Nat Commun . 2019 Sep 20;10(1):4303.

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

Affiliations

  • 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.

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