scholarly journals STEM-26. ALTERED LIPID METABOLISM MARKS GLIOBLASTOMA STEM AND NON-STEM CELLS IN SEPARATE TUMOR NICHES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi239-vi239
Author(s):  
Lisa Wallace ◽  
Anthony Gromovsky ◽  
James Hale ◽  
Arnon Knudsen ◽  
Briana Prager ◽  
...  
Keyword(s):  
Stem Cells ◽  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Neutral Lipids ◽  
Cell Populations ◽  
Lower Grade ◽  
High Lipid ◽  
Lipid Species ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

Abstract Clinical glioblastoma is marked by a strikingly heterogeneous mix of cell types, cellular metabolisms, and cellular microenvironments spread in different spatial locations throughout a tumor. We have created 3-dimensional organoid models that partially mimic the transition zone between nutrient-rich cellular tumor regions and nutrient-poor psuedopallisading and perinecrotic tumor zones. We found a dramatic disparity in lipid droplet presence between these regions with high lipid accumulation in the hypoxic organoid cores of a wide spectrum of patient derived specimens. This is accompanied by regionally restricted upregulation of HILPDA gene expression in the cores of our models, in clinical GBM specimens but not lower grade brain tumors, and localized specifically to pseudopallisading regions of patient tumors. We further show that lipid droplet accumulation overall marks perinecrotic and pseudopallisading regions in clinical GBM, indicating broadly altered lipid metabolism between these distinct cell populations. High lipid droplet accumulation is largely restricted to the non-stem cell populations of GBM organoids and sorted xenograft tumors whereas the stem cells are lipid-poor, suggesting lipid levels may not be simply a product of the microenvironment but also may be a reflection of cell state. We performed global lipidomic analysis on prospectively sorted stem and non-stem cells of multiple patient-derived models and found that GBM stem cells have comparatively decreased levels of neutral lipids, indicating a significant metabolic shift compared to non-stem cells from the same patient. Conversely, GBM stem cells have significantly increased levels of rare specific lipid species, and also display altered phospholipid synthesis and species specific alterations in phospholipid classes. Our findings suggest avenues for therapy by targeting the altered lipid metabolic pathways of these disparate tumor cell populations.

scholarly journals Altered lipid metabolism marks glioblastoma stem and non-stem cells in separate tumor niches

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Sajina Shakya ◽  
Anthony D. Gromovsky ◽  
James S. Hale ◽  
Arnon M. Knudsen ◽  
Briana Prager ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Lipid Droplet ◽  
Striking Difference ◽  
Significant Shift ◽  
Lower Grade ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

AbstractGlioblastoma (GBM) displays marked cellular and metabolic heterogeneity that varies among cellular microenvironments within a tumor. Metabolic targeting has long been advocated as a therapy against many tumors including GBM, but how lipid metabolism is altered to suit different microenvironmental conditions and whether cancer stem cells (CSCs) have altered lipid metabolism are outstanding questions in the field. We interrogated gene expression in separate microenvironments of GBM organoid models that mimic the transition between nutrient-rich and nutrient-poor pseudopalisading/perinecrotic tumor zones using spatial-capture RNA-sequencing. We revealed a striking difference in lipid processing gene expression and total lipid content between diverse cell populations from the same patient, with lipid enrichment in hypoxic organoid cores and also in perinecrotic and pseudopalisading regions of primary patient tumors. This was accompanied by regionally restricted upregulation of hypoxia-inducible lipid droplet-associated (HILPDA) gene expression in organoid cores and pseudopalisading regions of clinical GBM specimens, but not lower-grade brain tumors. CSCs have low lipid droplet accumulation compared to non-CSCs in organoid models and xenograft tumors, and prospectively sorted lipid-low GBM cells are functionally enriched for stem cell activity. Targeted lipidomic analysis of multiple patient-derived models revealed a significant shift in lipid metabolism between GBM CSCs and non-CSCs, suggesting that lipid levels may not be simply a product of the microenvironment but also may be a reflection of cellular state. CSCs had decreased levels of major classes of neutral lipids compared to non-CSCs, but had significantly increased polyunsaturated fatty acid production due to high fatty acid desaturase (FADS1/2) expression which was essential to maintain CSC viability and self-renewal. Our data demonstrate spatially and hierarchically distinct lipid metabolism phenotypes occur clinically in the majority of patients, can be recapitulated in laboratory models, and may represent therapeutic targets for GBM.

scholarly journals Altered lipid metabolism marks glioblastoma stem and non-stem cells in separate tumor niches

2020 ◽  
Author(s):  
Sajina Shakya ◽  
Anthony D. Gromovsky ◽  
James S. Hale ◽  
Arnon M. Knudsen ◽  
Briana Prager ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Cancer Stem Cells ◽  
Lipid Content ◽  
Cell Populations ◽  
Lipidomic Analysis ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

