Alcoholism causes an imbalance of endoplasmic reticulum (ER) homeostasis in pancreatic acini. In those cells, the ER is involved in the synthesis and folding of pancreatic enzymes. Ufm1 (Ubiquitin-fold modifier 1) is part of a novel ubiquitin-like modification system involved in maintaining ER homeostasis. Among the components of the Ufm1 system, Regulator of C53 and DDRGK1 (RCAD) has recently been identified as an Ufm1-specific E3 ligase that promotes ufmylation of DDRGK1, a RCAD-interacting protein. We determined the importance of RCAD in the proper synthesis and secretion of pancreatic enzymes using RCAD-deficient mice. The pancreas of RCAD-deficient mice was of normal size and histology. Using quantitative PCR and Western-blotting, we found that amylase was up-regulated in pancreas from RCAD KO mice. The constitutive amylase secretion was much higher in isolated pancreatic acini from RCAD KO mice, while CCK-stimulated amylase secretion was disturbed. RCAD deficiency caused a down-regulation in the expression of ER chaperone BiP, which affected ER homeostasis and activated both apoptosis and trypsin. Both RCAD and DDRGK1 transcript levels were up-regulated in pancreatic acini from alcohol-preferring rats. The elevated expression of RCAD and DDRGK1 was associated with increased ER stress and UPR activation. Caspase 3 and trypsin activation was enhanced in RCAD-deficient pancreatic acini upon treatment with ethanol and CCK. In conclusion, RCAD/BiP pathway is required for the proper synthesis and secretion of pancreatic enzymes. In alcoholism, the increased levels of components of the Ufm1 system could prevent alcohol's deleterious effects in the pancreas by regulating BiP levels.
|Original language||English (US)|
|Journal||American journal of physiology. Gastrointestinal and liver physiology|
|State||E-pub ahead of print - Jan 19 2017|