Inactivation of NF-κB2 (p52) Restrains Hepatic Glucagon Response via Preserving PDE4B Induction

Wen-Song Zhang  ¹ , An Pan  ¹ , Xu Zhang  ¹ , Ang Ying  ¹ , Gaoxiang Ma  ^{1   2} , Bao-Lin Liu  ¹ , Lian-Wen Qi  ^{3   4} , Qun Liu  ⁵ , Ping Li  ⁶

• ¹ State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
• ² Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, 211198, China.
• ³ State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Qilw@cpu.edu.cn.
• ⁴ Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, 211198, China. Qilw@cpu.edu.cn.
• ⁵ State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. liuquncpu@126.com.
• ⁶ State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. liping2004@126.com.

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.