Signal-dependent control of gluconeogenic key enzyme genes through coactivator-associated arginine methyltransferase 1.
Together with impaired glucose uptake in skeletal muscle, elevated hepatic gluconeogenesis is largely responsible for the hyperglycemic phenotype in type II diabetic patients. Intracellular glucocorticoid and cyclic adenosine monophosphate (cAMP)/protein kinase A-dependent signaling pathways contribute to aberrant hepatic glucose production through the induction of gluconeogenic enzyme gene expression. Here we show that the coactivator-associated arginine methyltransferase 1 (CARM1) is required for cAMP-mediated activation of rate-limiting gluconeogenic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) and glucose-6-phosphatase genes. Mutational analysis showed that CARM1 mediates its effect via the cAMP-responsive element within the PEPCK promoter, which is identified here as a CARM1 target in vivo. In hepatocytes, endogenous CARM1 physically interacts with cAMP-responsive element binding factor CREB and is recruited to the PEPCK and glucose-6-phosphatase promoters in a cAMP-dependent manner associated with increased promoter methylation. CARM1 might, therefore, represent a critical component of cAMP-dependent glucose metabolism in the liver.
Krones-Herzig
Anja
A
Department of Molecular Metabolic Control, German Cancer Research Center Heidelberg, Heidelberg 69120, Germany.
Mesaros
Andrea
A
Metzger
Dagmar
D
Ziegler
Anja
A
Lemke
Ulrike
U
Brüning
Jens C
JC
Herzig
Stephan
S
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004252:DNA Mutational Analysis; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000378:metabolism; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D019298:Glucose-6-Phosphate / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
D005938:Glucocorticoids; D005576:Colforsin; D019298:Glucose-6-Phosphate; D000242:Cyclic AMP; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose