PANCREATIC EXOCRINE DYSFUNCTION


One of our main research efforts concerns dysfunction of the exocrine pancreas. The basis for this project is the discovery (Ræder et al., Nature Genetics 2006) that mutations in the CEL gene can cause the disorder MODY8, characterized by both diabetes and exocrine pancreatic disease. The CEL gene encodes the digestive enzyme carboxyl-ester lipase, also known as bile salt-dependent lipase. We aim to understand the molecular processes that cause MODY8 and are also investigating whether variants in CEL associate with chronic pancreatitis and pancreatic cancer. Click here for a description of some newer results with regard to the disease mechanism.

 

pancreas x20 atrofi metaplasi
Section of pancreatic tissue in the disease MODY8. Areas of atrophy
(upper left), fibrosis (lower left) and metaplasia (right) are seen.


Recently, we have discovered a hybrid gene variant (CEL-HYB) that has originated from a crossover between CEL and its neighboring pseudogene (CELP). This variant is a significant risk factor for chronic pancreatitis and our findings implicate a new pathway in this disease. The data were published in Nature Genetics (Fjeld et al. 2015), whereas a popular description can be found here.

 

Participants/collaborators

Researcher Karianne Fjeld, Section for Pediatrics, Dept. of Clinical Science, UoBergen
Researcher Bente B. Johansson, Section for Pediatrics, Dept. of Clinical Science, UoBergen
PhD fellow Monica Dalva, Gade Laboratory, Dept. of Clinical Medicine, UoBergen
PhD fellow Khadija El Jellas, Dept. of Pathology, Haukeland Univ. Hospital, Bergen
Senior technician Solrun Steine, Gade Laboratory, Dept. of Clinical Medicine, UoBergen
Master student Anny Gravdal, Section for Pediatrics, Dept. of Clinical Science, UoBergen
Consultant/PhD Erling Tjora, Dept. of Pediatrics, Haukeland Univ. Hospital, Bergen
Professor Stefan Johansson, Section for Pediatrics, Dept. of Clinical Science, UoBergen
Professor Pål R. Njølstad, Section for Pediatrics, Dept. of Clinical Science, UoBergen
International collaborators from USA, Germany and France

Publications

Dalva M, El Jellas K, Steine SJ, Ringdal M, Torsvik J, Immervoll H, Lerch MM, Johansson BB, Hoem D, Johansson A, Njølstad PR, Weiss U, Fjeld K & Molven A (2017). Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer. Pancreatology (in press).

Fjeld K, Beer S, Johnstone M, Zimmer C, Mössner J, Ruffert C, Krehan M, Zapf C, Njølstad PR, Johansson S, Bugert P, Miyajima F, Liloglou T, Brown LJ, Winn SA, Davies K, Latawiec D, Gunson BK, Criddle DN, Pirmohamed M, Grützmann R, Michl P, Greenhalf W, Molven A, Sutton R & Rosendahl J (2016). Length of variable numbers of tandem repeats in the carboxyl ester lipase (CEL) gene may confer susceptibility to alcoholic liver cirrhosis but not alcoholic chronic pancreatitis. PLoS One 11 (11): e0165567.

Kolar MJ, Kamat SS, Parsons WH, Homan EA, Maher T, Peroni OD, Syed I, Fjeld K, Molven A, Kahn BB, Cravatt BF & Saghatelian A (2016). Branched fatty acid esters of hydroxy fatty acids are preferred substrates of the MODY8 protein carboxyl ester lipase. Biochemistry 55: 4636-4641.

Molven A, Fjeld K & Lowe ME (2016). Lipase genetic variants in chronic pancreatitis: When the end is wrong, all’s not well. Gastroenterology 150: 1515-1518.

Fjeld K, Weiss FU, Lasher D, Rosendahl J, Chen JM, Johansson BB, Kirsten H, Ruffert C, Masson E, Steine SJ, Bugert P, Cnop M, Grützmann R, Mayerle J, Mössner J, Ringdal M, Schulz HU, Sendler M, Simon P, Sztromwasser P, Torsvik J, Scholz M, Tjora E, Férec C, Witt H, Lerch MM, Njølstad PR, Johansson S & Molven A (2015). A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. Nature Genetics 47: 518-522.

Molven A, Njølstad PR & Weiss FU (2015). Lipase gene fusion: a new route to chronic pancreatitis. Oncotarget 6: 30443-30444.

Torsvik J, Johansson BB, Dalva M, Marie M, Fjeld K, Johansson S, Bjørkøy G, Saraste J, Njølstad PR & Molven A (2014). Endocytosis of secreted carboxyl-ester lipase in a syndrome of diabetes and pancreatic exocrine dysfunction. Journal of Biological Chemistry 289: 29097-29111.

