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Published on: November 16, 2011
SCH772984 ameliorates lipopolysaccharide-induced hypoglycemia in mice through reversing MEK/ERK/Foxo1-mediated
Yirong Wang1, Shuyun Qing1, Jing Yang1
1Department of Pharmacy, The Third People's Hospital of Chengdu, The Second Affiliated Clinical College of Chongqing Medical University, Chengdu 610014, People's Republic of China.
Abstract:
Lipopolysaccharide (LPS) results in a lethal hypoglycemic response. However, the main molecular mechanism involved in LPS-induced 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.
Insights
Lipopolysaccharide (LPS) causes hypoglycemia by inhibiting glucose production via the MEK/ERK/Foxo1 pathway. An ERK inhibitor, SCH772984, reversed this effect, offering a potential treatment for LPS-induced low blood sugar.
Area of Science:
- Biochemistry
- Endocrinology
- Pharmacology
Background:
- Lipopolysaccharide (LPS) triggers a severe hypoglycemic response.
- The precise molecular mechanisms underlying LPS-induced glucose metabolism disruption remain unclear.
Purpose of the Study:
- Investigate the signaling pathways implicated in LPS-induced hypoglycemia.
- Evaluate the therapeutic potential of the extracellular signal-regulated kinase (ERK) inhibitor, SCH772984.
Main Methods:
- Assessed gluconeogenesis, glucose absorption, and glycogenolysis using pyruvate tolerance, oral glucose tolerance, and glucagon tests, respectively.
- Analyzed mRNA and protein expression of key gluconeogenic enzymes (G6Pase, PEPCK).
- Examined the role of the MEK/ERK/Foxo1 signaling pathway.
Main Results:
- LPS administration significantly reduced blood glucose levels and gluconeogenic capacity.
- LPS decreased the expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK).
- LPS induced MEK/ERK/Foxo1 pathway activation, inhibiting gluconeogenesis; SCH772984 reversed these effects.
Conclusions:
- LPS induces hypoglycemia by suppressing gluconeogenesis through the MEK/ERK/Foxo1 signaling pathway.
- ERK inhibition with SCH772984 effectively counteracted LPS-induced hypoglycemia in mice.
- Targeting the ERK pathway presents a novel therapeutic strategy for LPS-induced metabolic disorders.
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