title: A systems biology analysis of brain microvascular endothelial cell lipotoxicity.
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  System 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.
authors.forename: Hnin H
authors.initials: HH
authors.lastname: Aung
authors.forename: Athanasios
authors.initials: A
authors.lastname: Tsoukalas
authors.forename: John C
authors.initials: JC
authors.lastname: Rutledge
authors.affiliation: UC Davis Genome Center, University of California, Davis, CA 95616, USA. iliast@ucdavis.edu.
authors.forename: Ilias
authors.initials: I
authors.lastname: Tagkopoulos
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000098:blood supply*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008066:Lipolysis / Q000187:drug effects; D008074:Lipoproteins / Q000737:chemistry / Q000494:pharmacology; D008659:Metabolic Diseases / Q000378:metabolism* / Q000473:pathology; D055806:Microvessels / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D049490:Systems Biology; D014280:Triglycerides / Q000737:chemistry
chemical_list: D051700:Activating Transcription Factor 3; D008074:Lipoproteins; D014280:Triglycerides