# CEL

## Overview
The CEL gene encodes the carboxyl ester lipase, a crucial enzyme involved in the digestion and metabolism of dietary lipids. This enzyme is primarily expressed in pancreatic acinar cells and lactating mammary glands, where it plays a significant role in the hydrolysis of cholesteryl esters, triglycerides, and other lipid substrates. As a member of the alpha/beta hydrolase fold family, carboxyl ester lipase is characterized by a catalytic triad essential for its enzymatic activity. The enzyme's function is vital for the digestion and absorption of dietary fats, impacting energy homeostasis and nutrient assimilation. Mutations in the CEL gene have been linked to several pancreatic diseases, including maturity-onset diabetes of the young type 8 (MODY8) and hereditary pancreatitis, highlighting its clinical significance (Johansson2018The; El2021Two).

## Structure
The carboxyl ester lipase (CEL) protein is characterized by its membership in the alpha/beta hydrolase fold family, featuring a catalytic triad partially covered by a surface loop. This triad consists of Ser194, Asp320, and His435, which are crucial for its enzymatic activity (Holmes2011Comparative). The protein's structure includes a carboxyl terminus region that regulates enzymatic activity by forming hydrogen bonds with the surface loop, shielding the active site (Holmes2011Comparative). CEL also has a loop domain that binds bile salt, allowing the active site to access water-insoluble substrates (Holmes2011Comparative).

The primary structure of CEL includes 722 amino acids, with a 20 amino acid leader peptide. The protein is rich in proline, particularly in the final 25% of the sequence, due to a tandem repetition of a proline-rich sequence at the carboxyl terminus (Reue1991cDNA). This proline-rich domain contributes to the protein's nonglobular configuration and high molecular weight (Reue1991cDNA). CEL is a glycoprotein with a potential N-linked glycosylation site at Asn residue 187 (Reue1991cDNA). The protein forms dimeric subunit structures with active sites facing each other (Holmes2011Comparative).

## Function
The carboxyl ester lipase (CEL) gene encodes an enzyme that plays a crucial role in the digestion and metabolism of dietary lipids in healthy human cells. CEL is primarily expressed in pancreatic acinar cells and lactating mammary glands. In the pancreas, CEL is one of the major lipases secreted into the duodenum, where it requires bile salts for activation. It is involved in the hydrolysis of cholesteryl esters, triglycerides, and branched fatty acid esters of hydroxy fatty acids (FAHFAs), which have anti-diabetic and anti-inflammatory properties (Johansson2018The; Kolar2016Branched).

CEL's enzymatic activity is essential for the digestion and absorption of dietary fats, impacting energy homeostasis and nutrient assimilation. The enzyme has a globular N-terminal catalytic domain and a C-terminal region with repeated 11-amino acid segments, which are important for its secretion and activity (Johansson2018The). In lactating mammary glands, CEL is secreted with milk, aiding in the digestion of milk triglycerides and cholesteryl/retinyl esters in breastfed infants (Johansson2018The).

CEL is also involved in the metabolism of fatty acid ethyl esters (FAEEs), products of the non-oxidative metabolism of ethanol and fatty acids, contributing to the hydrolysis of dietary lipids in the duodenum (Fjeld2016Length).

## Clinical Significance
Mutations in the CEL gene are linked to several pancreatic diseases, most notably maturity-onset diabetes of the young type 8 (MODY8) and hereditary pancreatitis. MODY8 is characterized by both exocrine and endocrine pancreatic dysfunction, resulting from frameshift mutations in the variable number of tandem repeats (VNTR) region of the CEL gene. These mutations lead to a dominant-negative, gain-of-function effect, causing the mutant CEL protein to aggregate and disrupt normal cellular functions (Johansson2011Diabetes; El2021Two). The aggregation of mutant proteins is associated with cellular stress responses, such as the unfolded protein response, and can lead to pancreatic lipomatosis and dysfunction (Johansson2011Diabetes; Torsvik2014Endocytosis).

Another variant, CEL-HYB, predisposes individuals to chronic pancreatitis by forming a CEL-CELP fusion protein with reduced lipolytic activity and increased autophagy induction (Dalva2020Pathogenic). The pathogenicity of CEL mutations is not due to reduced enzymatic activity but rather a dominant-negative gain-of-function effect, which affects protein secretion and causes endoplasmic reticulum stress (Gravdal2021The). These mutations have been identified in various populations, emphasizing the need for careful genetic screening to correctly diagnose MODY8 cases (El2021Two).

## Interactions
Carboxyl ester lipase (CEL) interacts with various proteins, influencing its function and stability. Pathogenic variants of CEL, such as CEL-MODY and CEL-HYB, have been shown to interact with the normal CEL protein (CEL-WT) in pancreatic cells, affecting its secretion and stability. CEL-MODY, in particular, leads to increased accumulation of CEL-WT in the insoluble fraction and reduces its secretion into the medium, suggesting a disruptive interaction that may contribute to disease pathology (Dalva2020Pathogenic).

CEL also interacts with glucose-regulated protein 94 (GRP94), a molecular chaperone. This interaction is altered by certain CEL variants, such as the p.R540C variant, which changes the electrostatic potential of the CEL protein surface, potentially affecting its interactions with other macromolecules (Wu2023Identification).

The CEL-MUT protein, associated with maturity onset diabetes of the young (CEL-MODY), forms higher-order oligomeric forms and aggregates, which are not observed in the wild-type CEL protein. This aggregation is linked to amyloidogenic sequence motifs on the protein's surface, suggesting interactions with cell membranes similar to those seen in amyloid diseases (Johansson2011Diabetes). These interactions highlight the complex role of CEL in cellular processes and its potential involvement in disease mechanisms.


## References


[1. (Fjeld2016Length) Karianne Fjeld, Sebastian Beer, Marianne Johnstone, Constantin Zimmer, Joachim Mössner, Claudia Ruffert, Mario Krehan, Christian Zapf, Pål Rasmus Njølstad, Stefan Johansson, Peter Bugert, Fabio Miyajima, Triantafillos Liloglou, Laura J. Brown, Simon A. Winn, Kelly Davies, Diane Latawiec, Bridget K. Gunson, David N. Criddle, Munir Pirmohamed, Robert Grützmann, Patrick Michl, William Greenhalf, Anders Molven, Robert Sutton, and Jonas Rosendahl. 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, November 2016. URL: http://dx.doi.org/10.1371/journal.pone.0165567, doi:10.1371/journal.pone.0165567. This article has 17 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0165567)

[2. (Dalva2020Pathogenic) Monica Dalva, Ida K. Lavik, Khadija El Jellas, Anny Gravdal, Aurelia Lugea, Stephen J. Pandol, Pål R. Njølstad, Richard T. Waldron, Karianne Fjeld, Bente B. Johansson, and Anders Molven. Pathogenic carboxyl ester lipase (cel) variants interact with the normal cel protein in pancreatic cells. Cells, 9(1):244, January 2020. URL: http://dx.doi.org/10.3390/cells9010244, doi:10.3390/cells9010244. This article has 14 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cells9010244)

[3. (Gravdal2021The) Anny Gravdal, Xunjun Xiao, Miriam Cnop, Khadija El Jellas, Stefan Johansson, Pål R. Njølstad, Mark E. Lowe, Bente B. Johansson, Anders Molven, and Karianne Fjeld. 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, January 2021. URL: http://dx.doi.org/10.1016/j.jbc.2021.100661, doi:10.1016/j.jbc.2021.100661. This article has 15 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jbc.2021.100661)

