The MODY-Causing Mutation of the Human Carboxyl Ester Lipase Gene (CEL) Triggers Chronic Pancreatitis But Not Diabetes in Mice

Anny Gravdal¹, Steven J Wilhelm²; CEL-MODY Mouse Project; Mark E Lowe², Anders Molven⁸, Xunjun K Xiao², Karianne Fjeld⁹

Collaborators, Affiliations

Collaborators

CEL-MODY Mouse Project:
Ivan Abbedissen³, Heidi Espedal⁴, Jahedul Alam³, Ranveig S Brekke¹, Janniche Torsvik⁵, Renate V Seierstad⁵, Khadija El Jellas³, Solrun J Steine³, Sammy Zino², Guoying Zhu², Hugh Walker Ferry², Pål R Njølstad⁶, Bente B Johansson⁶, Caroline Verbeke⁷, Ingfrid S Haldorsen⁴

Affiliations

¹ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
² Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.
³ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁴ Section of Radiology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Mohn Medical Imaging and Visualization Centre, Department of Radiology, Haukeland University Hospital, Bergen, Norway.
⁵ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁶ Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway.
⁷ Department of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Pathology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁸ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Section for Cancer Genomics, Laboratory Clinic, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway.
⁹ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway. Electronic address: karianne.fjeld@uib.no.

PMID: 39956334
PMCID: PMC12185230
DOI: 10.1053/j.gastro.2025.01.243

The MODY-Causing Mutation of the Human Carboxyl Ester Lipase Gene (CEL) Triggers Chronic Pancreatitis But Not Diabetes in Mice

Anny Gravdal et al. Gastroenterology. 2025 Jul.

. 2025 Jul;169(1):161-164.e6.

doi: 10.1053/j.gastro.2025.01.243. Epub 2025 Feb 14.

Authors

Anny Gravdal¹, Steven J Wilhelm²; CEL-MODY Mouse Project; Mark E Lowe², Anders Molven⁸, Xunjun K Xiao², Karianne Fjeld⁹

Collaborators

CEL-MODY Mouse Project:
Ivan Abbedissen³, Heidi Espedal⁴, Jahedul Alam³, Ranveig S Brekke¹, Janniche Torsvik⁵, Renate V Seierstad⁵, Khadija El Jellas³, Solrun J Steine³, Sammy Zino², Guoying Zhu², Hugh Walker Ferry², Pål R Njølstad⁶, Bente B Johansson⁶, Caroline Verbeke⁷, Ingfrid S Haldorsen⁴

Affiliations

¹ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
² Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri.
³ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁴ Section of Radiology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Mohn Medical Imaging and Visualization Centre, Department of Radiology, Haukeland University Hospital, Bergen, Norway.
⁵ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁶ Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway.
⁷ Department of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Pathology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁸ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Section for Cancer Genomics, Laboratory Clinic, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway.
⁹ The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway; Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway. Electronic address: karianne.fjeld@uib.no.

PMID: 39956334
PMCID: PMC12185230
DOI: 10.1053/j.gastro.2025.01.243

No abstract available

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Conflict of interest statement

Conflicts of interest

The authors disclose no conflicts.

Figures

**Figure 1.**
Pancreas pathology in carboxyl ester lipase (CEL) maturity-onset diabetes of the young (*Cel-MODY*) mice. Control (*Cel*^+/+), heterozygous (*Cel*^+/MODY) and homozygous (*Cel*^MODY/MODY) male mice were analyzed as depicted in the panels. Human samples were included in panels J and M. (A) Pancreas weight at age 1, 2, 3, 4, 6, and 12 months. (B) hematoxylin and eosin (H&E)–stained pancreas sections from mice at age 1, 3, 6, and 12 months. Scale bars are 200 μm. (C) Serum amylase activity at age 1, 2, 3, 4, 6, and 12 months. (D) Pancreas sections from mice at age 3, 6, and 12 months stained by Masson’s trichrome stain. (E) Hydroxyproline content in pancreatic tissue extracts (at age 6 and 12 months). (F) Chromogenic staining for the macrophage marker F4/80 in pancreas sections (age 12 months). (G) Intrapancreatic lipase, amylase and trypsin activity at age 3, 6, and 12 months. For each enzyme, total pancreatic activity was calculated. (H) Chromogenic staining of CEL protein in pancreas sections (age 6 months). The lower panels are higher magnifications of the rectangles in the upper panels. Scale bar is 300 μm. (I) mRNA levels of endoplasmic reticulum (ER) stress markers *Hspa5* (encoding binding immunoglobulin protein [BiP]) and *Ddit3* (encoding CHOP) at age 1, 3, 6, and 12 months. (J) Fluorescent immunostaining of the BiP protein (*green*) in representative pancreas sections from *Cel*^+/+ and *Cel*^+/MODY mice (age 6 months), a healthy human control, and a maturity-onset diabetes of the young, type 8 (MODY8) patient. 4’,6-diamidino-2-phenylindole (DAPI) staining of nuclei is in *blue*. Scale bars are 50 μm. (K) Transmission electron microscopy of pancreas sections. Scale bars are 500 nm. *(L)* Pancreatic structure in *Cel-MODY* mice. Abdominal MRI was performed at age 6 months. Coronal T1- and T2-weighted magnetic resonance imaging (MRI) shows the pancreas with its boundaries demarcated by *white arrows*. In the in situ images, the boundaries of the pancreas are marked with a *dashed white line*. In each row, the MRI, in situ, and pancreas histology images are from one representative mouse, either a *Cel*^+/+ control mouse (*upper panel*) or a *Cel*^MODY/MODY mouse (*lower panel*). Scale bars are 500 μm. *(M)* Pancreatic structure in human MODY8. Axial T1- and T2-weighted MRI depicting the pancreas with its boundaries demarcated by *white arrows* in a healthy individual (*upper panel*) and a MODY8 patient (*lower panel*). H&E sections from a healthy individual and a MODY8 patient are presented to the *right*. Scale bars are 250 mm. In panels *A, C, E, G* and I, individual values with mean (horizontal bar) ± SD are shown. bl, bladder; cy, cyst; ER, endoplasmic reticulum; li, liver; M, mitochondria; N, nucleus; pa, pancreas; sp, spleen; st, stomach; Z, zymogen granules. *P≤ .05; **P≤ .001; ***P≤ .0001.

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References

1. Johansson BB, et al. Pancreatology 2018;18:12–19. - PubMed
1. Ræder H, et al. Nat Genet 2006;38:54–62. - PubMed
1. El Jellas K, et al. J Clin Endocrinol Metab 2022; 107:e1455–e1466. - PMC - PubMed
1. Gravdal A, et al. J Biol Chem 2021;296:100661. - PMC - PubMed
1. Vesterhus M, et al. Pancreatology 2010;10:467–476. - PMC - PubMed

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The MODY-Causing Mutation of the Human Carboxyl Ester Lipase Gene (CEL) Triggers Chronic Pancreatitis But Not Diabetes in Mice

Collaborators

Affiliations

The MODY-Causing Mutation of the Human Carboxyl Ester Lipase Gene (CEL) Triggers Chronic Pancreatitis But Not Diabetes in Mice

Authors

Collaborators

Affiliations

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources