Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol

Cashikar, Anil G.; Toral-Ríos, Danira; Timm, David; Romero, Johnathan; Strickland, Michael R.; Long, Justin M.; Han, Xianlin; Holtzman, David M.; Paul, StevenM

doi:10.1016/j.jlr.2023.100350

Cited by 25 publications

(20 citation statements)

References 66 publications

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“…Accumulating evidence indicates that altered lipid metabolism is associated with reactive astrogliosis 29,30 . We recently reported that 25HC markedly suppresses cholesterol biosynthesis and increases cholesterol esterification as well as cholesterol efflux via ApoE lipoproteins in murine primary astrocytes 14 and suggests a possible role for 25HC in astroglial activation. Therefore, to evaluate how 25HC influences astrogliosis in vivo , we immunostained mouse brain sections for glial fibrillary acidic marker (GFAP) (Figure 4A).…”

Section: Resultsmentioning

confidence: 96%

“…Many microglial factors including cytokines (IL1α, TNF) as well as other secreted factors have been shown to mediate astrocyte activation 51,52 . We recently showed that 25HC can dramatically modulate lipid metabolism in astrocytes via its effects in inhibiting SREBP-mediated gene expression and stimulating LXRs 14 . Thus, it is possible that changes in astrocyte lipid metabolism due to 25HC secreted by microglia might play a role in astrocyte activation and/or function.…”

Section: Discussionmentioning

confidence: 99%

“…The cellular mechanisms by which 25HC regulates immune function appear to stem from its ability to strongly influence cholesterol metabolism, including suppression of cholesterol biosynthesis and enhancement of cholesterol esterification 13,14 . Recent studies have provided conflicting evidence about the function of CH25H in modulating inflammation, with some studies reporting greater pro-inflammatory cytokine release 5 and others finding less pro-inflammatory cytokine expression in Ch25h -deficient mice 12,16,17 .…”

Section: Introductionmentioning

confidence: 99%

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25-hydroxycholesterol mediates brain cytokine production and neutrophil infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation

Romero,

Toral-Rios,

et al. 2023

Preprint

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Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and in response to different inflammatory stimuli overexpress a proinflammatory signature of genes. Among these,Ch25his a gene overexpressed in brain tissue from Alzheimer’s disease as well as various mouse models of neuroinflammation.Ch25hencodes cholesterol 25-hydroxylase, an enzyme that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC, an immune-oxysterol primarily produced by activated microglia, is further metabolized to 7α,25-dihydroxycholesterol, which is a potent chemoattractant for leukocytes. We have also previously shown that 25HC increases production and secretion of the proinflammatory cytokine, IL-1β, by mouse microglia treated with lipopolysaccharide (LPS). In the present study, wildtype (WT) andCh25h-knockout (CKO) mice were peripherally administered LPS to induce an inflammatory state in the brain. In LPS-treatedWTmice,Ch25hexpression and 25HC levels increased in brain relative to vehicle-treatedWTmice. Interestingly, 25HC levels were significantly higher in LPS-treatedWTfemale compared to male mice. Activation of microglia and astrocytes in response to systemic LPS was suppressed inCKOmice relative toWTmice. Proinflammatory cytokine production and intra-parenchymal infiltration of neutrophils strongly correlated with brain 25HC levels and were significantly lower inCKOcompared toWTmice. Overall, our results show that 25HC mediates a sex-specific proinflammatory response in the brain characterized by activation of both microglia and astrocytes but also by neutrophil migration into the brain parenchyma presumably due to 7α,25-diHC produced from 25HC.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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25-hydroxycholesterol mediates brain cytokine production and neutrophil infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation

Romero,

Toral-Rios,

et al. 2023

Preprint

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“…As the strongest AD risk variant, ApoE4 is associated with higher Aβ plaque burden and more severe tau pathology in the postmortem brain, whereas the opposite effect was observed for ApoE2, a protective isoform [109][110][111]. Some mechanistic studies show that ApoE4 directly dysregulates the cholesterol pathway in different cell types, which further impairs myelination of oligodendrocytes [112], induces malfunction of astrocytes and microglia [113][114][115], and promotes pathogenesis of AD [111,116,117]. ApoE4 also affects sphingolipid metabolism [118] and LD storage [115,116,[119][120][121][122] to facilitate AD progression.…”

Section: Cholesterol In Admentioning

confidence: 99%

“…Some mechanistic studies show that ApoE4 directly dysregulates the cholesterol pathway in different cell types, which further impairs myelination of oligodendrocytes [112], induces malfunction of astrocytes and microglia [113][114][115], and promotes pathogenesis of AD [111,116,117]. ApoE4 also affects sphingolipid metabolism [118] and LD storage [115,116,[119][120][121][122] to facilitate AD progression. ApoJ, besides its direct involvement in lipid transport and metabolism, can bind to Aβ oligomers and interfere with Aβ aggregation, which further induces neurotoxicity with excess amounts of Aβ [123].…”

Section: Cholesterol In Admentioning

confidence: 99%

Brain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders

Zhao,

Zhang,

Sanders

et al. 2023

Complex Psychiatry

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Background: Lipids are essential components of the structure and for the function of brain cells. The intricate balance of lipids, including phospholipids, glycolipids, cholesterol, cholesterol ester, and triglycerides, is crucial for maintaining normal brain function. The roles of lipids and lipid droplets and their relevance to neurodegenerative and neuropsychiatric disorders (NPDs) remain largely unknown. Summary: Here, we reviewed the basic role of lipid components as well as a specific lipid organelle, lipid droplets, in brain function, highlighting the potential impact of altered lipid metabolism in the pathogenesis of Alzheimer’s disease (AD) and NDPs. Key Messages: Brain lipid dysregulation plays a pivotal role in the pathogenesis and progression of neurodegenerative and NPDs including AD and schizophrenia. Understanding the cell type-specific mechanisms of lipid dysregulation in these diseases is crucial for identifying better diagnostic biomarkers and for developing therapeutic strategies aiming at restoring lipid homeostasis.

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Oxygen-induced pathological angiogenesis promotes intense lipid synthesis and remodeling in the retina

et al. 2023

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Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol

Cited by 25 publications

References 66 publications

25-hydroxycholesterol mediates brain cytokine production and neutrophil infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation

25-hydroxycholesterol mediates brain cytokine production and neutrophil infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation

Brain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders

Oxygen-induced pathological angiogenesis promotes intense lipid synthesis and remodeling in the retina

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