Insulin inhibits hepatocellular glucose production by utilizing liver-enriched transcriptional inhibitory protein to disrupt the association of CREB-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter.
Hormones regulate glucose homeostasis, in part, by controlling the expression of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK). Insulin and glucocorticoids reciprocally regulate PEPCK expression primarily at the level of gene transcription. We demonstrate here that glucocorticoids promote, whereas insulin disrupts, the association of CREB-binding protein (CBP) and RNA polymerase II with the hepatic PEPCK gene promoter in vivo. We also show that accessory factors, such as CCAAT/enhancer-binding protein beta (C/EBP beta), can recruit CBP to drive transcription. Insulin increases protein levels of liver-enriched transcriptional inhibitory protein (LIP), an inhibitory form of C/EBP beta, in a phosphatidylinositol 3-kinase-dependent manner. LIP concomitantly replaces liver-enriched transcriptional activator protein on the PEPCK gene promoter, which can abrogate the recruitment of CBP and polymerase II, culminating in the repression of PEPCK expression and the attenuation of hepatocellular glucose production.
Duong
David T
DT
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Waltner-Law
Mary E
ME
Sears
Rosalie
R
Sealy
Linda
L
Granner
Daryl K
DK
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002843:Chromatin / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors*; D005938:Glucocorticoids / Q000494:pharmacology; D005947:Glucose / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007700:Kinetics; D008114:Liver Neoplasms, Experimental; D008156:Luciferases / Q000235:genetics; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D022782:CCAAT-Enhancer-Binding Protein-beta; D002843:Chromatin; D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids; D007328:Insulin; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D000242:Cyclic AMP; D008156:Luciferases; D012319:RNA Polymerase II; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose