Retinoids stimulate fibrinogen production both in vitro (hepatocytes) and in vivo. Induction requires activation of the retinoid X receptor.
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 mumol/L all-trans retinoic acid (T-RA) for 24 hours. A comparable increase was observed for both de novo fibrinogen synthesis and fibrinogen beta chain mRNA level. In primary cultures of human hepatocytes, treatment with 1 mumol/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]benzoi c 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 alpha (RAR alpha) 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 alpha agonist. However, incubation of HepG2 cells with RXR agonist together with RAR alpha agonist resulted in a further increase in fibrinogen production. The secretion of two other acute-phase proteins, alpha-antichymotrypsin and caeruloplasmin, was also stimulated by retinoids in HepG2 cells but by a different regulatory mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
Nicodeme
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Laboratoires Glaxo, Centre de Recherches, ZA de Courtaboeuf, Les Ulis, France.
Nicaud
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Issandou
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D000818:Animals; D000077610:Bexarotene; D002478:Cells, Cultured; D005340:Fibrinogen / Q000096:biosynthesis*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism*; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D014212:Tretinoin; D005340:Fibrinogen; D000077610:Bexarotene