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Oxygen-Dependent Modulation of Insulin-Like Growth Factor Binding Protein Biosynthesis in Primary Cultures of Rat Hepatocytes

Medizinische Klinik und Poliklinik (J.-G.S.), Georg-August-Universität, D-37075 Göttingen, Germany; Department Biochemistry (T.K.), Faculty of Chemistry, University Kaiserslautern, D-67663 Kaiserslautern, Germany; and Departments of Medicine and Physiology and Biophysics (T.G.U.), University of Illinois at Chicago and Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612

Address all correspondence and requests for reprints to: Dr. Thomas Kietzmann, Department of Biochemistry, Faculty of Chemistry, University of Kaiserslautern, D-67663 Kaiserslautern, Germany. E-mail: tkietzm{at}gwdg.de.

Higher levels of IGF-binding protein 1 (IGFBP-1) mRNA are expressed in the less aerobic perivenous zone of the liver. Because gradients in oxygen tension (pO₂) may contribute to zonated gene expression, the influence of arterial and venous pO₂ on IGFBP-1 biosynthesis was studied in primary cultures of rat hepatocytes. Maximal IGFBP-1 mRNA and protein levels were observed under venous pO₂, whereas less than 30% of maximal levels were observed under arterial pO₂. In contrast, the expression of IGFBP-4 was greatest under arterial pO₂, indicating that this effect of hypoxia on IGFBP-1 gene expression is specific. The response to hypoxia appears to involve reactive oxygen species, because treatment with H₂O₂ results in a dose-dependent decrease of IGFBP-1 mRNA levels under venous pO₂, whereas IGFBP-1 mRNA expression under arterial pO₂ was not affected. Inhibition of the hypoxia-dependent IGFBP-1 mRNA induction by actinomycin D indicates that this effect is mediated at the level of gene transcription, and inhibition of IGFBP-1 mRNA by the iron chelator desferrioxamine under both venous and arterial pO₂ suggested the involvement of hypoxia-inducible transcription factors (HIF). Transfection experiments demonstrated that especially HIF-3 and HIF-2, and to a lesser extent HIF-1, contribute to the induction of IGFBP-1 mRNA expression in isolated hepatocytes, whereas experiments with vectors for the HIF prolyl hydroxylases (PHD) indicated a major role of PHD-2 in destabilization of HIFs, attenuating the induction of IGFBP-1 under venous pO₂. Reporter gene studies indicate that hypoxia stimulates IGFBP-1 expression through a putative HIF response element located approximately 250 bp upstream from the transcription initiation site. Together, these results support the concept that iron, radical oxygen species, and the HIF-2 and -3 as well as the PHD pathways play important roles in mediating effects of hypoxia on IGFBP-1 gene expression in the liver.

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