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

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Publication Year:
2022
Authors:
Jinhyuk Choi, Tae Gyu Oh, Hee-Won Jung, Kun-Young Park, Hyemi Shin, Taehee Jo, Du-Seock Kang, Dipanjan Chanda, Sujung Hong, Jina Kim, Hayoung Hwang, Moongi Ji, Minkyo Jung, Takashi Shoji, Ayami Matsushima, Pilhan Kim, Ji Young Mun, Man-Jeong Paik, Sung Jin Cho, In-Kyu Lee, David C Whitcomb, Phil Greer, Brandon Blobner, Mark O Goodarzi, Stephen J Pandol, Jerome I Rotter, Weiwei Fan, Sagar P Bapat, Ye Zheng, Chris Liddle, Ruth T Yu, Annette R Atkins, Michael Downes, Eiji Yoshihara, Ronald M Evans, Jae Myoung Suh
PubMed ID:
35461826
Funding Grants:
Public Summary:
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 gamma (ERRgamma) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRgamma inhibition, GSK5182-treated wild-type mice and ERRgamma conditional knock-out (cKO) mice, were established to investigate ERRgamma function in the exocrine pancreas. To identify the functional role of ERRgamma in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRgamma 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 ERRgamma 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 ERRgamma 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 ERRgamma deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRgamma-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRgamma in acinar-to-ductal metaplasia. Consistent with our findings in ERRgamma cKO mice, ERRgamma 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 ERRgamma that are associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRgamma in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRgamma and exocrine pancreas disorders.
Scientific 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 gamma (ERRgamma) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRgamma inhibition, GSK5182-treated wild-type mice and ERRgamma conditional knock-out (cKO) mice, were established to investigate ERRgamma function in the exocrine pancreas. To identify the functional role of ERRgamma in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRgamma 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 ERRgamma 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 ERRgamma 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 ERRgamma deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRgamma-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRgamma in acinar-to-ductal metaplasia. Consistent with our findings in ERRgamma cKO mice, ERRgamma 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 ERRgamma that are associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRgamma in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRgamma and exocrine pancreas disorders.