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

Abstract

Thyroid hormones are important regulators of differentiation, growth, metabolism, and physiological function of virtually all tissues. Active thyroid hormone T(3) 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 T(3) stimulates HIF-1 activation, which intimately links T(3) and HIF-1 induced gene expression. Here, we studied intracellular pathways that mediate HIF-1alpha regulation by T(3). We found that T(3)-dependent HIF-1 activation is not limited to hepatoma cells but is also observed in primary human hepatocytes, kidney and lung carcinoma cells. T(3) increased the HIF-1alpha subunit mRNA and protein within a few hours through activation of the thyroid hormone receptor beta retinoid X receptor alpha heterodimer because knockdown of each of the partners abrogated the stimulation by T(3). However, T(3) had no direct effect on transcription of HIF-1alpha, but activation of the thyroid hormone receptor beta/retinoid X receptor alpha heterodimer by T(3) stimulated expression of the hepatic leukemia factor, which increases HIF-1alpha gene expression.