A Hepatic GAbp-AMPK Axis Links Inflammatory Signaling to Systemic Vascular Damage

被引：8

作者：

Niopek, Katharina ^{[1
,2
,3
]}

Uestuenel, Bilgen Ekim ^{[1
,2
,3
]}

Seitz, Susanne ^{[1
,2
,3
]}

Sakurai, Minako ^{[1
,2
,3
]}

Zota, Annika ^{[1
,2
,3
]}

Mattijssen, Frits ^{[1
,2
,3
]}

Wang, Xiaoyue ^{[4
]}

Sijmonsma, Tjeerd ^{[4
]}

Feuchter, Yvonne ^{[4
]}

Gail, Anna M. ^{[4
]}

Leuchs, Barbara ^{[5
]}

Niopek, Dominik ^{[6
,7
,8
]}

Staufer, Oskar ^{[1
,2
,3
]}

Brune, Maik ^{[1
,2
,3
]}

Sticht, Carsten ^{[9
]}

Gretz, Norbert ^{[9
]}

Mueller-Decker, Karin ^{[10
]}

Hammes, Hans-Peter ^{[11
]}

Nawroth, Peter ^{[1
,2
,3
,12
]}

Fleming, Thomas ^{[12
]}

Conkright, Michael D. ^{[13
]}

Blueher, Matthias ^{[14
]}

Zeigerer, Anja ^{[1
,2
,3
]}

Herzig, Stephan ^{[1
,2
,3
]}

Diaz, Mauricio Berriel ^{[1
,2
,3
]}

机构：

[1] Helmholtz Ctr Munich, IDC, D-85764 Neuherberg, Germany

[2] Tech Univ Munich, D-85764 Neuherberg, Germany

[3] Heidelberg Univ Hosp, Inner Med 1, Joint Heidelberg IDC Translat Diabet Program, D-69120 Heidelberg, Germany

[4] German Canc Res Ctr, Joint Div Mol Metab Control DKFZ ZMBH Alliance &, D-69120 Heidelberg, Germany

[5] German Canc Res Ctr, Div Tumor Virol, D-69120 Heidelberg, Germany

[6] German Canc Res Ctr, Div Theoret Bioinformat B080, D-69120 Heidelberg, Germany

[7] Heidelberg Univ, Inst Pharm & Biotechnol, Dept Bioinformat & Funct Genom, D-69120 Heidelberg, Germany

[8] Heidelberg Univ, BioQuant, D-69120 Heidelberg, Germany

[9] Klinikum Mannheim, Med Res Ctr, D-68167 Mannheim, Germany

[10] German Canc Res Ctr, Core Facil Tumor Models, D-69120 Heidelberg, Germany

[11] Heidelberg Univ, Univ Med Mannheim, Med Dept 5, D-68167 Mannheim, Germany

[12] Heidelberg Univ, Dept Internal Med & Clin Chem 1, D-69120 Heidelberg, Germany

[13] Scripps Res Inst, Dept Canc Biol, Jupiter, FL 33458 USA

[14] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany

来源：

CELL REPORTS | 2017年 / 20卷 / 06期

关键词：

ACTIVATED PROTEIN-KINASE; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; INSULIN-RESISTANCE; BINDING-PROTEIN; TRANSCRIPTION FACTOR; TNF-ALPHA; THERAPEUTIC TARGET; DNA-BINDING; MICE;

D O I：

10.1016/j.celrep.2017.07.023

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 alpha and beta subunits of transcription factor GA-binding protein (GAbp) as a negative target of tumor necrosis factor alpha (TNF-alpha) signaling. TNF-alpha prevented GAbp alpha and beta complex formation via reactive oxygen species (ROS), leading to the non-energy-dependent transcriptional inactivation of AMP-activated kinase (AMPK) beta 1, which was identified as a direct hepatic GAbp target. Impairment of AMPK beta 1, in turn, elevated downstream cellular cholesterol biosynthesis, and hepatocyte-specific ablation of GAbp alpha induced systemic hypercholesterolemia and early macro-vascular lesion formation in mice. As GAbp alpha and AMPK beta 1 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.

引用

页码：1422 / 1434

页数：13