Abstract 2178: Diet-modulated SCAP-SREBP signaling is essential for acinar cell differentiation, pancreatic morphogenesis, and pancreatic adiposity

Abstract

Abstract High levels of dietary fats are associated with pancreatitis, diabetes, and pancreatic cancer. Sterol regulatory element binding protein Cleavage-Activating Protein (SCAP) is an essential intermediate in lipid-regulated activation of Sterol Regulatory Element Binding Protein (SREBP) transcription factors, which induce expression of genes regulating lipid homeostasis. We previously demonstrated that the elevated SREBP1 arising from inhibition of the cholesterol biosynthetic pathway in mice genetically predisposed to pancreatic cancer additionally transcribed genes that induced epithelial-mesenchymal transition, promoting basal rather than glandular cancer. To further evaluate SCAP and SREBP function in the pancreas, we developed a new mouse model with selective pancreatic knockout of the Scapf/f gene under the control of the Pdx1-Cre promoter (ScapΔpanc mice). Although size of the pancreas in ScapΔpanc neonates was unaffected, and number of islets was normal, there was a reduced number of acinar cells, and some evidence of disorganized tissue structure. Preliminary histopatholgical assessment of pancreatic tissue of ScapΔpanc neonates indicated no acinar cell apoptosis, and unimpaired acinar proliferation, suggesting loss of Scap may cause a differentiation defect. Further supporting this idea, siRNA depletion of Scap in the rat AR42J acinar cell line resulted in loss of markers of mature acinar cell identity. ScapΔpanc pancreata underwent progressive and selective loss of acinar cells as mice aged, with three-month old mice having large areas of acinar cell loss, and mislocalization of ductal cells. Coupled with this loss was a large increase in pancreatic adipocytes and mesenchymal cells, resulting in a highly disorganized tissue morphology accompanied by signs of inflammation. These phenotypes were exacerbated in mice maintained on high fat or high carbohydrate diet. Together, these results imply that SCAP and SREBP signaling in the pancreas plays an important role in mediating dietary modulation of pancreatic development, acinar cell homeostasis, and restraint of pancreatic adiposity. Intrapancreatic fat, associated with obesity and chronic pancreatitis, is a known risk factor for pancreatic cancer, and SCAP polymorphisms have been to interact with diet in regulating obesity and blood pressure in humans; we propose SCAP-SREBP signaling in the pancreas may mediate dietary promotion of pancreatic cancer risk. Citation Format: Anna C. Lilly, Aizhan Surumbayeva, Theodore Nguyen, Igor Astsaturov, Erica A. Golemis. Diet-modulated SCAP-SREBP signaling is essential for acinar cell differentiation, pancreatic morphogenesis, and pancreatic adiposity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2178.