糖尿病等代谢性疾病严重危害人体健康，而糖脂代谢紊乱是该类疾病的共同病理基础。申请人研究表明，胰高血糖素能够激活非经典NF-κB信号通路进而转录抑制PDE4B的表达，促进肝糖异生。同时，敲降该通路的关键转录因子NF-κB2（p52）能够综合改善糖脂代谢紊乱。此外，神经酰胺代谢在糖尿病的发病过程中的作用日渐得到重视。基于此，本项目提出科学假设：胰高血糖素紊乱能够激活p52进而通过转录调控促进神经酰胺生成。蓄积的神经酰胺通过AMPK/CRTC/CREB同时调控肝糖异生与肝脂蓄积。预期研究内容有：1）明确胰高血糖素紊乱中p52激活与神经酰胺生成的关系；2）确定p52转录调控神经酰胺合成酶表达；3）发现神经酰胺通过调控CREB的转录活性同时促进肝糖异生和肝脂蓄积。本课题将糖脂代谢紊乱综合关联，以神经酰胺代谢为基础提出p52调控代谢紊乱的共同机制，能够为深入研究糖尿病中代谢紊乱发生的机制提供有益借鉴。

Diabetes and other metabolic diseases are major risk factors for other serious medical conditions. And glucose and lipid metabolism is usually considered the common pathological basis in the development of these diseases. According to our earlier research, glucagon activates the noncanonical nuclear factor kappa B signaling and promotes hepatic gluconeogenesis via transcriptionally inhibiting phosphodiesterase 4B during fasting. Inactivation of p52, a key activator of the noncanonical NF-κB signaling, alleviated high fat diet-induced glucose and lipid metabolism disorder. Meanwhile, the role of ceramides in metabolic disorder has attracted more attention in recent years. Based on these previous works, we hypothesize that glucagon activates p52 and then transcriptionally regulates ceramides synthesis. The accumulation of ceramides comprehensively stimulates hepatic gluconeogenesis and liver accumulation through AMPK/CRTC/CREB pathway. The major contents include: 1) to confirm the relationship between the activation of NF-κB2 during glucagon disorder and ceramides accumulation; 2) to know how p52 transcriptionally promotes ceramides synthesis; 3) to clarify the common mechanism of ceramides aggravating glucose and lipid metabolism disorder through regulating the transcriptional activity of CREB. Our findings will reveal the mechanism of p52 regulating metabolism disorder including hepatic gluconeogenesis and lipid metabolism. And the approach and idea of this study will provide a useful reference for the research related to metabolism disorder in diabetes.