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A hepatic GAbp-AMPK axis links inflammatory signaling to systemic vascular damage

Increased pro-inflammatory signaling is a hallmark of metabolic dysfunction in obesity and diabetes. Although both inflammatory and energy substrate handling processes represent critical layers of metabolic control, their molecular integration sites remain largely unknown. Here, we identify the hete...

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Main Authors: Niopek, Katharina (Author) , Sakurai, Minako (Author) , Feuchter, Yvonne (Author) , Leuchs, Barbara (Author) , Niopek, Dominik (Author) , Brune, Maik (Author) , Sticht, Carsten (Author) , Gretz, Norbert (Author) , Hammes, Hans-Peter (Author) , Nawroth, Peter Paul (Author) , Fleming, Thomas (Author) , Herzig, Stephan (Author) , Berriel Diaz, Mauricio (Author)
Format: Article (Journal)
Language:English
Published: August 8, 2017
In: Cell reports
Year: 2017, Volume: 20, Issue: 6, Pages: 1422-1434
ISSN:2211-1247
DOI:10.1016/j.celrep.2017.07.023
Online Access:Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1016/j.celrep.2017.07.023
Verlag, kostenfrei, Volltext: http://www.sciencedirect.com/science/article/pii/S2211124717309890
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Author Notes:Katharina Niopek, Bilgen Ekim Üstünel, Susanne Seitz, Minako Sakurai, Annika Zota, Frits Mattijssen, Xiaoyue Wang, Tjeerd Sijmonsma, Yvonne Feuchter, Anna M. Gail, Barbara Leuchs, Dominik Niopek, Oskar Staufer, Maik Brune, Carsten Sticht, Norbert Gretz, Karin Müller-Decker, Hans-Peter Hammes, Peter Nawroth, Thomas Fleming, Michael D. Conkright, Matthias Blüher, Anja Zeigerer, Stephan Herzig, and Mauricio Berriel Diaz
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Summary:Increased pro-inflammatory signaling is a hallmark of metabolic dysfunction in obesity and diabetes. Although both inflammatory and energy substrate handling processes represent critical layers of metabolic control, their molecular integration sites remain largely unknown. Here, we identify the heterodimerization interface between the α and β subunits of transcription factor GA-binding protein (GAbp) as a negative target of tumor necrosis factor alpha (TNF-α) signaling. TNF-α prevented GAbpα and β complex formation via reactive oxygen species (ROS), leading to the non-energy-dependent transcriptional inactivation of AMP-activated kinase (AMPK) β1, which was identified as a direct hepatic GAbp target. Impairment of AMPKβ1, in turn, elevated downstream cellular cholesterol biosynthesis, and hepatocyte-specific ablation of GAbpα induced systemic hypercholesterolemia and early macro-vascular lesion formation in mice. As GAbpα and AMPKβ1 levels were also found to correlate in obese human patients, the ROS-GAbp-AMPK pathway may represent a key component of a hepato-vascular axis in diabetic long-term complications.
Item Description:Gesehen am 26.07.2018
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2017.07.023

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