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

David T. Duong, Mary E. Waltner-Law, Rosalie Sears, Linda Sealy, Daryl K. Granner

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

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 β (C/EBPβ), can recruit CBP to drive transcription. Insulin increases protein levels of liver-enriched transcriptional inhibitory protein (LIP), an inhibitory form of C/EBPβ, 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.

Original languageEnglish (US)
Pages (from-to)32234-32242
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number35
DOIs
StatePublished - Aug 30 2002
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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