The gene encoding fibrinogen-β is a target for retinoic acid receptor-related orphan receptor α

Abstract

Fibrinogen is a plasma protein synthesized by the liver. It is composed of three chains (α, β, γ). In addition to its main function as a coagulation factor, this acute phase protein is also a risk marker for atherosclerosis. Retinoic acid receptor-related orphan receptor (ROR)α is a nuclear receptor modulating physiopathological processes such as cerebellar ataxia, inflammation, atherosclerosis, and angiogenesis. In this study, we identified RORα as a regulator of fibrinogen-β gene expression in human hepatoma cells and in mouse liver. A putative RORα response element (RORE) was identified in the human fibrinogen-β promoter. EMSA showed that RORα binds specifically to this RORE, and cotransfection experiments in HepG2 hepatoma cells indicated that this RORE confers RORα-dependent transcriptional activation to both the human fibrinogen-β and the thymidine kinase promoters. Stable transfection experiments in HepG2 and Hep3B hepatoma cells demonstrated that overexpression of RORα specifically increases endogenous fibrinogen-β mRNA levels. Chromatin immunoprecipitation experiments revealed that the fibrinogen-β RORE is occupied by RORα in HepG2 cells. Thus, the human fibrinogen-β gene is a direct target for RORα. Furthermore, fibrinogen-β mRNA levels in liver and plasma fibrinogen concentrations are specifically decreased in staggerer mice, which are homozygous for a deletion invalidating the Rora gene. Taken together, these data add further evidence for an important role of RORα in the control of liver gene expression with potential pathophysiological consequences on coagulation and cardiovascular risk. Copyright © 2005 by The Endocrine Society.