B-cell translocation gene-2 increases hepatic gluconeogenesis via induction of CREB.
Hepatic gluconeogenesis is mediated by the network of transcriptional factors and cofactors. Here, we show that B-cell translocation gene-2 (BTG2) plays a crucial cofactor in hepatic gluconeogenesis via upregulation of the cyclic AMP (cAMP) response element binding (CREB) in hepatocytes. cAMP/dexamethasone (Dex) significantly increased BTG2 and other gluconeogenic genes such as Nur77, phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) in hepatocytes. In contrast, insulin treatment completely blocks their expressions. Interestingly, overexpression of BTG2 using adenoviral system (Ad-BTG2) significantly elevated hepatic glucose production via the increase of transcriptional activity and gene expression of CREB, PEPCK, and G6Pase in hepatocytes, suggesting that BTG2 is the key player on hepatic glucose production. Physiological interaction studies demonstrated that BTG2 correlated CREB recruitment on the PEPCK gene promoter via a direct interaction. Finally, knockdown of endogenous BTG2 expression markedly inhibits the cAMP/Dex-induced transcriptional activity of gluconeogenic genes and glucose production in hepatocytes. Overall, the present study provides us with a novel molecular mechanism of BTG2-mediated induction of hepatic gluconeogenesis and suggests that BTG2 plays an important role in hepatic glucose metabolism.
Department of Herbology, College of Oriental Medicine, Daegu Hanny University, Daegu 706-060, Republic of Korea.
Seung-Lark
SL
Hwang
Okyun
O
Kwon
Soo Jin
SJ
Lee
Seong-Soo
SS
Roh
Yong Deuk
YD
Kim
Jang Hyun
JH
Choi
D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation; D005934:Glucagon / Q000378:metabolism / Q000494:pharmacology; D005943:Gluconeogenesis / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D051381:Rats; D020218:Response Elements / Q000235:genetics*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C521959:BTG2 protein, rat; D017874:Immediate-Early Proteins; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone; D005934:Glucagon; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C069767:phosphoenolpyruvate carboxylase kinase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose