Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Orbitrap Fusion
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Douglas Mashek
PROVIDER: MSV000091575 | MassIVE | Tue Mar 28 08:46:00 BST 2023
REPOSITORIES: MassIVE
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Project description:Organelle interactions play a significant role in compartmentalizing metabolism and signaling. Lipid droplets (LDs) interact with numerous organelles including mitochondria, which is largely assumed to facilitate lipid transfer and catabolism. However, quantitative proteomics of hepatic peridroplet (PDM) and cytosolic mitochondria (CM) revealed that CM are enriched in proteins comprising various oxidative metabolism pathways whereas PDM are enriched in proteins involved in lipid anabolism. Isotope tracing and super-resolution imaging confirmed that fatty acids (FAs) are selectively trafficked to and oxidized in CM during fasting. In contrast, PDM facilitate FA esterification and LD expansion in nutrient-replete media. Additionally, mitochondrial-associated membranes (MAMs) around PDM and CM differed in their proteomes and ability to support distinct lipid metabolic pathways. We conclude that CM and CM-MAM support lipid catabolic pathways whereas PDM and PDM-MAM allow hepatocytes to efficiently store excess lipids in LDs to prevent lipotoxicity in contrast to existing dogma.
2023-03-28 | MSV000091576 | MassIVE
Project description:Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of young adult mice treated with a single systemic dose of MAM display DNA damage (O6-methylguanine lesions) that peaks at 48 hours and decline to near-normal levels at 7 days post-treatment. By contrast, at this time, MAM-treated mice lacking the gene encoding the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT), showed persistent O6-methylguanine DNA damage. The DNA damage was linked to cell-signaling pathways that are perturbed in cancer and neurodegenerative disease. These data are consistent with the established carcinogenic and developmental neurotoxic properties of MAM in rodents, and they support the proposal that cancer and neurodegeneration share common signal transduction pathways. They also strengthen the hypothesis that early life exposure to the MAM glucoside cycasin has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for medicine and/or food. Exposure to environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer’s disease, as well as cancer. Mouse brains from eleven-week-old male C57BL6 wild-type and Mgmt-/- mice were exposed to either MAM or Vehicle for 6 hr, 24 hr, 48 hr, 168 hr. Five or six mice per group for a total of 94 mice.
2013-01-10 | E-GEOD-26600 | biostudies-arrayexpress
Project description:Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of young adult mice treated with a single systemic dose of MAM display DNA damage (O6-methylguanine lesions) that peaks at 48 hours and decline to near-normal levels at 7 days post-treatment. By contrast, at this time, MAM-treated mice lacking the gene encoding the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT), showed persistent O6-methylguanine DNA damage. The DNA damage was linked to cell-signaling pathways that are perturbed in cancer and neurodegenerative disease. These data are consistent with the established carcinogenic and developmental neurotoxic properties of MAM in rodents, and they support the proposal that cancer and neurodegeneration share common signal transduction pathways. They also strengthen the hypothesis that early life exposure to the MAM glucoside cycasin has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for medicine and/or food. Exposure to environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer’s disease, as well as cancer.
2013-01-10 | GSE26600 | GEO
Project description:A better understanding of the molecular mechanisms underlying the development and progression of diabetic neuropathy (DN) is essential for the design of mechanism-based therapies. We examined changes in global gene expression to define pathways regulated by diabetes in peripheral nerve. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes (DEGs); DEGs were further used for functional enrichment analysis and network analysis to identify biological processes and pathways differentially regulated in the db/db nerve. Expression profile clustering was performed to identify co-expressed DEGs. A set of co-expressed lipid metabolism genes was used for promoter sequence analysis.We identified 4,017 DEGs; 2,122 genes were up-regulated and 1,895 genes were down-regulated in the db/db relative to the db+ samples. Over-represented biological processes identified by the functional enrichment analysis include cell cycle, lipid metabolic process, lipid transport, carbohydrate metabolic process, response to stress, apoptosis, axonogenesis and cell adhesion. Pathways regulated in the db/db nerve include lipid metabolism, carbohydrate metabolism, energy metabolism, PPAR signaling, apoptosis, and axon guidance. The majority of DEGs in the glycolysis, TCA cycle, oxidative phosphorylation, fatty acid metabolism, glycerolipid metabolism, mitochondrial