The role of the carboxyl ester lipase (CEL) gene in pancreatic disease

Johansson, Bente B.; Fjeld, Karianne; Jellas, Khadija El; Gravdal, Anny; Dalva, Monica; Tjora, Erling; Ræder, Helge; Kulkarni, Rohit; Johansson, Stefan; Njølstad, Pål R.; Molven, Anders

doi:10.1016/j.pan.2017.12.001

Cited by 72 publications

(47 citation statements)

References 91 publications

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“…Notably, pancreas cancer is usually diagnosed in these patients within 2 years of diagnosis of diabetes. A peculiar form (sometimes referred to as MODY8) is caused by mutations in the CEL (carboxy‐ester lipase) gene, and these patients develop both early‐onset diabetes and pancreatitis . An interesting hypothesis has suggested that an exocrine inflammation can trigger an autoimmune reaction and thereby type 1 diabetes.…”

Section: Secondary Diabetes After Pancreatitismentioning

confidence: 99%

Precision medicine in type 2 diabetes

Prasad

Groop

2018

J Intern Med

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Section: Secondary Diabetes After Pancreatitismentioning

confidence: 99%

Precision medicine in type 2 diabetes

Prasad

Groop

2018

J Intern Med

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“…functionalglycomics.org/glycomics/publicdata/primaryscreen. jsp) 4 or on a glycopeptide array (56 compounds, Table S1), and probed for binding using fluorescent Alexa Fluor 488 antimouse antibody (Invitrogen, cat. A-10680).…”

Section: Glycan Arraysmentioning

confidence: 99%

“…The 11 exons of the CEL gene code for a short signal peptide and a globular N-terminal domain of 535 amino acid residues in which the bile salt-binding site and the catalytic activity of the enzyme reside (4). The last exon contains a variable number of tandem repeats (VNTR) that give rise to a flexible C terminus protruding from the globular core (5).…”

mentioning

confidence: 99%

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

Jellas

Johansson

Fjeld

et al. 2018

Journal of Biological Chemistry

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Carboxyl-ester lipase (CEL) is a pancreatic fat-digesting enzyme associated with human disease. Rare mutations in the CEL gene cause a syndrome of pancreatic exocrine and endocrine dysfunction denoted MODY8, whereas a recombined CEL allele increases the risk for chronic pancreatitis. Moreover, CEL has been linked to pancreatic ductal adenocarcinoma (PDAC) through a postulated oncofetal CEL variant termed feto-acinar pancreatic protein (FAPP). The monoclonal antibody mAb16D10 was previously reported to detect a glycotope in the highly O-glycosylated, mucin-like C terminus of CEL/FAPP. We here assessed the expression of human CEL in malignant pancreatic lesions and cell lines. CEL was not detectably expressed in neoplastic cells, implying that FAPP is unlikely to be a glycoisoform of CEL in pancreatic cancer. Testing of the mAb16D10 antibody in glycan microarrays then demonstrated that it recognized structures containing terminal GalNAc-␣1,3(Fuc-␣1,2)Gal (blood group A antigen) and also repeated protein sequences containing GalNAc residues linked to Ser/Thr (Tn antigen), findings that were supported by immunostainings of human pancreatic tissue. To examine whether the CEL glycoprotein might be modified by blood group antigens, we used high-sensitivity MALDI-TOF MS to characterize the released O-glycan pool of CEL immunoprecipitated from human pancreatic juice. We found that the O-glycome of CEL consisted mainly of core 1/core 2 structures with a composition depending on the subject's FUT2 and ABO gene polymorphisms. Thus, among digestive enzymes secreted by the pancreas, CEL is a glycoprotein with some unique characteristics, supporting the view that it could serve additional biological functions to its cholesteryl esterase activity in the duodenum.

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“…Other examples include the CEL gene, where only variants within the first or fourth repeats of the VNTR region are pathogenic(15); RFX6, where there is only evidence to implicate protein truncating variants(16); and the sole heterozygous PDX1 pathogenic variant, p.P63fs, known to cause monogenic diabetes through a dominant negative effect…”

mentioning

confidence: 99%