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-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.
National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Jagannath
J
Misra
National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Dipanjan
D
Chanda
National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Don-Kyu
DK
Kim
National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Seung-Rye
SR
Cho
Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Seung-Hoi
SH
Koo
Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Chul-Ho
CH
Lee
School of Biological Sciences, University of Ulsan, Ulsan, South Korea.
Sung Hoon
SH
Back
National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea ; Research Institute of Medical Sciences, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
Hueng-Sik
HS
Choi
D000438:Alcohols / Q000008:administration & dosage; D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D000438:Alcohols; C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C490916:Esrrg protein, mouse; D011960:Receptors, Estrogen; D002097:C-Reactive Protein