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 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.