Thyroid hormones are essential for correct function of nearly all tissues and have major effects on proliferation, angiogenesis, gluconeogenesis and apoptosis, which is also part of the hypoxic adaptational response regulated by the transcription factor complex hypoxia inducible factor 1 (HIF-1). Especially in the liver many genes like e.g. Transforming Growth Factor b (TGFb) and Adrenomedullin (ADM) are target genes of both: the active form of thyroid hormones, 3,5,3'-tri-iodo-L-thyronine (T3), and HIF-1. HIF-1 is composed of an O2-labile a- and a constitutive b- subunit. We have recently reported that HIF-1a is elevated by T3, but whether this is mediated by nuclear or non-nuclear effects of T3 remains to be resolved. In this study we demonstrate that HIF-1a accumulation is caused by an increase in HIF-1a mRNA levels and that HIF-1 target genes are regulated by T3 in hepatocellular carcinoma cells (HepG2) as well as in primary human hepatocytes. We found that the thyroid hormone receptor b (TRb) plays an important role in regulating HIF-1a?transcription and thereby its target genes. In addition, analysis of several intracellular signal transduction pathways and nuclear receptors demonstrated a significant contribution of nuclear signalling to elicit T3 effects on HIF-1 as a link to T3 dependent genes.

Supported by a grant from the Deutsche Forschungsgemeinschaft

(Fa 225/18-2)