Environmental and genetic stressors and the unfolded protein response in exocrine pancreatic function - a hypothesis

The exocrine pancreas has the greatest protein synthetic capacity of any mammalian organ and is challenged with the synthesis, processing and transporting a large load of digestive enzymes. Based on recent findings we present a hypothesis proposing that mutations in the digestive enzymes and environmental risks impacting the pancreas (i.e., alcohol abuse, smoking, metabolic disorders, and drugs) cause endoplasmic reticulum (ER) stress. We review recent findings showing that in normal pancreas the ER stress resulting from alcohol abuse leads to an adaptive unfolded protein response (UPR) allowing for maintenance of protein synthesis, processing, and transport. However, when key pathways necessary for the adaptive UPR are altered, the exocrine cell of the pancreas is unable to maintain these processes and cellular pathology results. These findings may explain why some individuals with alcohol abuse disorders develop organ injury and disease while most do not. Further, the findings allow us to hypothesize that the UPR in the exocrine pancreas adapts the protein synthetic machinery of the ER stress resulting from mutational and environmental stressors. When the ability of the UPR to adapt to the stressors is exceeded, pathologic pathways and disease develop.