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- Title
Pathogenic Carboxyl Ester Lipase (CEL) Variants Interact with the Normal CEL Protein in Pancreatic Cells.
- Authors
Dalva, Monica; Lavik, Ida K.; El Jellas, Khadija; Gravdal, Anny; Lugea, Aurelia; Pandol, Stephen J.; Njølstad, Pål R.; Waldron, Richard T.; Fjeld, Karianne; Johansson, Bente B.; Molven, Anders
- Abstract
Mutations in the gene encoding the digestive enzyme carboxyl ester lipase (CEL) are linked to pancreatic disease. The CEL variant denoted CEL-HYB predisposes to chronic pancreatitis, whereas the CEL-MODY variant causes MODY8, an inherited disorder of endocrine and exocrine pancreatic dysfunction. Both pathogenic variants exhibit altered biochemical and cellular properties compared with the normal CEL protein (CEL-WT, wild type). We here aimed to investigate effects of CEL variants on pancreatic acinar and ductal cell lines. Following extracellular exposure, CEL-HYB, CEL-MODY, and CEL-WT were endocytosed. The two pathogenic CEL proteins significantly reduced cell viability compared with CEL-WT. We also found evidence of CEL uptake in primary human pancreatic acinar cells and in native ductal tissue. Moreover, coexpression of CEL-HYB or CEL-MODY with CEL-WT affected secretion of the latter, as CEL-WT was observed to accumulate intracellularly to a higher degree in the presence of either pathogenic variant. Notably, in coendocytosis experiments, both pathogenic variants displayed a modest effect on cell viability when CEL-WT was present, indicating that the normal protein might diminish toxic effects conferred by CEL-HYB and CEL-MODY. Taken together, our findings provide valuable insight into how the pathogenic CEL variants predispose to pancreatic disease and why these disorders develop slowly over time
- Subjects
PANCREATIC acinar cells; LIPASES; DIGESTIVE enzymes; PANCREATIC diseases; CELL survival
- Publication
Cells (2073-4409), 2020, Vol 9, Issue 1, p1
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells9010244