BET Inhibition Rescues Acinar-Ductal-Metaplasia and Ciliogenesis and Ameliorates Chronic Pancreatitis-Driven Changes in Mice With Loss of the Polarity Protein Par3.

Autor:	Shields MA; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois. Electronic address: mario.shields@stonybrook.edu., Metropulos AE; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois., Spaulding C; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois., Alzahrani KA; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois., Hirose T; Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama, Japan; Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan., Ohno S; Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama, Japan., Pham TND; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois., Munshi HG; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois; Jesse Brown VA Medical Center, Chicago, Illinois. Electronic address: h-munshi@northwestern.edu.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2024; Vol. 18 (5), pp. 101389. Date of Electronic Publication: 2024 Aug 10.
DOI:	10.1016/j.jcmgh.2024.101389
Abstrakt:	Background & Aims: The apical-basal polarity of pancreatic acinar cells is essential for maintaining tissue architecture. However, the mechanisms by which polarity proteins regulate acinar pancreas injury and regeneration are poorly understood. Methods: Cerulein-induced pancreatitis was induced in mice with conditional deletion of the polarity protein Par3 in the pancreas. The impact of Par3 loss on pancreas injury and regeneration was assessed by histologic analyses and transcriptional profiling by RNA sequencing. Mice were pretreated with the bromodomain and extraterminal domain (BET) inhibitor JQ1 before cotreatment with cerulein to determine the effect of BET inhibition on pancreas injury and regeneration. Results: Initially, we show that Par3 is increased in acinar-ductal metaplasia (ADM) lesions present in human and mouse chronic pancreatitis specimens. Although Par3 loss disrupts tight junctions, Par3 is dispensable for pancreatogenesis. However, with aging, Par3 loss results in low-grade inflammation, acinar degeneration, and pancreatic lipomatosis. Par3 loss exacerbates acute pancreatitis-induced injury and chronic pancreatitis-induced acinar cell loss, promotes pancreatic lipomatosis, and prevents regeneration. Par3 loss also results in suppression of chronic pancreatitis-induced ADM and primary ciliogenesis. Notably, targeting BET proteins attenuates chronic pancreatitis-induced loss of primary cilia and promotes ADM in mice lacking pancreatic Par3. Targeting BET proteins also attenuates cerulein-induced acinar cell loss and enhances recovery of acinar cell mass and body weight of mice lacking pancreatic Par3. Conclusions: Combined, this study demonstrates how Par3 restrains chronic pancreatitis-induced changes in the pancreas and identifies a potential role for BET inhibitors to attenuate pancreas injury and facilitate regeneration. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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