Abstract
The orphan nuclear receptor estrogen-related receptor-γ (ERRγ) 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 ERRγ directly regulates CREBH gene expression in response to ER stress. ERRγ bound to the ERRγ response element (ERRE) in the CREBH promoter. Overexpression of ERRγ by adenovirus significantly increased expression of CREBH as well as C-reactive protein (CRP), whereas either knockdown of ERRγ or inhibition of ERRγ by ERRγ specific inverse agonist, GSK5182, substantially inhibited ER stress-mediated induction of CREBH and CRP. The transcriptional coactivator PGC1α was required for ERRγ mediated induction of the CREBH gene as demonstrated by the chromatin immunoprecipitation (ChIP) assay showing binding of both ERRγ and PGC1α on the CREBH promoter. The ChIP assay also revealed that histone H3 and H4 acetylation occurred at the ERRγ and PGC1α 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 ERRγ directly regulates the ER-bound transcription factor CREBH in response to ER stress and other metabolic conditions.
Highlights
Estrogen-related receptors (ERRs) are members of the NR3B subfamily of nuclear receptors which include ERRa, ERRb, and estrogen-related receptor-c (ERRc)
We previously reported that hepatic ERRc regulates hepatic gluconeogenesis by directly binding to the Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose 6phosphatase (G6Pase) promoters along with coactivator PGC-1a
endoplasmic reticulum (ER) stress activates the unfolded protein response to generate multiple transcription factors that function in different cellular phenomena including chromatin remodeling [40,41,42,43,44]
Summary
Estrogen-related receptors (ERRs) are members of the NR3B subfamily of nuclear receptors which include ERRa, ERRb, and ERRc. We previously reported that hepatic ERRc regulates hepatic gluconeogenesis by directly binding to the Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose 6phosphatase (G6Pase) promoters along with coactivator PGC-1a [5]. Previous results from our laboratory demonstrated that ERRc directly binds to the LIPIN1 promoter along with coactivator PGC-1a to regulate LIPIN1 gene expression, and inhibits hepatic insulin signaling [6]. ERRa and ERRc regulate mitochondrial programs involved in oxidative phosphorylation and a nuclear-encoded mitochondrial genetic network that coordinates the postnatal metabolic transition in the heart [9]. Though all these reports clearly suggest a key role of ERRc in different cellular processes, its role in ER stress is yet to be determined
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