epigenetic perturbations sustains, a double-stranded RNA-activated IFN-I response. Mechanistically, CPT1A recruits the endoplasmic reticulum-localized ZDHHC4 to catalyze MAVS Cys79-palmitoylation, which promotes MAVS stabilization and activation by inhibiting K48- but facilitating K63-linked ubiquitination. Further elevation of CPT1A incrementally increases MAVS palmitoylation and amplifies the IFN-I response, which enhances control of viral infection and epigenetic perturbation-induced antitumor immunity. Moreover, CPT1A chemical inducers augment the therapeutic effect of combined epigenetic treatment with PD-1 blockade in refractory tumors. Our study identifies CPT1A as a stabilizer of MAVS activation, and its link to epigenetic perturbation can be exploited for cancer immunotherapy.
2023-10-12 | GSE206747 | GEO
Project description:Targeting epigenetic regulators to potentiate anti-PD-1 immunotherapy converges on the activation of type I interferon (IFN-I) response, mimicking cellular response to viral infection, but how its strength and duration are regulated to impact combination therapy efficacy remains largely unknown. Here, we show that mitochondrial CPT1A downregulation following viral infection restrains, while its induction by epigenetic perturbations sustains, a double-stranded RNA-activated IFN-I response. Mechanistically, CPT1A recruits the endoplasmic reticulum-localized ZDHHC4 to catalyze MAVS Cys79-palmitoylation, which promotes MAVS stabilization and activation by inhibiting K48- but facilitating K63-linked ubiquitination. Further elevation of CPT1A incrementally increases MAVS palmitoylation and amplifies the IFN-I response, which enhances control of viral infection and epigenetic perturbation-induced antitumor immunity. Moreover, CPT1A chemical inducers augment the therapeutic effect of combined epigenetic treatment with PD-1 blockade in refractory tumors. Our study identifies CPT1A as a stabilizer of MAVS activation, and its link to epigenetic perturbation can be exploited for cancer immunotherapy.
2023-10-12 | GSE206746 | GEO