Pathogenic Carboxyl Ester Lipase (CEL) Variants Interact with the Normal CEL Protein in Pancreatic Cells

Cells. 2020 Jan 18;9(1):244. doi: 10.3390/cells9010244.


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.

Keywords: BSDL; CEL; cell viability; coexpression; endocytosis; pancreatic cell models.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / metabolism
  • Apoptosis
  • Carboxylesterase / genetics*
  • Carboxylesterase / metabolism*
  • Cell Line
  • Cell Survival
  • Diabetes Mellitus, Type 2 / pathology
  • Endocytosis
  • HEK293 Cells
  • Humans
  • Mutation / genetics*
  • Pancreas / enzymology*
  • Pancreatic Ducts / metabolism
  • Protein Binding


  • Carboxylesterase

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 8, with Exocrine Dysfunction