Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Liver dysfunction in obesity is associated with cerebrovascular health independently of diabetes and hypertension.

ABSTRACT: It is unclear whether liver dysfunction is implicated in obesity-related detrimental changes in brain structure and function. This study examineed associations between liver dysfunction and brain health in middle-aged participants with obesity and early-stage metabolic dysfunction-associated steatotic liver disease (MASLD). Using brain magnetic resonance imaging, neuropsychological tests, histological and biochemical characterization of liver biopsies, we showed that specific hallmarks of liver dysfunction (e.g. free cholesterol accumulation, early fibrosis) are associated with increased white matter hyperintensities and larger variations in cerebral blood flow indicating poorer cerebrovascular function. These associations were independent of age, sex, body mass index, diabetes and hypertension and corroborated by independent liver RNA-seq and pathway analysis highlighting the role of liver inflammation and cellular stress. Further associations with circulating IL-6 suggest systemic low-grade inflammation as potential mediator between liver and brain. Hence, in obesity at midlife, cerebrovascular health is independently associated with the pathological state of the liver.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249997 | GEO | 2024/09/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Liver dysfunction in obesity is associated with cerebrovascular health independently of diabetes and hypertension.

Project description:Liver dysfunction in obesity is associated with cerebrovascular health independently of diabetes and hypertension.

| PRJNA1051582 | ENA

Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation

Project description:Astrocytes are intimately linked with brain vessels, a relationship that is critical for neuronal health and function. However, key astroglial molecular factors that drive these physical and functional associations during postnatal brain development have not yet been identified. We characterized structural and transcriptional changes in mouse cortical astrocytes and microvessels during the first two postnatal weeks and found that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, was highly expressed in astrocytes at birth to then decreased rapidly. Astrocyte-selective ablation of Hmgb1 in newborn mice affected astrocyte morphology and endfoot placement, induced disruption of endfoot proteins connexin43 and aquaporin-4, induced transcriptional changes in astrocytes, and profoundly altered endothelial cell ultrastructure. While lack of astroglial Hmgb1 did not affect the blood-brain barrier or angiogenesis postnatally, it impaired neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as a key player in postnatal gliovascular maturation.

2023-06-13 | GSE224784 | GEO

Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation

Project description:Astrocytes are intimately linked with brain blood vessels, a relationship critical for neuronal function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. By characterizing structural and transcriptional changes in mouse cortical astrocytes during the first two postnatal weeks, we find that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, is highly expressed in astrocytes at birth and then decreases rapidly. Astrocyte-selective ablation of Hmgb1 at birth affects astrocyte morphology and endfoot placement, alters distribution of endfoot proteins connexin43 and aquaporin-4, induces transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupts endothelial ultrastructure. While lack of astroglial Hmgb1 does not affect the blood-brain barrier or angiogenesis postnatally, it impairs neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as a key player in postnatal gliovascular maturation.

2023-07-10 | GSE236429 | GEO

Peripherally-expressed apoE4 impairs brain functions and exacerbates amyloid pathogenesis by compromising cerebrovascular functions

Project description:The apolipoprotein E4 (APOE4) gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE is a lipid carrier abundantly expressed in both brain and periphery. As peripheral apoE is separated from brain apoE by the blood-brain barrier, it remains unclear whether peripheral apoE impacts brain functions and AD pathogenesis. To investigate this, we developed novel mouse models that conditionally express human APOE3 or APOE4 only in the liver with no detectable apoE in the brain. We found that liver-expressed apoE4 compromised synaptic plasticity and cognitive behaviors likely by impairing cerebrovascular functions. Remarkably, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate a pathogenic effect of peripheral apoE4, providing strong rationale for targeting peripheral apoE to treat AD.

2022-06-15 | GSE125501 | GEO

Transcriptional profiling reveals running promotes cerebrovascular remodeling in young but not midlife mice

Project description:Transcriptional profiling reveals running promotes cerebrovascular remodeling in young but not midlife mice

| PRJNA549482 | ENA

The Sarcoglycan complex is expressed in the cerebrovascular system and is specifically regulated by astroglial Cx30 channels

Project description:Astrocytes, the most prominent glial cell type in the brain, send specialized processes called endfeet around blood vessels and express a large molecular repertoire regulating the cerebrovascular system physiology. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction protein Connexin 43 and 30 (Cx43 and Cx30) allowing in particular for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. In this study, we addressed the specific role of Cx30 at the gliovascular interface. Using an inactivation mouse model for Cx30 (Cx30M-NM-^T/M-NM-^T), we showed that absence of Cx30 does not affect blood-brain barrier (BBB) organization and permeability. However, it results in the cerebrovascular fraction, in a strong upregulation of Sgcg encoding g-Sarcoglycan (SG), a member of the Dystrophin-associated protein complex (DAPC) connecting cytoskeleton and the extracellular matrix. The same molecular event occurs in Cx30T5M/T5M mutated mice, where Cx30 channels are closed, demonstrating that Sgcg regulation relied on Cx30 channel functions. We further characterized the cerebrovascular Sarcoglycan complex (SGC) and showed the presence of M-NM-1-, M-NM-2-, M-NM-4-, M-NM-3-, M-NM-5- and M-NM-6- SG, as well as Sarcospan. Altogether, our results suggest that the Sarcoglycan complex is present in the cerebrovascular system, and that expression of one of its members, g-Sarcoglycan, depends on Cx30 channels. As described in skeletal muscles, the SGC may contribute to membrane stabilization and signal transduction in the cerebrovascular system, which may therefore be regulated by Cx30 channel-mediated functions. Comparison of 3-month-old Cx30 deleted mice against WT genetic background.

