title: Endocytosis of secreted carboxyl ester lipase in a syndrome of diabetes and pancreatic exocrine dysfunction.
abstract: Maturity-onset diabetes of the young, type 8 (MODY8) is characterized by a syndrome of autosomal dominantly inherited diabetes and exocrine pancreatic dysfunction. It is caused by deletion mutations in the last exon of the carboxyl ester lipase (CEL) gene, resulting in a CEL protein with increased tendency to aggregate. In this study we investigated the intracellular distribution of the wild type (WT) and mutant (MUT) CEL proteins in cellular models. We found that both CEL-WT and CEL-MUT were secreted via the endoplasmic reticulum and Golgi compartments. However, their subcellular distributions differed, as only CEL-MUT was observed as an aggregate at the cell surface and inside large cytoplasmic vacuoles. Many of the vacuoles were identified as components of the endosomal system, and after its secretion, the mutant CEL protein was re-internalized, transported to the lysosomes, and degraded. Internalization of CEL-MUT also led to reduced viability of pancreatic acinar and beta cells. These findings may have implications for the understanding of how the acinar-specific CEL-MUT protein causes both exocrine and endocrine pancreatic disease.
authors.affiliation: From the KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Janniche
authors.initials: J
authors.lastname: Torsvik
authors.affiliation: From the KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Bente B
authors.initials: BB
authors.lastname: Johansson
authors.affiliation: From the KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway, Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, N-5021 Bergen, Norway.
authors.forename: Monica
authors.initials: M
authors.lastname: Dalva
authors.affiliation: Department of Biomedicine and Molecular Imaging Center, University of Bergen, Bergen, Norway.
authors.forename: Michaël
authors.initials: M
authors.lastname: Marie
authors.affiliation: From the KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Karianne
authors.initials: K
authors.lastname: Fjeld
authors.affiliation: From the KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway, Department of Technology, University College of Sør-Trøndelag, Trondheim, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Bjørkøy
authors.affiliation: Department of Biomedicine and Molecular Imaging Center, University of Bergen, Bergen, Norway.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Saraste
authors.affiliation: From the KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway, Department of Pediatrics, Haukeland University Hospital, Bergen, Norway, and.
authors.forename: Pål R
authors.initials: PR
authors.lastname: Njølstad
authors.affiliation: From the KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway, Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, N-5021 Bergen, Norway, Department of Pathology, Haukeland University Hospital, Bergen, Norway anders.molven@gades.uib.no.
authors.forename: Anders
authors.initials: A
authors.lastname: Molven
mesh_terms: D000818:Animals; D017209:Apoptosis; D043182:Carboxylesterase / Q000378:metabolism*; D002462:Cell Membrane / Q000201:enzymology; D002470:Cell Survival; D017077:Culture Media, Conditioned / Q000737:chemistry; D003513:Cycloheximide / Q000737:chemistry; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics*; D004705:Endocytosis; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D009154:Mutation; D046790:Pancreas, Exocrine / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats
chemical_list: D017077:Culture Media, Conditioned; D003513:Cycloheximide; D043182:Carboxylesterase; C054621:CEL protein, human; D008049:Lipase
keywords: Carboxyl Ester Lipase; Diabetes; Endocytosis; Fluorescence; MODY8; Pancreas; Protein Aggregation