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

• DOI: 10.1053/j.gastro.2022.04.013
• Publication Date: 2022-04-21T10:01:48Z
• 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
• Keywords: Acinar-to-Ductal Metaplasia; 1.1 Normal biological development and functioning; Knockout; Clinical Sciences; 610; Clinical sciences; Acinar Cells; Paediatrics and Reproductive Medicine; Mice; Pancreatic Acinar Cells; Pancreatitis, Chronic; Genetics; 2.1 Biological and endogenous factors; Animals; Humans; ERR gamma; Chronic; Pancreas; Cancer; Mice, Knockout; Nutrition and Dietetics; Biomedical and Clinical Sciences; Gastroenterology & Hepatology; Mitochondrial Oxidative Phosphorylation; ERRγ; Neurosciences; Estrogens; Pancreas, Exocrine; 3. Good health; Nutrition and dietetics; Pancreatitis; North American Pancreatitis Study 2 (NAPS2) Consortium; Digestive Diseases; Reactive Oxygen Species; Exocrine

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.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.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.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.