Regulation of corticosteroid-binding globulin synthesis by 1α,25-dihydroxyvitamin D 3 (calcitriol), 9- cis-retinoic acid and triiodothyronine in cultured rat fetal hepatocytes

Abstract

Evidence regarding the nature of the regulatory factors which directly act upon liver cells and extra-hepatic tissues to alter CBG synthesis is scarce. The present study used cultured rat fetal hepatocytes to investigate the involvement and possible interplay in this process of several members of the nuclear receptors superfamily: vitamin D (VDR), retinoic acids (RAR/RXR) and thyroid hormones (TR). Treatment of cells with 1α,25-(OH) 2D 3 (1,25-D) elicited a dose-dependent inhibition of basal CBG concentration in culture medium. Maximum inhibition to about 15% of control level was achieved with 0.1–1.0 nM, with an IC 50 of 3.8 × 10 −12 M and with no significant change in binding affinity. Differential activation of RAR and RXR with either 9- cis-retinoic acid (9- cis-RA) or the RAR-selective synthetic retinoid TTNPB revealed that high doses of both drugs diminished CBG expression, though the former proved about 10-times more potent than the latter in this regard. Amplification by triiodothyronine (T 3) of CBG synthesis failed to block the inhibitory effects of either 1,25-D or retinoids, as revealed by both binding capacity and mRNA measurements. Relative to CBG, 1,25-D similarly depressed the synthesis of α-fetoprotein (AFP), while on the contrary, retinoids and T 3 were shown to cause opposite effects, as 9- cis-RA and TTNPB elevated and T 3 decreased AFP expression. The present findings identify for the first time ligands of VDR and RAR/RXR as powerful negative regulators of both basal and T 3-stimulated CBG biosynthesis in fetal hepatocytes and suggest lack of a functional interplay between TR and VR or RAR/RXR in these processes.