AbstractBackgroundGlioblastoma (GBM) is marked by cellular heterogeneity, including metabolic heterogeneity, that varies among cellular microenvironments in the same tumor. Altered cellular metabolism in cancer is well-established, but how lipid metabolism is altered to suit different microenvironmental conditions and cellular states within a tumor remains unexplored.MethodsWe assessed GBM organoid models that mimic the transition zone between nutrient-rich and nutrient-poor pseudopalisading/perinecrotic tumor zones and performed spatial RNA-sequencing of cells to interrogate lipid metabolism. Using targeted lipidomic analysis, we assessed differences in acutely enriched cancer stem cells (CSCs) and non-CSCs from multiple patient-derived models to explore the link between the stem cell state and lipid metabolism.ResultsSpatial analysis revealed a striking difference in lipid content between microenvironments, with lipid enrichment in the hypoxic organoid cores and the perinecrotic and pseudopalisading regions of primary patient tumors. This was accompanied by regionally restricted upregulation of hypoxia-inducible lipid droplet-associated (HILPDA) gene expression in organoid cores and in clinical GBM specimens, but not lower-grade brain tumors, that was specifically localized to pseudopalisading regions of patient tumors. CSCs have low lipid droplet accumulation compared to non-CSCs in organoid models and xenograft tumors, and prospectively sorted lipid-low GBM cells are functionally enriched for stem cell activity. Targeted lipidomic analysis revealed that CSCs had decreased levels of major classes of neutral lipids compared to non-CSCs but had significantly increased polyunsaturated fatty acid production due to high fatty acid desaturase (FADS1/2) expression.ConclusionsOur data demonstrate that lipid metabolism is differentially altered across GBM microenvironments and cellular hierarchies, providing guidance for targeting of these altered lipid metabolic pathways.Key pointsGBM cells in nutrient-poor tumor regions have increased accumulation of lipid droplets.CSCs have reduced lipid content compared to non-CSCs.GBM CSCs and non-CSCs have disparate lipid metabolisms that may be uniquely targetable.Importance of the StudyMetabolic targeting has long been advocated as a therapy against many tumors including GBM, and it remains an outstanding question whether cancer stem cells (CSCs) have altered lipid metabolism. We demonstrated striking differences in lipid metabolism between diverse cell populations from the same patient. These spatially and phenotypically distinct lipid phenotypes occur clinically in the majority of patients and can be recapitulated in laboratory models. Lipidomic analysis of multiple patient-derived models shows a significant shift in lipid metabolism between GBM CSCs and non-CSCs, suggesting that lipid levels may not be simply a product of the microenvironment but also may be a reflection of cellular state. Our results suggest that therapeutic targeting of GBM lipid metabolism must consider multiple separate tumor cell populations to be effective, and we provide a methodologic framework for studying these metabolically diverse cellular populations.

Integrated Metabolomics and Transcriptomics Analyses Reveal Altered Lipid Metabolism in Mouse Placentas Exposed to Alcohol

Placenta ◽  
2021 ◽  
Vol 112 ◽  
pp. e33
Author(s):  
Sze Ting (Cecilia) Kwan ◽  
Manjot Virdee ◽  
Nipun Saini ◽  
Kaylee Helfrich ◽  
Susan Smith
Keyword(s):  
Lipid Metabolism ◽  
Altered Lipid Metabolism ◽  
Altered Lipid ◽  
Integrated Metabolomics

The Decline of the Immune Response during Aging: the Role of an Altered Lipid Metabolism

1991 ◽  
Vol 621 (1 Physiological) ◽  
pp. 277-290 ◽  
Author(s):  
GEORG WICK ◽  
LUKAS A. HUBER ◽  
XU QING-BO ◽  
ELMAR JAROSCH ◽  
DIETHER SCHÖNITZER ◽  
...  
Keyword(s):  
Immune Response ◽  
Lipid Metabolism ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

Low carnitine intake and altered lipid metabolism in infants

1989 ◽  
Vol 49 (4) ◽  
pp. 624-628 ◽  
Author(s):  
A L Olson ◽  
S E Nelson ◽  
C J Rebouche
Keyword(s):  
Lipid Metabolism ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

scholarly journals Lysophosphatidylcholine acyltransferase 1 is downregulated by hepatitis C virus: impact on production of lipo-viro-particles

Gut ◽  
2016 ◽  
Vol 66 (12) ◽  
pp. 2160-2169 ◽  
Author(s):  
Frauke Beilstein ◽  
Matthieu Lemasson ◽  
Véronique Pène ◽  
Dominique Rainteau ◽  
Sylvie Demignot ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Hepatic Steatosis ◽  
Liver Lipid ◽  
Very Low Density Lipoproteins ◽  
Viral Particles ◽  
Triacylglycerol Content ◽  
Liver Lipid Metabolism ◽  
Infectious Cycle ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

