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dc.contributor.authorValvatne, Monica Dalvaen_US
dc.date.accessioned2018-09-21T07:53:46Z
dc.date.available2018-09-21T07:53:46Z
dc.date.issued2018-09-13
dc.identifier.isbn978-82-308-3680-4en_US
dc.identifier.urihttps://hdl.handle.net/1956/18546
dc.description.abstractCarboxyl-ester lipase (CEL) is a digestive enzyme mainly expressed in pancreatic acinar cells, from which it is secreted into the duodenum as a component of pancreatic juice. Mutations in the human CEL gene have been linked to pancreatic disease. All pathogenic CEL variants identified so far affect the C-terminal region of the protein, which is very polymorphic due to repeated segments of 11 amino acids. A single-base deletion in the CEL repeat region causes a dominantly inherited syndrome of exocrine and endocrine pancreatic dysfunction denoted MODY8, whereas a copy number variant of the CEL locus, designated CEL-HYB, predisposes for chronic pancreatitis. To explore the role of CEL variants in pancreatic disease, we examined if CEL CNVs and VNTR length polymorphisms could affect the risk for developing pancreatic cancer. No studies have so far linked this disease to CEL, despite the fact that chronic pancreatitis is a known risk factor for pancreatic cancer. Our results from CNV screening and DNA fragment analyses in two pancreatic cancer cohorts of Caucasian origin did, however, not show an association between pancreatic cancer and the investigated CEL variants. Still, the CEL gene is highly polymorphic and a role of CEL variants in influencing pancreatic cancer risk cannot be excluded. To gain knowledge of how the pathogenic CEL protein variants, CEL-MODY and CEL-HYB, may cause or predispose for pancreatic disease, we started studies in cellular model systems. We found that both normal CEL and CEL-MODY most likely followed a classical secretory pathway. Their subcellular distributions did, however, differ as only CEL-MODY was observed as an aggregate at the cell surface and inside large cytoplasmic vacuoles, identified as components of the endosomal system. We further aimed to investigate the uptake of CEL protein variants in pancreatic acinar, beta and ductal cell lines and to study their effect on cell viability, as endocytosis may play a central role in disease pathogeneses. We found all CEL variants to be internalized, and compared to normal CEL, endocytosed CEL-MODY protein significantly reduced viability of all pancreatic cell line models, manifesting as a decrease in cellular metabolism and increased caspase3/7 activity. We found that also endocytosed CEL-HYB significantly reduced the viability of pancreatic acinar and ductal cell lines, as compared to normal CEL. Moreover, we developed a co- expression model as patients are heterozygous carriers of either CEL-MODY or CEL- HYB along with one copy of the normal CEL gene. Interestingly, we found both CEL- MODY and CEL-HYB to affect the intracellular fate of normal CEL, whilst the cellular toxicity of the two pathogenic variants after co-endocytosis became reduced in the presence of normal CEL. In conclusion, these studies highlight the exceedingly polymorphic nature of the human CEL gene and may be important for our understanding of how the pathogenic CEL variants predispose for pancreatic disease.en_US
dc.language.isoengeng
dc.publisherThe University of Bergeneng
dc.relation.haspartPaper I : Dalva M, El Jellas K, Steine S, Johansson BB, Ringdal M, Torsvik J, Immervoll H, Hoem D, Laemmerhirt F, Simon P, Lerch MM, Johansson S, Njølstad PR, Weiss FU, Fjeld K, Molven A. Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer. Pancreatology. 2017; 17:83-88. <a href="https://doi.org/10.1016/j.pan.2016.10.006" target="blank">https://doi.org/10.1016/j.pan.2016.10.006</a>en_US
dc.relation.haspartPaper II: Torsvik J, Johansson BB, Dalva M, Marie M, Fjeld K, Johansson S, Bjørkøy G, Saraste J, Njølstad PR, Molven A. Endocytosis of secreted carboxyl ester lipase in a syndrome of diabetes and pancreatic exocrine dysfunction. J Biol Chem. 2014; 289:29097-29111. <a href="https://doi.org/10.1074/jbc.m114.574244" target="blank"> https://doi.org/10.1074/jbc.m114.574244</a>en_US
dc.relation.haspartPaper III: Dalva M, Lavik IMK, El Jellas K, Gravdal A, Njølstad PR, Fjeld K, Johansson BB, Molven A. Pathogenic carboxyl-ester lipase (CEL) variants are endocytosed in pancreatic cell lines and may influence properties of the normal CEL protein. Manuscript.en_US
dc.titleGenetic and cellular studies of carboxyl-ester lipase (CEL), a protein involved in exocrine and endocrine pancreatic diseaseen_US
dc.typeDoctoral thesis
dc.rights.holderCopyright the author. All rights reserved.
dc.subject.nsiVDP::Medisinske Fag: 700::Klinisk medisinske fag: 750en_US


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