687 ATG5 Deficiency Worsens Experimental Pancreatitis in Two Genetic Mouse Models

Recent Insights Into the Pathogenic Mechanism of Pancreatitis

“…34,45,56,57 Blockade of autophagosome formation by Atg5 genetic ablation inhibits hormone-induced secretion in acinar cells. 58,59 CCK-induced amylase secretion is also inhibited in acinar cells from mice with genetic ablation of IKKα (the inhibitor of the nuclear factor κB (IκB) kinase α), which causes impaired completion of autophagy (unrelated to nuclear factor κB activity). 60 Similarly, inhibiting autophagic flux by disrupting lysosomal function in LAMP2 null mice decreases pancreatic digestive enzymes content and inhibits CCK-induced secretion.…”

“…58,59,61 Interestingly, CER-AP and Arg-AP responses, such as hyperamylasemia, were worsened in transgenic GFP-LC3 mice in which the increased autophagosome formation (due to overexpression of LC3) is not balanced by increased lysosomal degradation, resulting in retarded autophagic flux. 121,122 Collectively, the findings in experimental and genetic models 3,4,45,[56][57][58][59][60][61]76,101,105,[118][119][120]122 show the essential role of autophagy/lysosomal pathways in maintaining pancreatic acinar cell homeostasis; and strongly implicate the disordered pathways in initiation and development of pancreatitis. Of note, pancreatitis develops regardless of whether these pathways are disrupted at the level of autophagosome formation, as in Atg5 and Atg7 knockout mice, or at the completion of autophagy, as in LAMP2, IKKα or Gnptab knockout mice.…”

“…CCKinduced amylase secretion is inhibited in Atg5 null acinar cells. 58,59 D52 and Rab5, proteins that regulate MSP and the endosomal compartment, are depleted from CCK-hyperstimulated acinar cells and in vivo, in mouse CER-AP and CDE-AP. 69,72 Inhibition of VAMP8dependent secretion is associated with inhibition of autophagy.…”