TRIIODOTHYRONINE INCREASES INSULIN-LIKE-GROWTH-FACTOR BINDING PROTEIN-4 EXPRESSION IN RAT HEPATOCYTES

Previous in vivo studies demonstrated significant variations in insuli n-like growth factor binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-4 hepatic mRNAs and/or serum levels depending on the rat thyroid status. In this study we employed cultured hepatocytes from adult rats to dem onstrate a possible direct regulation of these genes by tri-iodothyron ine (T-3). Northern blot analysis revealed that IGFBP-1 and -4 message s were clearly expressed, whereas IGFBP-2 signal was barely detectable . No significant effects on IGFBP-1 mRNA level or on peptide secretion were detected in T-3-cultured hepatocytes. In contrast, significant i ncreases in IGFBP-4 mRNA steady-state levels as well as in IGFBP-4 sec retion were observed in hepatocytes cultured for 12-24 h in the presen ce of T-3. The T-3 effect on IGFBP-1 transcript levels appears to cons ist of enhanced gene transcription and is independent of ongoing prote in synthesis. The T-3-increased IGFBP-1 expression in cultured hepatoc ytes is consistent with our in vivo experiments demonstrating an incre ase in hepatic IGFBP-4 mRNA and serum IGFBP-4 levels in T-3-treated ra ts. Furthermore, significant decreases in hepatic IGFBP-4 message and serum IGFBP-4 levels were observed in hypothyroid rats compared with e uthyroid controls. Our data establish an important direct role for thy roid hormone in regulating IGFBP-4 expression and consequently IGF act ivity.