Fatty Acid Synthesis in Glial Cells of the CNS

Corrales, Aida V. Garcia; Haidar, Mansour; Bogie, Jeroen F. J.; Hendriks, Jerome J. A.

doi:10.3390/ijms22158159

Cited by 35 publications

(28 citation statements)

References 159 publications

(177 reference statements)

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“…Defining the effects of FASN blockade on the glioma microenvironment is important because fatty acid metabolism is a physiologic pathway that involves interactions between multiple cell types that reside in the same habitat. In non-neoplastic brain tissue, fatty acids are synthesized by astrocytes and are distributed to other cells including neurons and oligodendrocytes [28], where they drive physiologic and cellular functions like neuronal maturation, membrane synthesis [29], and neuroprotection [30]. We thus hypothesized blocking fatty acid synthesis pathway would interfere with the cells that make up tissue state B and/or their interactions, and therefore would lead to depletion of tissue state B signature in glioblastoma infiltrated brain.…”

Section: Resultsmentioning

confidence: 99%

Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states

Al‐Dalahmah

Argenziano

Boyett

et al. 2021

Preprint

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Glioblastoma is an aggressive diffusely infiltrating neoplasm that spreads beyond surgical resection margins, where it intermingles with non-neoplastic brain cells. This complex tissue harboring infiltrating glioma and non-neoplastic brain cells is the origin of tumor recurrence. Thus, understanding the cellular and molecular features of the glioma margin is therapeutically and prognostically important. Here, we used single-nucleus RNA sequencing (snRNAseq) of primary and recurrent glioma to define compositional tissue-states that correlate with radiographic and histopathologic features. We found that glioma cells can be clustered into proliferative, astrocyte-like/mesenchymal, and progenitor-like/proneural states in both the primary and post-treatment recurrence settings. We focused on non-neoplastic microenvironment cells including oligodendrocytes, myeloid cells, neurons, and astrocytes - the latter two are under-represented in single-cell RNAseq studies. Cell type-specific signatures of the astrocyte-like/mesenchymal glioma, and a subpopulation of non-neoplastic astrocytes correlated with poor prognosis, the latter correlated with glioma recurrence. Notably, astrocytes were enriched for metabolic and neurodegenerative gene signatures. Leveraging snRNAseq-derived compositional information, we define three tissue-states that correlate with radiographic localization of primary and recurrent glioma. Our findings define a compositional approach to the glioma microenvironment and reveal prognostically and anatomically relevant features paving the way to new mechanistic and therapeutic discoveries.

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Section: Resultsmentioning

confidence: 99%

Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states

Al‐Dalahmah

Argenziano

Boyett

et al. 2021

Preprint

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“…“Saturated” indicates no double bond formation, “monounsaturated” indicates a single double bond in the FA carbon chain (termed MUFAs), and “polyunsaturated” indicates multiple double bonds in the FA carbon chain (i.e., PUFAs). Saturated FAs and MUFAs can be synthesized de novo in the CNS ( 23 ), whereas PUFAs cannot be synthesized de novo without initial dietary uptake ( 24 ). The PUFAs α-linolenic acid and linolenic acid must be initially obtained from the diet, and are thus considered “essential” fatty acids ( 25 ).…”

Section: Fa Metabolism In the Cnsmentioning

confidence: 99%

Targeting fatty acid metabolism in glioblastoma

Miska¹,

Chandel²

2023

Journal of Clinical Investigation

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Glioblastoma (GBM) is a primary tumor of the brain defined by its uniform lethality and resistance to conventional therapies. There have been considerable efforts to untangle the metabolic underpinnings of this disease to find novel therapeutic avenues for treatment. An emerging focus in this field is fatty acid (FA) metabolism, which is critical for numerous diverse biological processes involved in GBM pathogenesis. These processes can be classified into four broad fates: anabolism, catabolism, regulation of ferroptosis, and the generation of signaling molecules. Each fate provides a unique perspective by which we can inspect GBM biology and gives us a road map to understanding this complicated field. This Review discusses the basic, translational, and clinical insights into each of these fates to provide a contemporary understanding of FA biology in GBM. It is clear, based on the literature, that there are far more questions than answers in the field of FA metabolism in GBM, and substantial efforts should be made to untangle these complex processes in this intractable disease.

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“…Astrocytes can synthesize lipids (even de novo) (e.g., FAs, cholesterol) and ketone bodies and can support neurons. De novo synthesized FAs (e.g., oleic acid, docosahexaenoic acid, arachidonic acid) or FAs released from astrocytic membranes by phospholipase A 2 can enter neurons via FA transporters or via Apo particles ( Table 1 ) [ 94 , 95 , 96 ]. Astroglial-derived FAs are mostly used in neurons as building blocks of membranes, which promotes axonal growth and drives neuronal exocytosis, as recently reviewed [ 5 , 94 , 97 ].…”

Section: Lipid Droplets In Astrocytesmentioning

confidence: 99%

“…De novo synthesized FAs (e.g., oleic acid, docosahexaenoic acid, arachidonic acid) or FAs released from astrocytic membranes by phospholipase A 2 can enter neurons via FA transporters or via Apo particles ( Table 1 ) [ 94 , 95 , 96 ]. Astroglial-derived FAs are mostly used in neurons as building blocks of membranes, which promotes axonal growth and drives neuronal exocytosis, as recently reviewed [ 5 , 94 , 97 ]. Cholesterol, in the form of cholesterol-carrying lipoproteins unable to pass the blood–brain barrier, is primarily produced in the brain by astrocytes, then serving in synaptogenesis supporting neurons [ 98 ].…”

Section: Lipid Droplets In Astrocytesmentioning

confidence: 99%

Pathophysiology of Lipid Droplets in Neuroglia

2021

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In recent years, increasing evidence regarding the functional importance of lipid droplets (LDs), cytoplasmic storage organelles in the central nervous system (CNS), has emerged. Although not abundantly present in the CNS under normal conditions in adulthood, LDs accumulate in the CNS during development and aging, as well as in some neurologic disorders. LDs are actively involved in cellular lipid turnover and stress response. By regulating the storage of excess fatty acids, cholesterol, and ceramides in addition to their subsequent release in response to cell needs and/or environmental stressors, LDs are involved in energy production, in the synthesis of membranes and signaling molecules, and in the protection of cells against lipotoxicity and free radicals. Accumulation of LDs in the CNS appears predominantly in neuroglia (astrocytes, microglia, oligodendrocytes, ependymal cells), which provide trophic, metabolic, and immune support to neuronal networks. Here we review the most recent findings on the characteristics and functions of LDs in neuroglia, focusing on astrocytes, the key homeostasis-providing cells in the CNS. We discuss the molecular mechanisms affecting LD turnover in neuroglia under stress and how this may protect neural cell function. We also highlight the role (and potential contribution) of neuroglial LDs in aging and in neurologic disorders.

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Fatty Acid Synthesis in Glial Cells of the CNS

Cited by 35 publications

References 159 publications

Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states

Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states

Targeting fatty acid metabolism in glioblastoma

Pathophysiology of Lipid Droplets in Neuroglia

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