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

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 (ERR gamma) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERR gamma inhibition, GSK5182-treated wild-type mice and ERR gamma conditional knockout (cKO) mice, were established to investigate ERR gamma function in the exocrine pancreas. To identify the functional role of ERR gamma in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERR gamma 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 ERR gamma 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 ERR gamma 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 ERR gamma deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERR gamma-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERR gamma in acinar-to-ductal metaplasia. Consistent with our findings in ERR gamma cKO mice, ERR gamma 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 ERR gamma that are associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERR gamma in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERR gamma and exocrine pancreas disorders.