fatty acid elongation, lipid transport, adipocytokine signaling, PPAR signaling, and apoptosis pathways are up-regulated, whereas most of the axonogenesis-related genes are down-regulated in db/db nerve. A network of DEGs based on their co-citation in literature identified regulatory relationship between Tnf-α and key genes from the regulated pathways. Promoter sequence analysis identified over-represented transcription factor binding site (TFBS) motifs in the promoter regions of twenty two co-expressed lipid metabolism-related genes suggesting coordinated regulation of these genes by multiple transcription factors (TF). Furthermore, TF binding to these TFBS and differentially regulated in our data are annotated with nervous system development and immune response suggesting possible co-regulation of lipid metabolism, nervous system development and stress response genes. Gene expression changes in our data are consistent with pathological characteristics observed in DN including axon degeneration and demyelination, and support existing hypotheses regarding hyperglycemia mediated nerve damage in DN. Our findings support the role of hyperglycemia-induced oxidative stress and ischemia in nerve injury. Our results also support the hypothesis of oxidized lipid-mediated nerve injury and increased mitochondrial oxidative stress in dyslipidemia. Moreover, our analyses revealed a possible co-regulation mechanism connecting hyperlipidemia, stress response and axonal degeneration. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes
2011-02-18 | E-GEOD-27382 | biostudies-arrayexpress
Project description:Macrophages form a primary immune cells population in tumor tissues and malignant ascites microenvironment (MAM). They can be activated and polarized into tumor-associated macrophages (TAM) by the embedded environment and promote tumor progression and metastasis However, the molecular mechanisms of MAM in macrophage polarization and the effects on epithelial ovarian cancer (EOC) metastatic progression remain elusive. Here, we found that that MAM modulates RhoA-GTPase-F-actin-Hippo signaling cascade in facilitating M2-like macrophage polarization that, in turn, promotes tumor dissemination. PUFA enriched magligant ascites microenvironment promote macrophage lipid oxidative phosphorylation and supression RhoA-GTPase-Yap1 axis. Genetic ablation Yap1 in macrophage exhibited M2-like polarization and enhanced ovrian tumor dissemination. Pharmacology inhibit Mst1/2 could rescue M2-like TAM polarization in MAM and alter the lipid oxidation of macrophages in MAM, more importantly, inhibit ovarian metastatic properties. Through comparasion primary TAM (P-TAM) and metastasis TAM (M-TAM), we proved that Hippo-Yap1 siganl results M-TAM with high M2/M1 ratio. These findings implicate critical functions of PUFA modulate RhoA-Hippo axis in facility TAM polarization and also suggest manipulation of PUFA metabolism or RhoA-Hippo siganl as a therapeutic strategy aganist EOC metastasis.
2024-05-01 | GSE175552 | GEO
Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late onset ALS. Although ALS results from MN’s death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a FUSR521H or a FUSP525L mutation and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette as described previously in our lab. Mutant and control iPSC differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Subsequent lipidomics studies demonstrated defects in myelin lipids, with a reduction of phospholipids in mutant OPCs. Among them, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most two abundant phospholipid in mammalian cells and regulate the mitochondria-associated ER membrane (MAM) integrity. Interestingly, FUSR521H mutant OPCs displayed a decrease in the PC/PE ratio, known to be associated with maintaining membrane (mitochondria) integrity. Proximity ligation assay further indicated that MAM was diminished in mutant OPCs. Moreover, mutant OPCs displayed stronger activation of unfolded protein response markers, a hallmark of increased susceptibility to endoplasmic reticulum (ER) stress, when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate that FUS mutant OPCs display defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and suppressed physiological Ca2+ signaling events.
2024-01-01 | GSE239403 | GEO
Project description:The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-mitochondria contact sites (ERMCS) serves as a platform for several critical cellular processes, in particular lipid synthesis. Enzymes involved in lipid biosynthesis are enriched at contacts and membrane lipid composition at contacts is distinct relative to surrounding membranes. How contacts are remodeled and the subsequent biological consequences of altered contacts such as perturbed lipid metabolism remains poorly understood. Here we investigate if the ER-tethered ubiquitin-X domain adaptor 8 (UBXD8) regulates the lipids found in mitochondria-associated membranes (MAM). LC-MS/MS lipidomics found significant changes in distinct lipid species in the MAM fraction of UBXD8 knockout cells. Our results suggest that lipids in MAM are regulated by UBXD8.