Ræder H, McAllister FE, Tjora E, Bhatt S, Haldorsen I, Hu J, Willems SM, Vesterhus M, ElOuamaari A, Liu M, Raeder MB, Immervoll H, Hoem D, Dimcevski G, Njølstad PR, Molven A, Gygi SP & Kulkarni RN (2014). Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid. Diabetes 63: 259-269.

Wathle GK, Tjora E, Ersland L, Dimcevski G, Salvesen ØO, Molven A, Njølstad PR & Haldorsen  IS (2014). Assessment of exocrine pancreatic function by secretin stimulated MRCP and DWI in healthy controls. Journal of Magnetic Resonance Imaging 39: 448-454.

Ragvin A, Fjeld K, Weiss FU, Torsvik J, Aghdassi A, Mayerle J, Simon P, Njølstad PR, Lerch MM, Johansson S & Molven A (2013). The number of tandem repeats in the carboxyl-ester lipase (CEL) gene as a risk factor in alcoholic and idiopathic chronic pancreatitis. Pancreatology 13: 29-32.

Tjora E, Wathle G, Engjom T, Erchinger F, Molven A, Aksnes L, Haldorsen IS, Dimcevski GG, Njølstad PR & Ræder H (2013). Severe pancreatic dysfunction but compensated nutritional status in monogenic pancreatic disease caused by carboxyl-ester lipase mutations. Pancreas  42: 1078-1084.

Tjora E, Wathle G, Erchinger F, Engjom T, Molven A, Aksnes L, Haldorsen IS, Dimcevski G, Ræder H & Njølstad PR (2013). Exocrine pancreatic function in HNF1B-MODY is only moderately reduced: compensatory hypersecretion from a hypoplastic pancreas. Diabetic Medicine 30: 946-955.

Ræder H, Vesterhus M, El Ouaamari A, Paulo JA, McAllister FE, Liew CW, Hu J, Kawamori D, Molven A, Gygi SP, Njølstad PR, Kahn CR & Kulkarni RN (2013). Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young). PloS ONE 8 (4): e60229.

Gonc EN, Ozturk BB, Haldorsen IS, Molnes J, Immervoll H, Ræder H, Molven A, Søvik O, & Njølstad PR (2012). HNF1B mutation in a Turkish child with renal and exocrine pancreas insufficiency, diabetes and liver disease. Pediatric Diabetes 13: e1-e5.

Johansson BB, Torsvik J, Bjørkhaug L, Vesterhus M, Ragvin A, Tjora E, Fjeld K, Hoem D, Johansson S, Ræder H, Lindquist S, Hernell O, Cnop M, Saraste J, Flatmark T, Molven A & Njølstad PR (2011). Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl-ester lipase gene (CEL): a protein misfolding disease. Journal of Biological Chemistry 286: 34593-34605.

Vesterhus M, Ræder H, Kurpad AJ, Kawamori D, Molven A, Kulkarni RN, Kahn CR & Njølstad PR (2010). Pancreatic function in carboxyl-ester lipase knockout mice. Pancreatology 10: 467–476.

Torsvik J, Johansson S, Johansen A, Ek J, Minton J, Ræder H, Ellard S, Hattersley A, Pedersen O, Hansen T, Molven A & Njølstad PR (2010). Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of  monogenic diabetes. Human Genetics 127: 55-64.

Vesterhus M, Ræder H, Aurlien H, Gjesdal CG, Bredrup C, Holm PI, Molven A, Bindoff L, Berstad A & Njølstad PR (2008). Neurological features and enzyme therapy in patients with endocrine and exocrine pancreas dysfunction due to CEL mutations. Diabetes Care 31: 1738-1740.

Vesterhus M, Haldorsen IS, Ræder H, Molven A & Njølstad PR (2008). Reduced pancreatic volume in hepatocyte nuclear factor 1A-maturity-onset diabetes of the young. Journal of Clinical Endocrinology & Metabolism 93: 3505-3509.

Haldorsen IS, Vesterhus M, Ræder H, Jensen DK, Søvik O, Molven A & Njølstad PR (2008). Lack of pancreatic body and tail in HNF1B mutation carriers. Diabetic Medicine 25: 782-787.

Vesterhus M, Ræder H, Johansson S, Molven A & Njølstad PR (2008). Pancreatic exocrine dysfunction in maturity-onset diabetes of the young type 3. Diabetes Care 31: 306-310.

Ræder H, Haldorsen IS, Ersland L, Grüner R, Taxt T, Søvik O, Molven A & Njølstad PR (2007). Pancreatic lipomatosis is a structural marker in non-diabetic children with mutations in carboxyl-ester lipase. Diabetes 56: 444-449.

Ræder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SÅ, Grevle L,  Bjørkhaug L, Sagen JV, Aksnes L, Søvik O, Lombardo D, Molven A & Njølstad PR (2006). Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nature Genetics 38: 54-62.