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

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