Molecular pathology of pancreatic diseases

The main research effort of the lab concerns chronic pancreatitis and the inherited form of diabetes called MODY8. The basis for this project is the discovery (Ræder et al., Nature Genetics 2006) that mutations in the CEL gene can cause MODY8, characterized by both diabetes and exocrine pancreatic dysfunction. 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 results with regard to the disease mechanism. We have also recently been involved in a study from Joslin Diabetes Center, Boston that further elucidated the pathogenesis of MODY8.

Expression of CEL mRNA (red) and protein (green) in an
acinus (encircled), the functional cell unit producing the
digestive enzymes of the exocrine pancreas (El Jellas 2018).

In 2015, we discovered a hybrid gene variant (CEL-HYB) that has originated from a recombination 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. We are performing in-depth analyses of the properties of CEL-HYB, including a characterization of how different subtypes of this risk factor contribute to chronic pancreatitis. Moreover, our ongoing studies now include efforts to produce new animal models for CEL-mediated chronic pancreatitis.

Current participants / main collaborators

Researcher Karianne Fjeld, Gade Laboratory for Pathology, UoBergen
Researcher Bente B. Johansson, Dept. of Clinical Science, UoBergen
Postdoc Jahedul Alam, Gade Laboratory for Pathology Bergen
Postdoc Khadija El Jellas, Joslin Diabetes Center, Harvard Medical School, Boston, USA
PhD fellow Anny Gravdal, Dept. of Medical Genetics, Haukeland Univ. Hospital, Bergen
PhD fellow Ranveig Seim Brekke, Gade Laboratory for Pathology, UoBergen
Master student Hanna Svendsen, Dept. of Biomedicine, UoBergen
Master student Diego I. López, Dept. of Biomedicine, UoBergen
Junior technician Miguel Juárez Garzón, Dept. of Biomedicine, UoBergen
Senior technician Solrun Steine, Gade Laboratory for Pathology, UoBergen
Senior technician Renate V. Seierstad, Gade Laboratory for Pathology, UoBergen
Consultant/postdoc Erling Tjora, Dept. of Pediatrics, Haukeland Univ. Hospital, Bergen
Research director Eric Mas, INSERM Cancer Research Center of Marseille, France
Professor Caroline S. Verbeke, University of Oslo, Norway
Professor Pål R. Njølstad, Dept. of Clinical Science, UoBergen
Professor Barbara Kahn, Beth Israel Deaconess Medical Center, Boston, USA
Professor Rohit N. Kulkarni, Joslin Diabetes Center, Harvard Medical School, Boston, USA
Ass. Professor Xunjun Xiao, Washington University, St. Louis, USA
Professor Mark E. Lowe, Washington University, St. Louis, USA

Publications

Fjeld K, Gravdal A, Brekke RS, Alam J, Wilhelm SJ, El Jellas K, Pettersen HN, Lin J, Solheim MH, Steine SJ, Johansson BB, Njølstad PR, Verbeke CS, Xiao X, Lowe ME & Molven A (2022). The genetic risk factor CEL-HYB1 causes proteotoxicity and chronic pancreatitis in mice. Pancreatology 22: 1099-1111.

Kahraman S, Dirice E, Basile G, Diegisser D, Alam J, Johansson BB, Gupta MK, Hu J, Huang L, Soh C-L, Huangfu D, Muthuswamy SK, Ræder H, Molven A & Kulkarni RN (2022). Abnormal exocrine-endocrine cell cross-talk promotes β-cell dysfunction and loss in MODY8. Nature Metabolism 4: 76-89.

El Jellas K, Dušátková P, Haldorsen IS, Molnes J, Tjora E, Johansson BB, Fjeld K, Johansson S, Průhová Š, Groop L, Löhr J-M, Pål R. Njølstad PR & Molven A (2022). Two new mutations in the CEL gene causing diabetes and hereditary pancreatitis: How to correctly identify MODY8 cases. Journal of Clinical Endocrinology & Metabolism 107: e1455-1466.

Gravdal A, Xiao X, Cnop M, El Jellas K, Johansson S, Njølstad PR, Lowe ME, Johansson BB, Molven A & Fjeld K (2021). The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity. Journal of Biological Chemistry 296: 100661.

Choi MH, Tjora E, Forthun RB, Engjom T, Ræder H, Hovland R & Molven A (2021). KRAS mutation analysis by droplet digital PCR of duodenal juice from patients with MODY8 and other pancreatic diseases. Pancreatology 21: 1460-1465.

Tjora E, Gravdal A, Engjom T, Johansson BB, Dimcevski GG, Molven A & Fjeld K (2021). First clinical reports on CEL-HYB-positive carriers: An interplay between protein misfolding and other risk factors in pancreatitis. European Journal of Gastroenterology & Hepatology 33: 839-843.

Fjeld K, Masson E, Lin JH, Michl P, Stokowy T, Gravdal A, El Jellas K, Steine SJ, Hoem D, Johansson BB, Dalva M, Ruffert C, Zou WB, Li ZS, Njølstad PR, Chen JM, Liao Z, Johansson S, Rosendahl J, Férec C & Molven A (2020). Characterization of CEL-DUP2: Complete duplication of the carboxyl ester lipase gene is unlikely to influence risk of chronic pancreatitis. Pancreatology 20: 377-384.

Cassidy B, Zino S, Fjeld K, Molven A, Lowe ME & Xiao X (2020). Single nucleotide polymorphisms in CEL-HYB1 increase risk for chronic pancreatitis through proteotoxic protein misfolding. Human Mutation 41: 1967-1978.

Dalva M, Lavik IK, El Jellas K, Gravdal A, Lugea A, Pandol SJ, Njølstad PR, Waldron RT, Fjeld K, Johansson BB & Molven A (2020). Pathogenic carboxyl-ester lipase (CEL) variants interact with the normal CEL protein in pancreatic cells. Cells 9: E244.

Oracz G, Kujko AA, Fjeld K, Wertheim-Tysarowska K, Adamus-Białek W, Steine SJ, Koziel D, Gluszek S, Molven A & Rygiel AM (2019). The hybrid allele 1 of carboxyl-ester lipase (CEL-HYB1) in Polish pediatric patients with chronic pancreatitis. Pancreatology 19: 531-534.

Johansson BB, Fjeld K, El Jellas K, Gravdal A, Dalva M, Tjora E, Ræder H, Kulkarni RN, Johansson S, Njølstad PR & Molven  A (2018). The role of the carboxyl ester lipase (CEL) gene in pancreatic disease. Pancreatology 18:12-19.

El Jellas K, Johansson BB, Fjeld K, Antonopoulos A, Immervoll H, Choi MH, Hoem D, Lowe ME, Lombardo D, Njølstad PR, Dell A, Mas E, Haslam SM & Molven A (2018). The mucinous domain of pancreatic carboxyl-ester lipase (CEL) contains core 1/core 2 O-glycans that can be modified by ABO blood group determinants. Journal of Biological Chemistry 293:19476-19491.

Dalva M, El Jellas K, Steine SJ, Ringdal M, Torsvik J, Immervoll H, Lerch MM, Johansson BB, Hoem D, Johansson S, 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 17: 83-88.

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.