ObjectiveHCV is intimately linked with the liver lipid metabolism, devoted to the efflux of triacylglycerols stored in lipid droplets (LDs) in the form of triacylglycerol-rich very-low-density lipoproteins (VLDLs): (i) the most infectious HCV particles are those of lowest density due to association with triacylglycerol-rich lipoproteins and (ii) HCV-infected patients frequently develop hepatic steatosis (increased triacylglycerol storage). The recent identification of lysophosphatidylcholine acyltransferase 1 (LPCAT1) as an LD phospholipid-remodelling enzyme prompted us to investigate its role in liver lipid metabolism and HCV infectious cycle.DesignHuh-7.5.1 cells and primary human hepatocytes (PHHs) were infected with JFH1-HCV. LPCAT1 depletion was achieved by RNA interference. Cells were monitored for LPCAT1 expression, lipid metabolism and HCV production and infectivity. The density of viral particles was assessed by isopycnic ultracentrifugation.ResultsUpon HCV infection, both Huh-7.5.1 cells and PHH had decreased levels of LPCAT1 transcript and protein, consistent with transcriptional downregulation. LPCAT1 depletion in either naive or infected Huh-7.5.1 cells resulted in altered lipid metabolism characterised by LD remodelling, increased triacylglycerol storage and increased secretion of VLDL. In infected Huh-7.5.1 cells or PHH, LPCAT1 depletion increased production of the viral particles of lowest density and highest infectivity.ConclusionsWe have identified LPCAT1 as a modulator of liver lipid metabolism downregulated by HCV, which appears as a viral strategy to increase the triacylglycerol content and hence infectivity of viral particles. Targeting this metabolic pathway may represent an attractive therapeutic approach to reduce both the viral titre and hepatic steatosis.

Metabolomics Reveals Altered Lipid Metabolism in a Mouse Model of Endometriosis

2016 ◽  
Vol 15 (8) ◽  
pp. 2626-2633 ◽  
Author(s):  
Mainak Dutta ◽  
Mallappa Anitha ◽  
Philip B. Smith ◽  
Christopher R. Chiaro ◽  
Meenu Maan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mouse Model ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

scholarly journals Nootkatone, a Dietary Fragrant Bioactive Compound, Attenuates Dyslipidemia and Intramyocardial Lipid Accumulation and Favorably Alters Lipid Metabolism in a Rat Model of Myocardial Injury: An In Vivo and In Vitro Study

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5656
Author(s):  
M.F. Nagoor Meeran ◽  
Sheikh Azimullah ◽  
M Marzouq Al Ahbabi ◽  
Niraj Kumar Jha ◽  
Vinoth-Kumar Lakshmanan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Rat Model ◽  
Lipid Accumulation ◽  
Heart Diseases ◽  
Radical Scavenging ◽  
Enzymatic Antioxidants ◽  
Protective Effects ◽  
Altered Lipid Metabolism ◽  
Altered Lipid

In the present study, we assessed whether nootkatone (NKT), a sesquiterpene in edible plants, can provide protection against dyslipidemia, intramyocardial lipid accumulation, and altered lipid metabolism in a rat model of myocardial infarction (MI) induced by subcutaneous injections of isoproterenol (ISO, 85 mg/kg) on days 9 and 10. The rats were pre- and co-treated with NKT (10 mg/kg, p.o.) administered daily for 11 days. A significant reduction in the activities of myocardial creatine kinase and lactate dehydrogenase, as well as non-enzymatic antioxidants, and alterations in lipids and lipoproteins, along with a rise in plasma lipid peroxidation and intramyocardial lipid accumulation, were observed in ISO-treated rats. ISO administration induced alterations in the activities of enzymes/expressions that played a significant role in altering lipid metabolism. However, NKT treatment favorably modulated all biochemical and molecular parameters altered by ISO and showed protective effects against oxidative stress, dyslipidemia, and altered lipid metabolism, attributed to its free-radical-scavenging and antihyperlipidemic activities in rats with ISO-induced MI. Additionally, NKT decreased the accumulation of lipids in the myocardium as evidenced from Oil red O staining. Furthermore, the in vitro observations demonstrate the potent antioxidant property of NKT. The present study findings are suggestive of the protective effects of NKT on dyslipidemia and the underlying mechanisms. Based on our findings, it can be suggested that NKT or plants rich in NKT can be promising for use as a phytopharmaceutical or nutraceutical in protecting the heart and correcting lipid abnormalities and dyslipidemia, which are risk factors for ischemic heart diseases.

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