p38 Mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis.

Cao W, Collins QF, Becker TC, Robidoux J, Lupo EG, Xiong Y, Daniel KW, Floering L, Collins S
J Biol Chem. 2005 280 (52): 42731-7

PMID: 16272151 · DOI:10.1074/jbc.M506223200

Hepatic gluconeogenesis is essential for maintaining blood glucose levels during fasting and is the major contributor to postprandial and fasting hyperglycemia in diabetes. Gluconeogenesis is a classic cAMP/protein kinase A-dependent process initiated by glucagon, which is elevated in the blood during fasting and in diabetes. In this study, we have shown that p38 mitogen-activated protein kinase (p38) was activated in liver by fasting and in primary hepatocytes by glucagon or forskolin. Fasting plasma glucose levels were reduced upon blockade of p38 with either a chemical inhibitor or small interference RNA in mice. In examining the mechanism, inhibition of p38 suppressed gluconeogenesis in liver, along with expression of key gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Peroxisome proliferator-activated receptor gamma coactivator 1alpha and cAMP-response element-binding protein have been shown to be important mediators of hepatic gluconeogenesis. We have shown that inhibition of p38 prevented transcription of the PPARgamma coactivator 1alpha gene as well as phosphorylation of cAMP-response element-binding protein. Together, our results from in vitro and in vivo studies define a model in which cAMP-dependent activation of genes involved in gluconeogenesis is dependent upon the p38 pathway, thus adding a new player to our evolving understanding of this physiology.

MeSH Terms (32)

Acetylcysteine Adenoviridae Animals Cell Line, Tumor Colforsin Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic AMP Response Element-Binding Protein Diabetes Mellitus, Type 1 Disease Models, Animal Enzyme Inhibitors Gene Silencing Glucagon Gluconeogenesis Glucose Glucose-6-Phosphatase Hepatocytes Imidazoles Liver Mice p38 Mitogen-Activated Protein Kinases Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Phosphoenolpyruvate Carboxykinase (GTP) Phosphorylation Promoter Regions, Genetic Pyridines Reverse Transcriptase Polymerase Chain Reaction RNA, Small Interfering Streptozocin Trans-Activators Transcription Factors Transfection

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