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

• Published in: Cell reports (Cambridge) 2017-08, Vol.20 (6), p.1422-1434
• Main Authors: Niopek, Katharina, Üstünel, Bilgen Ekim, Seitz, Susanne, Sakurai, Minako, Zota, Annika, Mattijssen, Frits, Wang, Xiaoyue, Sijmonsma, Tjeerd, Feuchter, Yvonne, Gail, Anna M., Leuchs, Barbara, Niopek, Dominik, Staufer, Oskar, Brune, Maik, Sticht, Carsten, Gretz, Norbert, Müller-Decker, Karin, Hammes, Hans-Peter, Nawroth, Peter, Fleming, Thomas, Conkright, Michael D., Blüher, Matthias, Zeigerer, Anja, Herzig, Stephan, Berriel Diaz, Mauricio
• Format: Article
• Language: English
• Subjects: AMPK; Animals; atherogenesis; Atherosclerosis - etiology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Cell Line; Cells, Cultured; Cholesterol - metabolism; GA-Binding Protein Transcription Factor - chemistry; GA-Binding Protein Transcription Factor - metabolism; GAbp; Hepatocytes - metabolism; Hypercholesterolemia - complications; Hypercholesterolemia - metabolism; liver; Male; Mice; Mice, Inbred C57BL; Protein Kinases - metabolism; Protein Multimerization; Protein Subunits - chemistry; Protein Subunits - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction; TNF-α; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.07.023

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. [Display omitted] •TNF-α-induced ROS formation diminishes hepatic GAbp transcription factor function•Impaired hepatic GAbp function results in transcriptional inactivation of AMPK•AMPK deficiency increases hepatic cholesterol secretion•Hypercholesterolemia upon GAbp inhibition induces atherosclerotic lesion formation Inflammatory signaling contributes to metabolic disease progression in obesity and diabetes. Niopek et al. identify the transcription factor GAbp to be inactivated in the liver by TNF-α-dependent oxidative stress. Inactivation of GAbp increases cholesterol levels through impaired hepatic AMPK function, contributing to macro-vascular lesion formation as a diabetic long-term complication.