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The effect of prosthetic rehabilitation and simple dietary counseling on food intake and oral health related quality of life among the edentulous individuals: A randomized controlled trial
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Estrogen-Related Receptor Ī³ Maintains Pancreatic Acinar Cell Function and Identity by Regulating Cellular Metabolism
Background & aimsMitochondrial 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 Ī³ (ERRĪ³) in pancreatic acinar cell mitochondrial homeostasis and energy production.MethodsTwo models of ERRĪ³ inhibition, GSK5182-treated wild-type mice and ERRĪ³ conditional knock-out (cKO) mice, were established to investigate ERRĪ³ function in the exocrine pancreas. To identify the functional role of ERRĪ³ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRĪ³ 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.ResultsBlocking ERRĪ³ 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 ERRĪ³ 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 ERRĪ³ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRĪ³-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRĪ³ in acinar-to-ductal metaplasia. Consistent with our findings in ERRĪ³ cKO mice, ERRĪ³ 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 ERRĪ³ that are associated with chronic pancreatitis.ConclusionsCollectively, our findings highlight an essential role for ERRĪ³ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRĪ³ and exocrine pancreas disorders