Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways

Aung, Hnin Hnin; Altman, Robin; Nyunt, Tun; Kim, Jeffrey; Nuthikattu, Saivageethi; Budamagunta, Madhu S.; Voss, John C.; Wilson, Dennis W; Rutledge, John C.; Villablanca, Amparo C.

doi:10.1194/jlr.m061853

Cited by 38 publications

(38 citation statements)

References 68 publications

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“…The authors concluded that heteroplasmic mtDNA variants correspond to the extent of atherosclerotic phenotypes [27]. In another study, it has been shown that ROS activated by post-prandial triglyceride lipolysis (TGRL) products (TL) increases the expression of the stress-responsive protein, activating transcription factor-3 (ATF-3), which injures human brain microvascular endothelial cells in vitro [28]. In a further study, it has been shown that ATF3-T4 predominantly regulates the TL-induced brain microvascular inflammation and TNF signaling [29].…”

Section: Discussionmentioning

confidence: 99%

Atherosclerosis Can Be Mitochondrial: A Review

Finsterer

2020

Cureus

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One of the systems that are potentially affected in mitochondrial disorders, but hardly get systematically investigated, are the arteries. One of the phenotypic manifestations in arteries is atherosclerosis. This review focuses on the current knowledge and recent advances of mitochondrial atherosclerosis. We conducted a systematic literature review via PubMed using appropriate search terms. Atherosclerosis in mitochondrial disorders may result from a primary pathomechanism or a secondary one due to mitochondrial diabetes, arterial hypertension, or hyperlipidemia. Anecdotal reports show that primary atherosclerosis can be a phenotypic feature of mitochondrial disorders. Predominantly, patients carrying mutations in mtDNA-located genes may develop primary mitochondrial atherosclerosis. Though not systematically investigated, it is conceivable that primary mitochondrial atherosclerosis results from increased oxidative stress, mitophagy, metabolic breakdown, or lactic acidosis. Mitochondrial disorder patients with primary mitochondrial atherosclerosis should receive not only antithrombotic medication but also antioxidants and cofactors. Atherosclerosis in mitochondrial disorders may occur even in the absence of classical atherosclerosis risk factors, suggesting that atherosclerosis can be a primary manifestation of the metabolic defect. Though primary atherosclerosis in mitochondrial disorders has not been systematically investigated, anecdotal data indicate that mitochondrial dysfunction can be a mechanism for the development of primary, mitochondrial atherosclerosis. These patients require antioxidants and cofactors in addition to antithrombotic medication.

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Section: Discussionmentioning

confidence: 99%

Atherosclerosis Can Be Mitochondrial: A Review

Finsterer

2020

Cureus

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“…The diseases associated with TUBB include cortical dysplasia with other brain malformations (https://www.genecards.org/). The ATF3 pathway is implicated in brain vascular damage [51]; it may be associated with amyloid deposition in AD [52]. The NOL6 is associated with ribosome biogenesis according to GeneCards database.…”

Section: Discussionmentioning

confidence: 99%

Identification of biomarkers and pathways to identify novel therapeutic targets in Alzheimer’s disease: Insights from a systems biomedicine perspective

