Vacuole Membrane Protein 1 Deficiency Promotes the Development of Pancreatitis Through Autophagy Impairment and Endoplasmic Reticulum Stress

Abstract

Pancreatitis is a potentially fatal inflammatory disease with significant morbidity and mortality but the exact molecular mechanisms remain largely obscure. We investigated the role of vacuole membrane protein 1 (VMP1), an endoplasmic reticulum (ER) resident protein, in the pathogenesis of pancreatitis. We examined VMP1 expression and ER stress in human pancreatitis samples. We also determined VMP1 level and ER stress in experimental pancreatitis induced by cerulein as well as in pancreatic acinar cell‐specific VMP1 knockout (VMP1Δacinar) mice. We found that VMP1 expression was significantly lower in human pancreatitis samples associated with extensive ER stress. In a mouse experimental pancreatitis model, treatment with ceruleint markedly decreased VMP1 expression but increased levels of several ER stress markers such as p‐elf2α, XBP1s and CHOP. Western blot and immune histochemical analysis of human and experimental mouse pancreatitis samples showed impaired autophagy with accumulation of p62, an autophagy substrate protein that generally is degraded by autophagy. Intriguingly, VMP1Δacinar mice developed spontaneous pancreatitis with pathological features of chronic pancreatitis. In addition, VMP1Δacinar caused accumulation of p62 as well as selective ER‐phagy receptor FAM134B. Moreover, VMP1Δacinar mice had increased ER tress accompanied with massive cell death, suggesting VMP1 may serve as a key mediator of pancreatic ER homeostasis. Collectively, these data indicate a critical role of VMP1 in maintaining ER homeostasis in acinar cells and decreased VMP1 expression may contribute to the development of pancreatitis.Support or Funding InformationR01 AA020518, R01 DK102142, U01 AA024733 and P30GM118247 (W.X.D).