scholarly journals Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

2010 ◽  
Vol 52 (3) ◽  
pp. 419-434 ◽  
Author(s):  
Roman Chrast ◽  
Gesine Saher ◽  
Klaus-Armin Nave ◽  
Mark H. G. Verheijen
Keyword(s):  
Lipid Metabolism ◽  
Mouse Models ◽  
Glial Cells ◽  
Inherited Disorders

Inherited Disorders of Complex Lipid Metabolism: A Clinical Review

2021 ◽  
Author(s):  
Changrui Xiao ◽  
Francis Rossignol ◽  
Frédéric M. Vaz ◽  
Carlos R. Ferreira
Keyword(s):  
Lipid Metabolism ◽  
Clinical Review ◽  
Inherited Disorders ◽  
Complex Lipid

scholarly journals PTRF/Cavin1 remodels phospholipid metabolism to promote tumor proliferation and suppress immune responses in glioblastoma by stabilizing cPLA2

2020 ◽  
Author(s):  
Kaikai Yi ◽  
Qi Zhan ◽  
Qixue Wang ◽  
Yanli Tan ◽  
Chuan Fang ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Immune Responses ◽  
Molecular Mechanism ◽  
Mouse Models ◽  
Phospholipid Composition ◽  
Tumor Infiltrating Lymphocytes ◽  
Intracranial Tumor ◽  
Tumor Proliferation

Abstract Background Metabolism remodeling is a hallmark of glioblastoma (GBM) that regulates tumor proliferation and the immune microenvironment. Previous studies have reported that increased polymerase 1 and transcript release factor (PTRF) levels are associated with a worse prognosis in glioma patients. However, the biological role and the molecular mechanism of PTRF in GBM metabolism remain unclear. Methods The relationship between PTRF and lipid metabolism in GBM was detected by non-targeted metabolomics profiling and subsequent lipidomics analysis. Western blotting, qRT-PCR, and immunoprecipitation were conducted to explore the molecular mechanism of PTRF in lipid metabolism. A sequence of in vitro and in vivo experiments (both xenograft tumor and intracranial tumor mouse models) were used to detect the tumor-specific impacts of PTRF. Results Here, we show that PTRF triggers a cytoplasmic phospholipase A2 (cPLA2)-mediated phospholipid remodeling pathway that promotes GBM tumor proliferation and suppresses tumor immune responses. Research in primary cell lines from GBM patients revealed that cells overexpressing PTRF show increased cPLA2 activity —resulting from increased protein stability —and exhibit remodeled phospholipid composition. Subsequent experiments revealed that PTRF overexpression alters the endocytosis capacity and energy metabolism of GBM cells. Finally, in GBM xenograft and intracranial tumor mouse models, we showed that inhibiting cPLA2 activity blocks tumor proliferation and prevents PTRF-induced reduction in CD8 + tumor-infiltrating lymphocytes. Conclusions The PTRF-cPLA2 lipid remodeling pathway promotes tumor proliferation and suppresses immune responses in GBM. In addition, our findings highlight multiple new therapeutic targets for GBM.

The Direct Interactions with Bone Marrow Microenvironment Confer Resistance to the Inhibition of Oxidative Phosphorylation in AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Yoko Tabe ◽  
Kaori Saito ◽  
Kotoko Yamatani ◽  
Haeun Yang ◽  
Rodrigo Jacamo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Mouse Models ◽  
Stromal Cells ◽  
Research Funding ◽  
Ldl Receptor ◽  
Leukemia Cells ◽  
Related Protein ◽  
Resistant Mouse ◽  
Argininosuccinate Synthase

Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival and continually adapt to the bone marrow (BM) microenvironment. We investigated how the BM microenvironment impacts the response to energy-depriving OxPhos inhibition in AML using a novel complex I OxPhos inhibitor (OxPhosi), IACS-010759. We have reported that OxPhosi-resistant primary AML samples demonstrated higher baseline transcription of genes related to cell adhesion, integrin and/or Rho GTPase family genes that modulate intracellular actin dynamics. (Yang et al. ASH 2019) In this study, we performed Cap Analysis of Gene Expression (CAGE) transcriptome analyses using IACS-010759-sensitive and -resistant AML PDXs. CAGE identifies and quantifies the 5' ends of capped mRNA transcripts (= transcription start sites) and allows investigating promoter structures necessary for gene expression. Primary AML cells from 9 AML PDXs were injected into irradiated NSG mice, which were randomized upon documented engraftment to receive IACS-010759 or vehicle (n = 3/group). The antileukemia efficacy of the treatment was monitored by serial measurements of circulating AML cells. Of the 9 models tested, we defined 4 PDXs as sensitive and 5 as resistant to OxPhos inhibitor therapy. In the resistant models, CAGE analysis of OxPhosi-induced changes (comparing pretreatment with posttreatment) identified upregulation of 77 promoters and downregulation of 207 promoters (log 2-fold change > 3.0, FDR < 0.05, EdgeR), including increased promoter expression (>3.0 fold) of genes associated with adhesion (CCR8,ADGRB2, LAG3, BMF, ATN1, PLXDC1), migration (CCR8, NKX3-2, TMEM123, IGLV7-43, FAM171A1, LBX2, TRAV21, PPP2R5C, BMF, PLXDC1), and actin cytoskeleton dynamics (FAM171A1, BMF, BEST1, PLXDC1). Of note, the 6 adhesion-associated promoters that were upregulated by OxPhosi in 5 of the OxPhosi-resistant mouse models were unchanged or downregulated in the 4 OxPhosi-sensitive models. We then used DEGseq, an R package for identifying differentially expressed genes, to identify promoters whose expression was different between OxPhosi-treated and vehicle-treated groups in the OxPhosi-resistant mouse models. DEGseq detected consistent changes of 214 upregulated and 626 downregulated promoters with OxPhosi treatment in all 5 mouse models. KEGG pathway enrichment analysis was performed with these consistently changed genes and revealed that OxPhos inhibitor treatment significantly upregulated the transcripts of cell adhesion pathway. We then confirmed that BM derived mesenchymal stem cells (MSC) protected OxPhosi-sensitive OCI-AML3 cells; the IC50 of IACS-010759 under MSC coculture was 80-fold higher than in monoculture conditions (IC50; 0.04 nM in monoculture vs. 3.25 nM in coculture), and IACS-010759 (10nM) induced 55% reduction of viable cells in coculture condition as compared to 70% reduction in monoculture. We further observed that OCI-AML3 cells adhered to MSCs were more profoundly protected from OxPhosi induced apoptosis than nonadherent cells. These results indicate that BM stromal cells, in particular those in direct contact with leukemia cells, play a key role in the microenvironment-mediated protection of AML cells from metabolic stress caused by OxPhos blockade. We further observed promoter upregulation of ASS1, coding Argininosuccinate Synthase 1 and of LRP1, coding LDL Receptor Related Protein 1. Argininosuccinate Synthase 1 is an epigenetically regulated key enzyme in the biosynthesis of arginine and energy starvation that induces adaptive transcriptional upregulation of ASS1. LDL Receptor Related Protein 1 plays a major role in lipid metabolism and has been reported to be responsible for hemin-induced autophagy in leukemia cells. These might contribute to intrinsic AML resistance to OxPhosi via activation of compensatory metabolic pathways, amino acid metabolism and lipid metabolism. Taken together, our data highlight the importance of direct interaction with BM stromal cells as well as complementally modification of amino acid- and lipid metabolism for the resistance of AML cells to OxPhos inhibition. While the mechanisms of stroma-leukemia interactions are likely complex, reducing the adhesion of AML cells to nurturing stromal cells ameliorates the resistance to the metabolic and energetic consequences of OxPhos inhibition. Disclosures Andreeff: Amgen: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding. Konopleva:Rafael Pharmaceutical: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Sanofi: Research Funding; AstraZeneca: Research Funding; Cellectis: Research Funding; AbbVie: Consultancy, Research Funding; Ablynx: Research Funding; Agios: Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Calithera: Research Funding.

scholarly journals Disordered Lipid Metabolism and the Pathogenesis of Insulin Resistance

2007 ◽  
Vol 87 (2) ◽  
pp. 507-520 ◽  
Author(s):  
David B. Savage ◽  
Kitt Falk Petersen ◽  
Gerald I. Shulman
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Lipid Metabolism ◽  
Mouse Models ◽  
Human Studies ◽  
Resonance Spectroscopy ◽  
Abnormal Glucose Metabolism ◽  
Mechanistic Insight

Although abnormal glucose metabolism defines type 2 diabetes mellitus (T2DM) and accounts for many of its symptoms and complications, efforts to understand the pathogenesis of T2DM are increasingly focused on disordered lipid metabolism. Here we review recent human studies exploring the mechanistic links between disorders of fatty acid/lipid metabolism and insulin resistance. As “mouse models of insulin resistance” were comprehensively reviewed in Physiological Reviews by Nandi et al. in 2004, we will concentrate on human studies involving the use of isotopes and/or magnetic resonance spectroscopy, occasionally drawing on mouse models which provide additional mechanistic insight.

scholarly journals Neuroinflammation in Parkinson's Disease and Related Disorders: A Lesson from Genetically Manipulated Mouse Models ofα-Synucleinopathies

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Kazunari Sekiyama ◽  
Shuei Sugama ◽  
Masayo Fujita ◽  
Akio Sekigawa ◽  
Yoshiki Takamatsu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Glial Cells ◽  
Genetic Modification ◽  
Early Stage ◽  
Related Model ◽  
Genetically Manipulated

