REGULATION OF CORTICOSTEROID-BINDING GLOBULIN SYNTHESIS BY 1-ALPHA,25-DIHYDROXY-VITAMIN-D-3 (CALCITRIOL), 9-CIS-RETINOIC ACID AND TRIIODOTHYRONINE IN CULTURED RAT FETAL HEPATOCYTES

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 i nvestigate the involvement and possible interplay in this process of s everal members of the nuclear receptors superfamily: vitamin D (VDR), retinoic acids (RAR/RXR) and thyroid hormones (TR). Treatment of cells with 1 alpha,25-(OH)(2)D-3 (1,25-D) elicited a dose-dependent inhibit ion of basal CBG concentration in culture medium. Maximum inhibition t o about 15% of control level was achieved with 0.1-1.0 nM, with an IC5 0 of 3.8 x 10(-12) M and with no significant change in binding affinit y. Differential activation of RAR and RXR with either 9-cis-retinoic a cid (9-cis-RA) or the RAR-selective synthetic retinoid TTNPB revealed that high doses of both drugs diminished CBG expression, though the fo rmer proved about 10-times more potent than the latter in this regard. Amplification by triiodothyronine (T-3) of CBG synthesis failed to bl ock 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 alpha-fetoprotein (AFP), while on the contrary, retinoids and T-3 were shown to cause opposite effect s, as 9-cis-RA and TTNPB elevated and T-3 decreased AFP expression. Th e present findings identify for the first time ligands of VDR and RAR/ RXR as powerful negative regulators of both basal and T-3-stimulated C BG biosynthesis in fetal hepatocytes and suggest lack of a functional interplay between TR and VR or RAR/RXR in these processes. (C) 1996 El sevier Science Ltd.