Inactivation of NF-kappa B2 (p52) restrains hepatic glucagon response via preserving PDE4B induction
Inactivation of NF-kappa B2 (p52) restrains hepatic glucagon response via preserving PDE4B induction
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NF-kappa B2 (p52) 失活通过保留 PDE4B 诱导来抑制肝胰高血糖素反应
DOI：
10.1038/s41467-019-12351-x
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发表时间：
2019
影响因子：
16.6
通讯作者：
Li Ping
中科院分区：
文献类型：
--
作者：
Zhang Wen Song;Pan An;Zhang Xu;Ying Ang;Ma Gaoxiang;Liu Bao Lin;Qi Lian Wen;Liu Qun;Li Ping
胰高血糖素促进肝脏糖异生，并在禁食期间维持全身葡萄糖水平。参与空腹胰高血糖素反应的调节因素尚不清楚。在这里，我们报道了p52在肝胰高血糖素反应中的作用，p52是非典型核因子- κ b信号传导的关键激活因子。我们发现p52在hfd喂养和胰高血糖素刺激小鼠的肝脏中被激活。p52的下调降低了胰高血糖素刺激的高血糖，而p52的过表达增强了胰高血糖素的反应。机制上，p52结合磷酸二酯酶4B启动子抑制其转录，促进cAMP积累，从而通过cAMP/PKA信号传导增强胰高血糖素反应。降糖药二甲双胍和人参皂苷Rb1至少部分通过抑制p52的激活来降低血糖。我们的研究结果表明p52介导胰高血糖素引发的肝脏糖异生，并提示药物干预以阻止p52加工是糖尿病的潜在治疗策略。
Glucagon promotes hepatic gluconeogenesis and maintains whole-body glucose levels during fasting. The regulatory factors that are involved in fasting glucagon response are not well understood. Here we report a role of p52, a key activator of the noncanonical nuclear factor-kappaB signaling, in hepatic glucagon response. We show that p52 is activated in livers of HFD-fed and glucagon-challenged mice. Knockdown of p52 lowers glucagon-stimulated hyperglycemia, while p52 overexpression augments glucagon response. Mechanistically, p52 binds to phosphodiesterase 4B promoter to inhibit its transcription and promotes cAMP accumulation, thus augmenting the glucagon response through cAMP/PKA signaling. The anti-diabetic drug metformin and ginsenoside Rb1 lower blood glucose at least in part by inhibiting p52 activation. Our findings reveal that p52 mediates glucagon-triggered hepatic gluconeogenesis and suggests that pharmacological intervention to prevent p52 processing is a potential therapeutic strategy for diabetes.