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Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by thyroid hormone: role of peroxisome proliferator activated receptor gamma coactivator (PGC‐1α)
Author(s) -
Attia Ramy Raafat,
Connaughton Sara,
Wang Fang,
Elam Marshall B.,
Cook George A.,
Park Edwards A.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.661.1
Subject(s) - pdk4 , pyruvate dehydrogenase kinase , pyruvate dehydrogenase complex , pyruvate dehydrogenase phosphatase , coactivator , endocrinology , phosphoenolpyruvate carboxykinase , chemistry , pyruvate decarboxylation , medicine , peroxisome proliferator activated receptor , gluconeogenesis , biology , biochemistry , receptor , gene , metabolism , transcription factor , enzyme
Pyruvate dehydrogenase kinase 4 (PDK4) regulates pyruvate oxidation through the phosphorylation and inhibition of the pyruvate dehydrogenase complex (PDC). PDC catalyzes the conversion of pyruvate to acetyl‐CoA and is an important control point in glucose and pyruvate metabolism. PDK4 gene expression is stimulated by thyroid hormone (T 3 ), glucocorticoids and long chain fatty acids. Here, we have identified two binding sites for the thyroid hormone receptor (TRß) in the promoter of the PDK4 gene. In addition, we have investigated the role of transcriptional coactivators and found that the peroxisome proliferator activated receptor gamma coactivator (PGC‐1α) enhances the T 3 induction of PDK4. Addition of T 3 to rat hepatocytes increased the abundance of the PGC‐1α and its association with the PDK4 promoter. Administration of T 3 to hypothyroid rats increased PGC‐1α protein levels in the liver. In addition, we observed enhanced association of PGC‐1α not only with the PDK4 gene but also with phosphoenolpyruvate carboxykinase (PEPCK) and carnitine palmitoyltransferase 1a (CPT‐1a) genes. Knock‐down of PGC‐1α in rat hepatocytes reduced the T 3 induction of PDK4, PEPCK and CPT‐1a genes. Our results indicate that T 3 regulates PGC‐1α abundance and association with hepatic genes and in turn PGC‐1α is an important participant in the T 3 induction of selected genes.