Rahman¹,

Islam

Zaman³

et al. 2018

Preprint

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M.A.M.). # These two authors have made an equal contribution and hold joint first authorship for this work. (M.A.M.).Abstract: Background and objectives: Alzheimer's disease (AD) is the progressive neurodegenerative disease characterized by dementia, but no peripheral biomarkers available yet that can detect the AD. This study aimed to identify systems biomarker signatures in the AD through integrative analyses. Materials and Methods: We used two microarray transcriptomics datasets of blood from AD patients to identify differentially expressed genes (DEGs).Geneset and protein overrepresentation analysis, protein-protein interaction (PPI), DEGs-Transcription Factor interactions, DEGs-MicroRNAs interactions, protein-drug interactions, and protein subcellular localizations analyses were done on common DEGs. Results: Total 25 DEGs were detected between the two datasets. Integration of DEGs with biomolecular networks revealed hub proteins (TUBB, ATF3, NOL6, UQCRC1, SND1, CASP2, BTF3, INPP5K, VCAM1, and CSTF1), TFs (FOXC1, ZNF3, GEMIN7, and SMG9), miRNAs (mir-20a-5p, mir-93-5p, mir-16-5p, let-7b-5p, mir-708-5p, mir-24-3p, mir-26b-5p, mir-17-5p, mir-4270, and mir-4441). The analyses revealed candidate blood based biomarkers in the AD. We evaluated the histone modifications of the identified biomolecules. The hub genes and transcription factors (TFs) revealed that they possess several histone modification sites associated with Alzheimer's disease. The protein-drug interactions revealed 10 candidate drugs consisting of antineoplastic (Vinorelbine, Vincristine, Vinblastine, Epothilone D, Epothilone B, CYT997, and ZEN-012), dermatologicals (Podofilox), and immunosuppressive agents (Colchicine) that may target the candidate systems biomarkers. The subcellular localization analysis revealed the interactions of the DEGs range from nucleus to plasma membrane through cytosol. Conclusions: This study presents blood based systems molecular biomarker signatures at RNA and protein levels which might be useful as peripheral biomarkers in the AD. The candidate drugs, histone modification sites, and subcellular localizations will be useful in future drug design in the AD.

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“…The contribution of circulating TG to brain lipid uptake is unclear, as a majority of research on brain uptake of peripheral lipids have focused on non-esterified fatty acids and LPC [55]. However, further research will be needed to clarify this difference, as triacylglycerol-rich lipoproteins and their lipolysis products in high physiological concentrations are known to cause endothelial injury and dysfunction in the periphery and in the cerebral circulation [33]. …”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms underpinning this association are not completely understood but broadly include capillary dysfunction; neurovascular inflammation; altered redox state and heightened oxidative stress [30–33]. With chronic ingestion of pro-inflammatory fat enriched diets, it is a reasonable proposition to suggest that changes of the brain lipidome may be realized and causally associated with some of the indicated mechanistic pathways.…”

Section: Introductionmentioning

confidence: 99%

The Effects of Long-Term Saturated Fat Enriched Diets on the Brain Lipidome

et al. 2016

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The brain is highly enriched in lipids, where they influence neurotransmission, synaptic plasticity and inflammation. Non-pathological modulation of the brain lipidome has not been previously reported and few studies have investigated the interplay between plasma lipid homeostasis relative to cerebral lipids. This study explored whether changes in plasma lipids induced by chronic consumption of a well-tolerated diet enriched in saturated fatty acids (SFA) was associated with parallel changes in cerebral lipid homeostasis. Male C57Bl/6 mice were fed regular chow or the SFA diet for six months. Plasma, hippocampus (HPF) and cerebral cortex (CTX) lipids were analysed by LC-ESI-MS/MS. A total of 348 lipid species were determined, comprising 25 lipid classes. The general abundance of HPF and CTX lipids was comparable in SFA fed mice versus controls, despite substantial differences in plasma lipid-class abundance. However, significant differences in 50 specific lipid species were identified as a consequence of SFA treatment, restricted to phosphatidylcholine (PC), phosphatidylethanolamine (PE), alkyl-PC, alkenyl-PC, alkyl-PE, alkenyl-PE, cholesterol ester (CE), diacylglycerol (DG), phosphatidylinositol (PI) and phosphatidylserine (PS) classes. Partial least squares regression of the HPF/CTX lipidome versus plasma lipidome revealed the plasma lipidome could account for a substantial proportion of variation. The findings demonstrate that cerebral abundance of specific lipid species is strongly associated with plasma lipid homeostasis.

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Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways

Cited by 38 publications

References 68 publications

Atherosclerosis Can Be Mitochondrial: A Review

Atherosclerosis Can Be Mitochondrial: A Review

Identification of biomarkers and pathways to identify novel therapeutic targets in Alzheimer’s disease: Insights from a systems biomedicine perspective

The Effects of Long-Term Saturated Fat Enriched Diets on the Brain Lipidome

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