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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1660-1667.)
© 1995 American Heart Association, Inc.

Articles

Retinoids Stimulate Fibrinogen Production Both In Vitro (Hepatocytes) and In Vivo

Induction Requires Activation of the Retinoid X Receptor

Edwige Nicodeme; Michael Nicaud; Marc Issandou

From the Laboratoires Glaxo, Centre de Recherches, ZA de Courtaboeuf, Les Ulis, France.

Correspondence to Marc Issandou, Laboratoires Glaxo, Centre de Recherches, ZA de Courtaboeuf, 25 avenue du Quebec, 91951 Les Ulis Cedex, France.

Abstract The in vitro effects of retinoids on fibrinogen synthesis were investigated in HepG2 cells and primary human hepatocytes. In vivo effects were studied in the rat. In HepG2 cells, maximal stimulation (twofold) of fibrinogen secretion was obtained when cells were incubated in the presence of 1 µmol/L all-trans retinoic acid (T-RA) for 24 hours. A comparable increase was observed for both de novo fibrinogen synthesis and fibrinogen ß chain mRNA level. In primary cultures of human hepatocytes, treatment with 1 µmol/L T-RA for 72 hours also gave a twofold increase in fibrinogen production. Furthermore, rats treated for 6 days with 100 mg · kg^-1 · d^-1 T-RA presented increased fibrinogen plasma levels (110%). A selective retinoic X receptor (RXR) agonist, 4-[1-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic acid (3-methyl TTNEB), as well as 9-cis retinoic acid, a natural RXR ligand, mimicked the effects of T-RA on fibrinogen synthesis in vitro at lower concentrations. In contrast, a selective retinoic A receptor (RAR) agonist was a poor activator. The ED₅₀ of the different retinoids on fibrinogen secretion by HepG2 cells was 25 nmol/L for T-RA, 4 nmol/L for 9-cis retinoic acid, 11 nmol/L for the synthetic RXR agonist, and >500 nmol/L for the RAR agonist. However, incubation of HepG2 cells with RXR agonist together with RAR agonist resulted in a further increase in fibrinogen production. The secretion of two other acute-phase proteins, -antichymotrypsin and caeruloplasmin, was also stimulated by retinoids in HepG2 cells but by a different regulatory mechanism. We conclude that activation of RXR by a specific ligand upregulates fibrinogen production by hepatocytes. Elevated levels of fibrinogen in rats treated with T-RA indicate that retinoids may be involved in the physiological regulation of fibrinogen, with a key role for RXR.

Key Words: retinoic A receptor • retinoic X receptor agonist • fibrinogen • retinoids