Inactivation of NF-κB2 (p52) restrains hepatic glucagon response via preserving PDE4B induction

Wen-Song Zhang, An Pan, Xu Zhang, Ang Ying, Gaoxiang Ma, Bao-Lin Liu, Lian-Wen Qi (), Qun Liu () and Ping Li ()
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Wen-Song Zhang: China Pharmaceutical University
An Pan: China Pharmaceutical University
Xu Zhang: China Pharmaceutical University
Ang Ying: China Pharmaceutical University
Gaoxiang Ma: China Pharmaceutical University
Bao-Lin Liu: China Pharmaceutical University
Lian-Wen Qi: China Pharmaceutical University
Qun Liu: China Pharmaceutical University
Ping Li: China Pharmaceutical University

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12351-x

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