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

[Author] 

Jinhyuk Choi ¹, Tae Gyu Oh ², Hee-Won Jung ¹, Kun-Young Park ¹, Hyemi Shin ¹, Taehee Jo ¹, Du-Seock Kang ¹, Dipanjan Chanda ^3 4, Sujung Hong ¹, Jina Kim ⁵, Hayoung Hwang ⁵, Moongi Ji ⁶, Minkyo Jung ⁷, Takashi Shoji ⁸, Ayami Matsushima ⁹, Pilhan Kim ¹, Ji Young Mun ⁷, Man-Jeong Paik ⁶, Sung Jin Cho ⁵, In-Kyu Lee ^3 4 10 11, David C. Whitcomb ^12 13 14, Phil Greer ^12 13, Brandon Blobner ¹³, Mark O. Goodarzi ¹⁵, Stephen J. Pandol ^16 17, Jerome I. Rotter ^18 19, North American Pancreatitis Study 2 (NAPS2) Consortium, Weiwei Fan ², Sagar P. Bapat ^{2 20 21 22}, Ye Zheng ²², Chris Liddle ²³, Ruth T. Yu ², Annette R. Atkins ², Michael Downes ², Eiji Yoshihara ^2 24 25, Ronald M. Evans ², Jae Myoung Suh ¹
 

¹ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

² Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California

³ Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea

⁴ Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu, Republic of Korea

⁵ New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea

⁶ College of Pharmacy, Sunchon National University, Suncheon, Republic of Korea

⁷ Neural Circuit Research Group, Korea Brain Research Institute, Daegu, Republic of Korea

⁸ Department of Medicine, Kyoto University, Kyoto, Japan

⁹ Laboratory of Structure-Function Biochemistry, Department of Chemistry, Faculty of Science, Kyushu University, Fukuoka, Japan

¹⁰ Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea

¹¹ Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

¹² Ariel Precision Medicine, Pittsburgh, Pennsylvania

¹³ Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

¹⁴ Department of Cell Biology and Molecular Physiology and the Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania

¹⁵ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California

¹⁶ Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, California

¹⁷ Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California

¹⁸ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California

¹⁹ Departments of Pediatrics and Human Genetics, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California

²⁰ Department of Laboratory Medicine, University of California-San Francisco, San Francisco, California

²¹ Diabetes Center, University of California-San Francisco, San Francisco, California

²² Nomis Laboratories for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, California

²³ Storr Liver Centre, Westmead Institute for Medical Research and Sydney School of Medicine, University of Sydney, Westmead, New South Wales, Australia

²⁴ The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California

²⁵ David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California

[Journal] 

Gastroenterology 2022;163:239–256


[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.