SCH772984 ameliorates lipopolysaccharide-induced hypoglycemia in mice through reversing MEK/ERK/Foxo1-mediated gluconeogenesis suppression

作者全名："Wang, Yirong; Qing, Shuyun; Yang, Jing; Qian, Dehui"

作者地址："[Wang, Yirong; Qing, Shuyun; Yang, Jing] Chongqing Med Univ, Peoples Hosp Chengdu 3, Dept Pharm, Affiliated Clin Coll 2, Chengdu 610014, Peoples R China; [Qian, Dehui] Army Med Univ, Affiliated Hosp 2, Dept Cardiol, Chongqing 400037, Peoples R China"

通信作者："Qian, DH (通讯作者)，Army Med Univ, Affiliated Hosp 2, Dept Cardiol, Chongqing 400037, Peoples R China."

来源：CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001124961500001

JCR分区：Q3

影响因子：1.7

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：lipopolysaccharide; SCH772984; hypoglycemia; gluconeogenesis; MEK/ERK/Foxo1 signaling

摘要："Lipopolysaccharide (LPS) results in a lethal hypoglycemic response. However, the main molecular mechanism involved in LPSinduced glucose metabolism disorder is poorly understood. This study intends to investigate the signaling pathways involved in LPS-induced hypoglycemia and potential efficacy of extracellular signal-regulated kinase (ERK) inhibitor SCH772984. The effects of LPS and SCH772984 on gluconeogenesis, glucose absorption, and glycogenolysis were evaluated by pyruvate tolerance test, oral glucose tolerance test, and glucagon test, respectively. After a single intraperitoneal injection of 0.5 mg/kg LPS, the mice's blood glucose levels and gluconeogenesis ability were significantly lower than that of control group. Besides, mRNA and protein expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) decreased significantly after LPS treatment. LPS induced the phosphorylation of ERK1/2, MEK1/2 (mitogen-activated protein kinase), and Foxo1 while inhibited Foxo1 expression in the nucleus, indicating an important role of the MEK/ERK/Foxo1 signaling in the inhibition of gluconeogenesis by LPS. Furthermore, SCH772984 elevated blood glucose, increased the G6Pase and PEPCK expression, and inhibited pERK1/2 and pFoxo1 expression in LPS-induced mice. In summary, LPS inhibited gluconeogenesis and induced hypoglycemia through the MEK/ERK/Foxo1 signal pathway, and ERK inhibitor could effectively reverse decreased blood glucose in mice with LPS treatment. These findings provide a novel therapeutic target for LPS-induced hypoglycemia."

基金机构：Young Doctor Talent Incubation Program [2022YQB029]

基金资助正文：This study was supported by grants from the Young Doctor Talent Incubation Program 2022YQB029.