Par3 deficiency promotes fatty replacement in chronic pancreatitis

Chronic pancreatitis, characterized by a progressive and irreversible damage of the pancreas, is a major clinical challenge causing significant morbidity and reduced life expectancy. The histologic hallmarks of chronic pancreatitis include loss of acinar parenchyma, fibrosis and steatosis or fat replacement. Interestingly, morphologic changes in the pancreas during aging are similar to those seen in chronic pancreatitis. The etiology and role of fatty replacement in chronic pancreatitis, aging and other diseases of the pancreas are not well understood. Previous studies have shown that deletion of transcription factor genes required for acinar identity and homeostasis results in fatty replacement through acinar-to-adipocyte transdifferentiation. We found that pancreatic specific loss of Par3, a major component of polarity complex that is important for tissue homeostasis, results in involution of the acinar compartment and near complete fatty replacement after chronic pancreatitis and in aged mice. Intriguingly, chronic pancreatitis-induced fat replacement in Par3 deficient pancreas is abrogated by inhibition of BET bromodomain activity, which has been shown to promote adipocyte differentiation. Together, we hypothesize that loss of Par3 promotes acinar-to-adipocyte transdifferentiation during chronic pancreatitis through activation of a BET bromodomain transcriptional program. We propose two specific aims to address our hypothesis. In Specific Aim 1, we will investigate whether loss of Par3 promotes acinar-to-adipocyte transdifferentiation in chronic pancreatitis. In specific Aim 2, we will determine the mechanism by which inhibition of BET bromodomain transcriptional activity limits fat replacement in Par3-deficient pancreas. We anticipate that our studies will elucidate the mechanism by which Par3 loss promotes chronic pancreatitis progression and fatty replacement. Furthermore, our studies may provide insights into treatment strategies to mitigate the disease and preserve pancreas function in aging.