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Estrogen-Related Receptor γ Maintains Pancreatic Acinar Cell Function and Identity by Regulating Cellular Metabolism

Authors
Choi, JinhyukOh, Tae GyuJung, Hee-WonPark, Kun-YoungShin, HyemiJo, TaeheeKang, Du-SeockChanda, DipanjanHong, SujungKim, JinaHwang, HayoungJi, MoongiJung, MinkyoShoji, TakashiMatsushima, AyamiKim, PilhanMun, Ji YoungPaik, Man-JeongCho, Sung JinLee, In-KyuWhitcomb, David C.Greer, PhilBlobner, BrandonGoodarzi, Mark O.Pandol, Stephen J.Rotter, Jerome I.Fan, WeiweiBapat, Sagar P.Zheng, YeLiddle, ChrisYu, Ruth T.Atkins, Annette R.Downes, MichaelYoshihara, EijiEvans, Ronald M.Suh, Jae Myoung
Issue Date
Jul-2022
Publisher
W. B. Saunders Co., Ltd.
Keywords
ERR gamma; Pancreatic Acinar Cells; Mitochondrial Oxidative Phosphorylation; Reactive Oxygen Species; Acinar-to-Ductal Metaplasia
Citation
Gastroenterology, v.163, no.1, pp.239 - 256
Journal Title
Gastroenterology
Volume
163
Number
1
Start Page
239
End Page
256
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/223
DOI
10.1053/j.gastro.2022.04.013
ISSN
0016-5085
Abstract
Background & Aims: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. Methods: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in 2 distinct human pancreatitis cohorts. Results: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss of ERRγ in primary acini abrogates messenger RNA expression and protein levels of mitochondrial oxidative phosphorylation complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared with normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants for ERRγ that are associated with chronic pancreatitis. Conclusions: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.
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