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

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

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9 Scopus citations

Abstract

Dysfunction of the cerebrovasculature plays an important role in vascular cognitive impairment (VCI). Lipotoxic injury of the systemic endothelium in response to hydrolyzed triglyceride-rich lipoproteins (TGRLs; TGRL lipolysis products) or a high-fat Western diet (WD) suggests similar mechanisms may be present in brain microvascular endothelium. We investigated the hypothesis that TGRL lipolysis products cause lipotoxic injury to brain microvascular endothelium by generating increased mitochondrial superoxide radical generation, upregulation of activating transcription factor 3 (ATF3)-dependent inflammatory pathways, and activation of cellular oxidative stress and apoptotic pathways. Human brain microvascular endothelial cells were treated with human TGRL lipolysis products that induced intracellular lipid droplet formation, mitochondrial superoxide generation, ATF3-dependent transcription of proinflammatory, stress response, and oxidative stress genes, as well as activation of proapoptotic cascades. Male apoE knockout mice were fed a high-fat/high-cholesterol WD for 2 months, and brain microvessels were isolated by laser capture microdissection. ATF3 gene transcription was elevated 8-fold in the hippocampus and cerebellar brain region of the WD-fed animals compared with chow-fed control animals. The microvascular injury phenotypes observed in vitro and in vivo were similar. ATF3 plays an important role in mediating brain microvascular responses to acute and chronic lipotoxic injury and may be an important preventative and therapeutic target for endothelial dysfunction in VCI.-Aung, H. H., R. Altman, T. Nyunt, J. Kim, S. Nuthikattu, M. Budamagunta, J. C. Voss, D. Wilson, J. C. Rutledge, and A. C. Villablanca. Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways.

Original languageEnglish (US)
Pages (from-to)955-968
Number of pages14
JournalJournal of Lipid Research
Volume57
Issue number6
DOIs
StatePublished - Jun 1 2016

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Keywords

  • Cell signaling
  • Cerebrovascular circulation
  • Diet and dietary lipids
  • Endothelial cells
  • Gene expression
  • Inflammation
  • Lipolysis
  • Mitochondria
  • Reactive oxygen species
  • Triglyceride-rich lipoproteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

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