BBB seminar: Karianne Fjeld
New insight into pancreatic disease etiology: the role of CEL in diabetes and pancreatitis
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen
The pancreas serves two roles in the body. Most of the organ consists of exocrine cells secreting digestive enzymes to the alimentary tract. Endocrine cells are found scattered in the pancreatic tissue as islets of Langerhans, which are crucial for regulation of glucose metabolism. Carboxyl ester lipase (CEL) is a digestive enzyme expressed in the exocrine pancreas. It is stimulated by bile salts and involved in breakdown of dietary cholesterol and fat.
The last exon of the human CEL gene contains a VNTR (variable number of tandem repeats) domain. In 2006, we reported that mutations in the CEL VNTR cause Maturity-Onset Diabetes of the Young, type 8 (MODY8/CEL-MODY), a dominantly inherited disease characterized by diabetes and pancreatic exocrine dysfunction. The C-terminus of the mutant CEL protein differs considerably from that of the normal CEL protein. This results in altered biochemical and cellular properties. We have recently suggested a disease mechanism that involves protein aggregation and stimulated reuptake of the secreted CEL protein by endocytosis.
The CEL gene is highly polymorphic. In addition to SNPs, VNTR length polymorphisms and copy number variants (CNVs) are common. We have recently characterized two CEL CNVs that most probably have originated from non-allelic homologous recombination between CEL and the neighboring CEL pseudogene. Intriguingly, one CEL deletion allele (CEL-HYB) was found to be a novel genetic risk factor for chronic pancreatitis. The CEL-HYB protein has properties indicating a new disease mechanism that involves intracellular protein retention and induced autophagy rather than stimulation of protease activity in the pancreatic acinar cells. We also have preliminary data indicating that another CEL CNV protects against chronic pancreatitis. Thus, our studies may suggest that variants of the CEL gene can act as both protective and risk factors in pancreatic disease.
Chairperson: Marit Bakke, Department of Biomedicine