Neuroinflammation in Parkinson's disease (PD) is a chronic process that is associated with alteration of glial cells, including astrocytes and microglia. However, the precise mechanisms remain obscure. To better understand neuroinflammation in PD, we focused on glial activation inα-synuclein (αS) transgenic and related model mice. In the majority ofαS transgenic mice, astrogliosis was observed concomitantly with accumulation ofαS during the early stage of neurodegeneration. However, microglia were not extensively activated unless the mice were treated with lipopolysaccharides or through further genetic modification of other molecules, including familial PD risk factors. Thus, the results inαS transgenic mice and related model mice are consistent with the idea that neuroinflammation in PD is a double-edged sword that is protective in the early stage of neurodegeneration but becomes detrimental with disease progression.

Effect of physical exercise on brain and lipid metabolism in mouse models of multiple sclerosis

2017 ◽  
Vol 207 ◽  
pp. 127-134 ◽  
Author(s):  
Léo Houdebine ◽  
Cristina Anna Gallelli ◽  
Marialetizia Rastelli ◽  
Nirmal Kumar Sampathkumar ◽  
Julien Grenier
Keyword(s):  
Multiple Sclerosis ◽  
Lipid Metabolism ◽  
Physical Exercise ◽  
Mouse Models

scholarly journals Split-ends is modulating lipid droplet content in adult Drosophila glial cells and is protective against paraquat toxicity

2020 ◽  
Author(s):  
Victor Girard ◽  
Valérie Goubard ◽  
Matthieu Querenet ◽  
Laurent Seugnet ◽  
Laurent Pays ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Glial Cells ◽  
Lipid Droplets ◽  
Notch Pathway ◽  
Mrna Levels ◽  
Data Mining Approach ◽  
Paraquat Toxicity ◽  
Human Ortholog ◽  
And Storage ◽  
Adult Drosophila

ABSTRACTGlial cells are early sensors of neuronal injury and are able to store lipids in lipid droplets under oxidative stress conditions. Here, we investigated the glial functions of Spen in the context of Parkinson’s disease (PD). Using a data mining approach, we first found that the human ortholog of spen, SPEN/SHARP belongs to the set of astrocyte-expressed genes which mRNA levels are significantly different in the substantia nigra of PD patients as compared to controls. Interestingly, the retrieved list of differentially expressed genes was enriched in genes involved in lipid metabolism. In a Drosophila model of PD, we observed that spen mutant flies were more sensitive to paraquat intoxication. Moreover, the glia-restricted knockdown of spen led to the expansion and the accumulation of lipid droplets as well as the inhibition of Notch pathway. Taken together our results show that Spen regulates lipid metabolism and storage in glial cells and by these means contribute to glia-mediated functions in the context of neurodegeneration.

scholarly journals Adipokinome Signatures in Obese Mouse Models Reflect Adipose Tissue Health and Are Associated with Serum Lipid Composition

2019 ◽  
Vol 20 (10) ◽  
pp. 2559 ◽  
Author(s):  
Birgit Knebel ◽  
Pia Fahlbusch ◽  
Gereon Poschmann ◽  
Matthias Dille ◽  
Natalie Wahlers ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Mouse Models ◽  
Serum Lipid ◽  
De Novo Lipogenesis ◽  
Whole Body ◽  
Obese Mouse ◽  
Obese People ◽  
Obob Mice ◽  
The Impact

Adipocyte and hepatic lipid metabolism govern whole-body metabolic homeostasis, whereas a disbalance of de novo lipogenesis (DNL) in fat and liver might lead to obesity, with severe co-morbidities. Nevertheless, some obese people are metabolically healthy, but the “protective” mechanisms are not yet known in detail. Especially, the adipocyte-derived molecular mediators that indicate adipose functionality are poorly understood. We studied transgenic mice (alb-SREBP-1c) with a “healthy” obese phenotype, and obob mice with hyperphagia-induced “sick” obesity to analyze the impact of the tissue-specific DNL on the secreted proteins, i.e., the adipokinome, of the primary adipose cells by label-free proteomics. Compared to the control mice, adipose DNL is reduced in both obese mouse models. In contrast, the hepatic DNL is reduced in obob but elevated in alb-SREBP-1c mice. To investigate the relationship between lipid metabolism and adipokinomes, we formulated the “liver-to-adipose-tissue DNL” ratio. Knowledge-based analyses of these results revealed adipocyte functionality with proteins, which was involved in tissue remodeling or metabolism in the alb-SREBP-1c mice and in the control mice, but mainly in fibrosis in the obob mice. The adipokinome in “healthy” obesity is similar to that in a normal condition, but it differs from that in “sick” obesity, whereas the serum lipid patterns reflect the “liver-to-adipose-tissue DNL” ratio and are associated with the adipokinome signature.

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