2015-03-03 | E-GEOD-59148 | biostudies-arrayexpress

Temporally Distinct Myeloid Cell Reponses Mediate Damage and Repair After Cerebrovascular Injury.

Project description:Cerebrovascular injuries can cause severe edema and inflammation that adversely affect human health. Here, we observed recanalization after successful endovascular thrombectomy for acute large vessel occlusion was associated with cerebral edema and poor clinical outcomes in patients who experienced hemorrhagic transformation. To understand this process, we developed a cerebrovascular injury model using transcranial ultrasound that enabled spatiotemporal evaluation of resident and peripheral myeloid cells. We discovered that injurious and reparative responses diverged based on time and cellular origin. Resident microglia initially stabilized damaged vessels in a purinergic receptor-dependent manner, which was followed by influx of myelomonocytic cells that caused severe edema. Prolonged blockade of myeloid cell recruitment with anti-adhesion molecule therapy prevented severe edema but also promoted neuronal destruction and fibrosis by interfering with vascular repair later orchestrated by pro-inflammatory monocytes and pro-angiogenic repair-associated microglia (RAM). These data demonstrate how temporally distinct myeloid cell responses can contain, exacerbate, and ultimately repair a cerebrovascular injury.

2021-02-10 | GSE161424 | GEO

Extracellular vesicles from early- and late-passage endothelial cells differentially regulate cerebrovascular and brain aging in mice via changes in a miR-17-5p-dependent pathway

Project description:Vascular aging, which is characterized by brain endothelial cell (EC) senescence and dysfunction, is known to contribute to various age-related cerebrovascular and neurodegenerative diseases. However, the underlying mechanisms remain unclear. EC-derived microvesicles (EMVs) and exosomes (EEXs) retain the characteristics of parent cells and transfer their contents to modulate the functions of recipient cells, showing potential for evaluation or regulation of vascular aging. Here, as indicated by analyses of senescence-associated beta-galactosidase (SA-β-gal) staining, cerebral blood flow, blood–brain barrier function, aging-related markers and cognitive ability, we found that young primary EC (passage 2-4) released EMVs alleviated mouse cerebrovascular and brain aging more effectively than EEXs. Aged EC (passage 15-16) released EMVs were more effective than their released EEXs at exacerbating mouse cerebrovascular and brain aging. We further revealed that these EMVs regulated cerebrovascular and brain aging by transferring miR-17-5p and modulated EC senescence and function via the miR-17-5p/PI3K/Akt pathway. Clinically, the levels of plasma EMVs and their associated miR-17-5p (EMV-miR-17-5p) were significantly increased or decreased in elderly individuals and were closely correlated with reactive oxygen species (ROS) and vascular aging. Receiver operating characteristic (ROC) analysis revealed that the area under the curve (AUC) was 0.724 for EMVs, 0.77 for EMV-miR-17-5p and 0.815 for their combination for distinguishing vascular aging. Our results identified novel roles for EMVs and showed that these vesicles more effectively modulated vascular and brain aging than did EEXs by regulating EC functions through the miR-17-5p/PI3K/Akt pathway; thus, EMVs and EMV-miR-17-5p are promising biomarkers and therapeutic targets for vascular aging.

2024-05-12 | GSE266940 | GEO

Global proteomic analysis of extracellular matrix in mouse and human brain highlights association with cerebrovascular disease

Project description:The extracellular matrix (ECM), a key interface between the cerebrovasculature and other cells within the neuro-glial-vascular unit , provides structural stability and modulates cell behaviour and signalling. These functions are dependent on ECM protein composition. Since ECM defects may contribute to a broad range of disorders including cerebrovascular disease, it is crucially important to characterize ECM composition to better understand the mechanisms by which the ECM modulates brain health and disease. To date, molecular studies of the cerebrovascular ECM have been limited. We therefore generated ECM extracts from vascular enriched tissues of both mouse and human post-mortem brain. We used mass spectrometry with off-line high-pH reversed-phase fractionation to increase proteome depth and characterized the identified proteins. This identified a large number of proteins (>1000 mouse, >2000 human) in the ECM-enriched fractions, with > 66% of the identified proteins covered in both human and mouse samples. We now report 147 ECM proteins, including collagens (as major ECM components), laminins, fibronectin and nidogens, that can be considered as the core constituents of the human brain vascular matrisome. We also identified 12 novel proteins in the ECM-enriched fraction, that may have regulate or interact with the matrisome, including several key regulators of neurovascular interactions, such as BCAM, CDH5 and PARVB. Many of the identified brain vascular matrisome proteins are encoded by genes identified in stroke and cerebral small vessel disease genome-wide association studies, underscoring the importance of the vascular ECM in health and disease. This brain vascular matrisome represents a powerful resource for investigating the impact of aging and disease on the cerebrovasculature.

2021-03-11 | PXD020436 | Pride

Analysis of cerebrovascular dysfunction caused by chronic social defeat in mice

Project description:Analysis of cerebrovascular dysfunction caused by chronic social defeat in mice

| PRJNA656809 | ENA