Deficient Endoplasmic Reticulum Acetyl-CoA Import in Pancreatic Acinar Cells Leads to Chronic Pancreatitis.

Abstract Background & Aims Maintaining endoplasmic reticulum (ER) proteostasis is essential for pancreatic acinar cell function. Under conditions of severe ER stress, activation of pathogenic unfolded protein response pathways plays a central role in the development and progression of pancreatitis. Less is known, however, of the consequence of perturbing ER-associated post-translational protein modifications on pancreatic outcomes. Here, we examined the role of the ER acetyl-CoA transporter AT-1 on pancreatic homeostasis. Methods We utilized an AT-1S113R/+ hypomorphic mouse model, and generated an inducible, acinar-specific AT-1 knockout mouse model, and performed histological and biochemical analyses to probe the effect of AT-1 loss on acinar cell physiology. Results We found that AT-1 expression is significantly downregulated during both acute and chronic pancreatitis. Furthermore, acinar-specific deletion of AT-1 in acinar cells induces chronic ER stress marked by activation of both the XBP1s and PERK pathways, leading to spontaneous mild/moderate chronic pancreatitis evidenced by accumulation of intracellular trypsin, immune cell infiltration, and fibrosis. Induction of acute on chronic pancreatitis in the AT-1 model led to acinar cell loss and glad atrophy. Conclusions These results indicate a key role for AT-1 in pancreatic acinar cell homeostasis, the unfolded protein response (UPR), and that perturbations in AT-1 function leads to pancreatic disease.