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 language | English (US) |
|---|---|
| Pages (from-to) | 955-968 |
| Number of pages | 14 |
| Journal | Journal of Lipid Research |
| Volume | 57 |
| Issue number | 6 |
| DOIs | |
| State | Published - 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
Cite this
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; Voss, John C; Wilson, Dennis W; Rutledge, John C; Villablanca, Amparo C.
In: Journal of Lipid Research, Vol. 57, No. 6, 01.06.2016, p. 955-968.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Lipotoxic brain microvascular injury is mediated by activating transcription factor 3-dependent inflammatory and oxidative stress pathways
AU - Aung, Hnin Hnin
AU - Altman, Robin
AU - Nyunt, Tun
AU - Kim, Jeffrey
AU - Nuthikattu, Saivageethi
AU - Budamagunta, Madhu
AU - Voss, John C
AU - Wilson, Dennis W
AU - Rutledge, John C
AU - Villablanca, Amparo C
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - Cell signaling
KW - Cerebrovascular circulation
KW - Diet and dietary lipids
KW - Endothelial cells
KW - Gene expression
KW - Inflammation
KW - Lipolysis
KW - Mitochondria
KW - Reactive oxygen species
KW - Triglyceride-rich lipoproteins
UR - http://www.scopus.com/inward/record.url?scp=84971578872&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84971578872&partnerID=8YFLogxK
U2 - 10.1194/jlr.M061853
DO - 10.1194/jlr.M061853
M3 - Article
C2 - 27087439
AN - SCOPUS:84971578872
VL - 57
SP - 955
EP - 968
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 6
ER -