Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-α ligands, glucocorticoids, and insulin

Boli Huang, Pengfei Wu, Melissa M. Bowker-Kinley, Robert Harris

Research output: Contribution to journalArticle

178 Citations (Scopus)

Abstract

Pyruvate dehydrogenase kinase (PDK) catalyzes phosphorylation and inactivation of the pyruvate dehydrogenase complex (PDC). Two isoforms of this mitochondrial kinase (PDK2 and PDK4) are induced in a tissue-specific manner in response to starvation and diabetes. Inactivation of PDC by increased PDK activity promotes gluconeogenesis by conserving three-carbon substrates. This helps maintain glucose levels during starvation, but is detrimental in diabetes. Factors that regulate PDK2 and PDK4 expression were examined in Morris hepatoma 7800 C1 cells. The peroxisome proliferato-activated receptor-α (PPAR-α) agonist WY-14,643 and the glucocorticoid dexamethasone increased PDK4 mRNA levels. Neither compound affected the half-life of the PDK4 message, suggesting that both increase gene transcription. Fatty acids caused an increase in the PDK4 message comparable to that induced by WY-14,643. Insulin prevented and reversed the stimulatory effects of dexamethasone on PDK4 gene expression, but was less effective against the stimulatory effects of WY-14,643 and fatty acids. Insulin also decreased the abundance of the PDK2 message. The findings suggest that decreased levels of insulin and increased levels of fatty acids and glucocorticoids promote PDK4 gene expression in starvation and diabetes. The decreased level of insulin is likely responsible for the increase in PDK2 mRNA level in starvation and diabetes.

Original languageEnglish
Pages (from-to)276-283
Number of pages8
JournalDiabetes
Volume51
Issue number2
StatePublished - 2002

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Peroxisome Proliferator-Activated Receptors
Starvation
Glucocorticoids
Insulin
Pyruvate Dehydrogenase Complex
Ligands
Fatty Acids
Dexamethasone
Experimental Liver Neoplasms
Gene Expression
Messenger RNA
Peroxisomes
Gluconeogenesis
Half-Life
Protein Isoforms
Phosphotransferases
Carbon
Phosphorylation
Glucose
pyruvate dehydrogenase (acetyl-transferring) kinase

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-α ligands, glucocorticoids, and insulin. / Huang, Boli; Wu, Pengfei; Bowker-Kinley, Melissa M.; Harris, Robert.

In: Diabetes, Vol. 51, No. 2, 2002, p. 276-283.

Research output: Contribution to journalArticle

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