肝GAbp-AMPK信号通路将炎症信号与系统性血管损伤联系起来
文献 A Hepatic GAbp-AMPK Axis Links Inflammatory Signaling to Systemic Vascular Damage 于 2017年 发表在 Cell Reports 原文链接
Abstract: 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.
摘要：增加的促炎症信号传导是肥胖和糖尿病代谢功能障碍的标志。尽管炎症和能量底物处理过程代表了关键的代谢控制层，但它们的分子整合位点仍然大部分未知。在这里，我们确定转录因子GA-结合蛋白（GAbp）的α和β亚基之间的异二聚化界面作为肿瘤坏死因子α（TNF-α）信号的负向靶标。 TNF-α通过活性氧（ROS）阻止GAbpα和β复合物形成，导致AMP-活化激酶（AMPK）β1的非能量依赖性转录失活，其被鉴定为直接肝GAbp靶。反过来，AMPKβ1的损伤增加下游细胞胆固醇生物合成，肝细胞特异性消融GAbpα诱导的小鼠全身性高胆固醇血症和早期大血管病变形成。由于GAbpα和AMPKβ1水平也被发现与肥胖的人类患者相关，所以ROS-GAbp-AMPK途径可能代表一个肝血管轴糖尿病长期并发症的关键组分。
使用试剂原文信息：oxLDL levels were measured in serum of five mice per experimental group using the commercial ELISA kit SEA527Mu for the detection of oxLDL (USCN).