Abstract
BackgroundNeurovascular inflammation is associated with a number of neurological diseases including vascular dementia and Alzheimer’s disease, which are increasingly important causes of morbidity and mortality around the world. Lipotoxicity is a metabolic disorder that results from accumulation of lipids, particularly fatty acids, in non-adipose tissue leading to cellular dysfunction, lipid droplet formation, and cell death.ResultsOur studies indicate for the first time that the neurovascular circulation also can manifest lipotoxicity, which could have major effects on cognitive function. The penetration of integrative systems biology approaches is limited in this area of research, which reduces our capacity to gain an objective insight into the signal transduction and regulation dynamics at a systems level. To address this question, we treated human microvascular endothelial cells with triglyceride-rich lipoprotein (TGRL) lipolysis products and then we used genome-wide transcriptional profiling to obtain transcript abundances over four conditions. We then identified regulatory genes and their targets that have been differentially expressed through analysis of the datasets with various statistical methods. We created a functional gene network by exploiting co-expression observations through a guilt-by-association assumption. Concomitantly, we used various network inference algorithms to identify putative regulatory interactions and we integrated all predictions to construct a consensus gene regulatory network that is TGRL lipolysis product specific.ConclusionSystem biology analysis has led to the validation of putative lipid-related targets and the discovery of several genes that may be implicated in lipotoxic-related brain microvascular endothelial cell responses. Here, we report that activating transcription factors 3 (ATF3) is a principal regulator of TGRL lipolysis products-induced gene expression in human brain microvascular endothelial cell.
Highlights
Neurovascular inflammation is associated with a number of neurological diseases including vascular dementia and Alzheimer’s disease, which are increasingly important causes of morbidity and mortality around the world
Our studies have shown that triglyceride-rich lipoprotein (TGRL) lipolysis products have a dramatic effect on endothelial cell injury, which is of much greater magnitude than TGRL particles, such as chylomicrons and VLDL [4]
The 79 differentially expressed (DE) genes that have been in parallel identified from all methods form a functional gene network with 54 functional categories that are significantly over-represented in this gene set, which implicates 12 KEGG pathways (Figure 3A)
Summary
Neurovascular inflammation is associated with a number of neurological diseases including vascular dementia and Alzheimer’s disease, which are increasingly important causes of morbidity and mortality around the world. The enormous personal and emotional cost to, the patient, and to family, friends, and co-workers, and we have a national tragedy that is about to unfold as the baby boomers transition to the elderly. One of the potential inducers of neurovascular inflammation is triglyceride-rich lipoprotein (TGRL) particles and their lipolysis products [2]. Lipoprotein lipase (LpL) is anchored to the brain microvascular endothelium, where it binds and hydrolyzes TGRL particles to smaller lipolysis products, such as fatty acids [3]. Our studies have shown that TGRL lipolysis products have a dramatic effect on endothelial cell injury, which is of much greater magnitude than TGRL particles, such as chylomicrons and VLDL [4]
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