2023-01-01 | ST002422 | MetabolomicsWorkbench
Project description:The mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) is the physical contact site between the ER and the mitochondria and plays a vital role in the regulation of calcium trafficking and bioenergetics. Previous studies suggest that disturbances in calcium trafficking and dysregulation of reactive oxygen species in the ER and mitochondria may contribute to the pathogenesis of diabetic retinopathy (DR). However, few studies have examined the impact of diabetes on the retinal MAM proteome profile. In the present study, we used Long Evans rats with streptozotocin-induced long-term Type 1 diabetes to identify key pathways and proteins in the retinal MAM that are potentially implicated in the pathogenesis of DR.
2022-10-15 | PXD033040 | Pride
Project description:Purpose: MetS consist of five risk factors: elevated blood pressure and fasting glucose, visceral obesity, dyslipidemia and hypercholesterinemia. The physiological impact of lipid metabolism indicated as visceral obesity and hepatic lipid accumulation is still under debate. One major cause of disturbed lipid metabolism might be dysfunction of cellular organelles controlling energy homeostasis, i.e. mitochondria and peroxisomes. Experimental design: The New Zealand Obese (NZO) mouse model exhibits a polygenic syndrome of obesity, insulin resistance, triglyceridemia and hypercholesterolemia that resembles human metabolic syndrome. We applied a combinatorial approach of lipidomics with liver transcriptomics, 2D-DIGETM and mass spectroscopy based organelle proteomics of highly purified mitochondria and peroxisomes in male mice, to investigate molecular mechanisms related to the impact of lipid metabolism in the pathophysiology of the metabolic syndrome. Conclusions and clinical relevance: Proteome analyses of liver organelles indicated differences in fatty acid metabolism, oxidative stress and response, mainly influenced by PG-C1α/PPARα mediated pathways. These results were in accordance with serum lipid profiles and elevated organelle functionality. These data emphasize that metabolic syndrome is accompanied with increased mitochondria and peroxisomal activity controlling directly cellular energy homeostasis to cope with dyslipidemia and hypercholesterinemia driven hepatic lipid overflow in developing a fatty liver.
2017-11-01 | GSE95489 | GEO
Project description:A better understanding of the molecular mechanisms underlying the development and progression of diabetic neuropathy (DN) is essential for the design of mechanism-based therapies. We examined changes in global gene expression to define pathways regulated by diabetes in peripheral nerve. Microarray data for 24 week-old BKS db/db and db/+ mouse sciatic nerve were analyzed to define significantly differentially expressed genes (DEGs); DEGs were further used for functional enrichment analysis and network analysis to identify biological processes and pathways differentially regulated in the db/db nerve. Expression profile clustering was performed to identify co-expressed DEGs. A set of co-expressed lipid metabolism genes was used for promoter sequence analysis.We identified 4,017 DEGs; 2,122 genes were up-regulated and 1,895 genes were down-regulated in the db/db relative to the db+ samples. Over-represented biological processes identified by the functional enrichment analysis include cell cycle, lipid metabolic process, lipid transport, carbohydrate metabolic process, response to stress, apoptosis, axonogenesis and cell adhesion. Pathways regulated in the db/db nerve include lipid metabolism, carbohydrate metabolism, energy metabolism, PPAR signaling, apoptosis, and axon guidance. The majority of DEGs in the glycolysis, TCA cycle, oxidative phosphorylation, fatty acid metabolism, glycerolipid metabolism, mitochondrial fatty acid elongation, lipid transport, adipocytokine signaling, PPAR signaling, and apoptosis pathways are up-regulated, whereas most of the axonogenesis-related genes are down-regulated in db/db nerve. A network of DEGs based on their co-citation in literature identified regulatory relationship between Tnf-α and key genes from the regulated pathways. Promoter sequence analysis identified over-represented transcription factor binding site (TFBS) motifs in the promoter regions of twenty two co-expressed lipid metabolism-related genes suggesting coordinated regulation of these genes by multiple transcription factors (TF). Furthermore, TF binding to these TFBS and differentially regulated in our data are annotated with nervous system development and immune response suggesting possible co-regulation of lipid metabolism, nervous system development and stress response genes. Gene expression changes in our data are consistent with pathological characteristics observed in DN including axon degeneration and demyelination, and support existing hypotheses regarding hyperglycemia mediated nerve damage in DN. Our findings support the role of hyperglycemia-induced oxidative stress and ischemia in nerve injury. Our results also support the hypothesis of oxidized lipid-mediated nerve injury and increased mitochondrial oxidative stress in dyslipidemia. Moreover, our analyses revealed a possible co-regulation mechanism connecting hyperlipidemia, stress response and axonal degeneration.
2011-02-18 | GSE27382 | GEO