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PERK mediates oxidative stress and adipogenesis in Graves' orbitopathy pathogenesis

Authors
 JaeSang Ko  ;  Ji-Young Kim  ;  Min Kyoung Chae  ;  Eun Jig Lee  ;  Jin Sook Yoon 
Citation
 JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol.66(4) : 313-323, 2021-05 
Journal Title
JOURNAL OF MOLECULAR ENDOCRINOLOGY
ISSN
 0952-5041 
Issue Date
2021-05
Keywords
Graves’ orbitopathy ; PERK ; endoplasmic reticulum stress ; protein kinase RNA-like endoplasmic reticulum kinase ; thyroid eye disease
Abstract
We examined endoplasmic reticulum (ER) stress-related gene expression in orbital tissues from patients with Graves' orbitopathy (GO) and the effects of silencing protein kinase RNA-like endoplasmic reticulum kinase (PERK) in primary orbital fibroblast cultures to demonstrate the therapeutic potential of PERK-modulating agents in GO management. The expression of ER stress-related genes in orbital tissue harvested from individuals with or without GO was studied using real-time PCR. The role of PERK in GO pathogenesis was examined through small-interfering RNA (siRNA)-mediated silencing in cultured primary orbital fibroblasts. Intracellular reactive oxygen species (ROS) levels induced in response to cigarette smoke extract (CSE) or hydrogen peroxide were measured using 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. Cells were stained with Oil Red O, and adipogenesis-related transcription factor expression was evaluated through Wwestern blotting after adipogenic differentiation. PERK, activating transcription factor 4 (ATF4), and CCAAT-enhancer-binding protein (C/EBP)-homologous protein (CHOP) mRNA levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. PERK silencing inhibited CSE- or hydrogen peroxide-induced ROS generation. After adipogenic differentiation, GO orbital fibroblasts revealed decreased lipid droplets and downregulation of C/EBPα, C/EBPβ, and peroxisome proliferator-activator gamma (PPARγ) in PERK siRNA-transfected cells. The orbital tissues of patients with GO were exposed to chronic ER stress and subsequently exhibited enhanced unfolded protein response (especially through the PERK pathway). PERK silencing reduced oxidative stress and adipogenesis in GO orbital fibroblasts in vitro. Our results imply that PERK-modulating agents can potentially be used to manage GO.
Full Text
https://jme.bioscientifica.com/view/journals/jme/66/4/JME-21-0057.xml
DOI
10.1530/JME-21-0057
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Ophthalmology (안과학교실) > 1. Journal Papers
Yonsei Authors
Ko, Jaesang(고재상) ORCID logo https://orcid.org/0000-0002-3011-7213
Yoon, Jin Sook(윤진숙) ORCID logo https://orcid.org/0000-0002-8751-9467
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/184264
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