This Article Full Text Full Text (PDF) All Versions of this Article: 149/5/2241    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Google Scholar Articles by Otto, T. Articles by Fandrey, J. PubMed PubMed Citation Articles by Otto, T. Articles by Fandrey, J.

Thyroid Hormone Induces Hypoxia-Inducible Factor 1 Gene Expression through Thyroid Hormone Receptor β/Retinoid X Receptor -Dependent Activation of Hepatic Leukemia Factor

Institut für Physiologie, Universität Duisburg-Essen, D-45122 Essen, Germany

Address all correspondence and requests for reprints to: Joachim Fandrey, M.D., Institut für Physiologie, Universität Duisburg-Essen, Hufelandstrasse 55, D-45122 Essen, Germany. E-mail: joachim.fandrey{at}uni-due.de.

Thyroid hormones are important regulators of differentiation, growth, metabolism, and physiological function of virtually all tissues. Active thyroid hormone T₃ affects expression of genes that encode for angiogenic proteins like adrenomedullin or vascular endothelial growth factor and erythropoietin, as well as for glucose transporters and phospho fructokinase that determine glucose use. Interestingly, those target genes are also hypoxia inducible and under the control of the oxygen-dependent transcription factor hypoxia-inducible factor (HIF)-1). We and others have reported that T₃ stimulates HIF-1 activation, which intimately links T₃ and HIF-1 induced gene expression. Here, we studied intracellular pathways that mediate HIF-1 regulation by T₃. We found that T₃-dependent HIF-1 activation is not limited to hepatoma cells but is also observed in primary human hepatocytes, kidney and lung carcinoma cells. T₃ increased the HIF-1 subunit mRNA and protein within a few hours through activation of the thyroid hormone receptor β retinoid X receptor heterodimer because knockdown of each of the partners abrogated the stimulation by T₃. However, T₃ had no direct effect on transcription of HIF-1, but activation of the thyroid hormone receptor β/retinoid X receptor heterodimer by T₃ stimulated expression of the hepatic leukemia factor, which increases HIF-1 gene expression.