Mechanisms responsible for regulation of pyruvate dehydrogenase kinase 4 gene expression

Hye Sook Kwon, Robert A. Harris

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Starvation and diabetes greatly increase expression of PDK4, one of four kinase isoenzymes responsible for phosphorylation and inactivation of the PDH complex. This leads to conservation of glucose and the three-carbon compounds (lactate, alanine, and pyruvate) that serve as primary substrates for gluconeogenesis. Conservation of gluconeogenic substrates helps maintain euglycemia during starvation but exacerbates hyperglycemia in diabetes. Human PDK4 expression appears to be highly repressed in the basal state by histone deacetylation. In starvation and diabetic states, elevated levels of glucocorticoids activate GR and thereby recruit a p300/CBP coactivator complex to the PDK4 gene. FOXO factors and activated RARs interact cooperatively with the p300/CBP coactivator complex to make a stable transcriptional initiation complex leading to full activation of PDK4 gene expression. Insulin promotes inactivation and translocation of FOXO factors from the nucleus to the cytoplasm and thereby suppresses glucocorticoid-stimulated PDK4 gene transcription. These mechanisms are important for regulation of the level of PDK4 expression in many tissues of the body in the fed, starved, and diabetic states. Related mechanisms are likely responsible for regulation of PDK4 gene expression in rodents.

Original languageEnglish (US)
Pages (from-to)109-121
Number of pages13
JournalAdvances in Enzyme Regulation
Volume44
Issue number1
DOIs
StatePublished - Dec 13 2004

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research

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