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Regulation of Hepatic Gene Expression by Thyroid Hormone
Author(s) -
Attia Ramy Raafat,
Connaughton Sara,
Cook George A,
Elam Marshall B,
Park Edwards A
Publication year - 2009
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.23.1_supplement.680.2
Subject(s) - pdk4 , pyruvate dehydrogenase kinase , coactivator , pyruvate dehydrogenase complex , pyruvate dehydrogenase phosphatase , response element , foxo1 , transcription factor , nuclear receptor , thyroid hormone receptor , biology , chemistry , endocrinology , biochemistry , receptor , gene , gene expression , promoter , enzyme
Thyroid hormone (T3) is a key regulator of several processes including development and metabolic rate. Our laboratory has investigated the regulation of hepatic genes by T3. Here, we examined the mechanisms by which T3 activates the pyruvate dehydrogenase kinase (PDK4) gene. 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 the metabolism of glucose and pyruvate. We identified a T3 response element in the PDK4 gene and demonstrated that the T3 receptor binds this element. The peroxisome proliferator activated receptor gamma coactivator (PGC‐1a) is a transcriptional coactivator that promotes hepatic gluconeogenesis and fatty acid oxidation. We found that PGC‐1a is associated with the PDK4 gene following T3 administration and that the abundance of PGC‐1a is increased by T3. We explored the role of several transcription factors including estrogen related receptor (ERRa), CCAAT/enhancer binding protein beta (C/EBPß), forkhead transcription factor (FOXO1) in the activation of the PDK4 gene by T3. Moreover, we identified a number of factors including ERRa that are induced by T3. Our results suggest that the hepatic actions of T3 are mediated in part by the induction of transcription factors as well as the recruitment of coactivators to T3 responsive genes.