Orphan Nuclear Receptor Errγ Induces C-Reactive Protein Gene Expression through Induction of ER-Bound Bzip Transmembrane Transcription Factor CREBH

The orphan nuclear receptor estrogen-related receptor-gamma (ERR gamma) is a constitutively active transcription factor regulating genes involved in several important cellular processes, including hepatic glucose metabolism, alcohol metabolism, and the endoplasmic reticulum (ER) stress response. cAMP responsive element-binding protein H (CREBH) is an ER-bound bZIP family transcription factor that is activated upon ER stress and regulates genes encoding acute-phase proteins whose expression is increased in response to inflammation. Here, we report that ERR gamma directly regulates CREBH gene expression in response to ER stress. ERR gamma bound to the ERR gamma response element (ERRE) in the CREBH promoter. Overexpression of ERR gamma by adenovirus significantly increased expression of CREBH as well as C-reactive protein (CRP), whereas either knockdown of ERR gamma or inhibition of ERR gamma by ERR gamma specific inverse agonist, GSK5182, substantially inhibited ER stress-mediated induction of CREBH and CRP. The transcriptional coactivator PGC1 alpha was required for ERR gamma mediated induction of the CREBH gene as demonstrated by the chromatin immunoprecipitation (ChIP) assay showing binding of both ERR gamma and PGC1 alpha on the CREBH promoter. The ChIP assay also revealed that histone H3 and H4 acetylation occurred at the ERR gamma and PGC1 alpha binding site. Moreover, chronic alcoholic hepatosteatosis, as well as the diabetic obese condition significantly increased CRP gene expression, and this increase was significantly attenuated by GSK5182 treatment. We suggest that orphan nuclear receptor ERR gamma directly regulates the ER-bound transcription factor CREBH in response to ER stress and other metabolic conditions.