[4. (El2021Two) Khadija El Jellas, Petra Dušátková, Ingfrid S Haldorsen, Janne Molnes, Erling Tjora, Bente B Johansson, Karianne Fjeld, Stefan Johansson, Štěpánka Průhová, Leif Groop, J Matthias Löhr, Pål R Njølstad, and Anders Molven. Two new mutations in the cel gene causing diabetes and hereditary pancreatitis: how to correctly identify mody8 cases. The Journal of Clinical Endocrinology & Metabolism, 107(4):e1455–e1466, November 2021. URL: http://dx.doi.org/10.1210/clinem/dgab864, doi:10.1210/clinem/dgab864. This article has 15 citations.](https://doi.org/10.1210/clinem/dgab864)

[5. (Wu2023Identification) Huixiao Wu, Meng Shu, Changmei Liu, Wanyi Zhao, Qiu Li, Yuling Song, Ting Zhang, Xinyu Chen, Yingzhou Shi, Ping Shi, Li Fang, Runbo Wang, and Chao Xu. Identification and characterization of novel carboxyl ester lipase gene variants in patients with different subtypes of diabetes. BMJ Open Diabetes Research & Care, 11(1):e003127, January 2023. URL: http://dx.doi.org/10.1136/bmjdrc-2022-003127, doi:10.1136/bmjdrc-2022-003127. This article has 1 citations.](https://doi.org/10.1136/bmjdrc-2022-003127)

[6. (Johansson2018The) Bente B. Johansson, Karianne Fjeld, Khadija El Jellas, Anny Gravdal, Monica Dalva, Erling Tjora, Helge Ræder, Rohit N. Kulkarni, Stefan Johansson, Pål R. Njølstad, and Anders Molven. The role of the carboxyl ester lipase (cel) gene in pancreatic disease. Pancreatology, 18(1):12–19, January 2018. URL: http://dx.doi.org/10.1016/j.pan.2017.12.001, doi:10.1016/j.pan.2017.12.001. This article has 66 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.pan.2017.12.001)

[7. (Johansson2011Diabetes) Bente B. Johansson, Janniche Torsvik, Lise Bjørkhaug, Mette Vesterhus, Anja Ragvin, Erling Tjora, Karianne Fjeld, Dag Hoem, Stefan Johansson, Helge Ræder, Susanne Lindquist, Olle Hernell, Miriam Cnop, Jaakko Saraste, Torgeir Flatmark, Anders Molven, and Pål R. Njølstad. Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl ester lipase gene-maturity onset diabetes of the young (cel-mody). Journal of Biological Chemistry, 286(40):34593–34605, October 2011. URL: http://dx.doi.org/10.1074/jbc.m111.222679, doi:10.1074/jbc.m111.222679. This article has 76 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m111.222679)

[8. (Holmes2011Comparative) Roger S. Holmes and Laura A. Cox. Comparative structures and evolution of vertebrate carboxyl ester lipase (cel) genes and proteins with a major role in reverse cholesterol transport. Cholesterol, 2011:1–15, November 2011. URL: http://dx.doi.org/10.1155/2011/781643, doi:10.1155/2011/781643. This article has 16 citations and is from a peer-reviewed journal.](https://doi.org/10.1155/2011/781643)

[9. (Reue1991cDNA) K Reue, J Zambaux, H Wong, G Lee, TH Leete, M Ronk, JE Shively, B Sternby, B Borgström, and D Ameis. Cdna cloning of carboxyl ester lipase from human pancreas reveals a unique proline-rich repeat unit. Journal of Lipid Research, 32(2):267–276, February 1991. URL: http://dx.doi.org/10.1016/s0022-2275(20)42088-7, doi:10.1016/s0022-2275(20)42088-7. This article has 67 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/s0022-2275(20)42088-7)

[10. (Kolar2016Branched) Matthew J. Kolar, Siddhesh S. Kamat, William H. Parsons, Edwin A. Homan, Tim Maher, Odile D. Peroni, Ismail Syed, Karianne Fjeld, Anders Molven, Barbara B. Kahn, Benjamin F. Cravatt, and Alan Saghatelian. Branched fatty acid esters of hydroxy fatty acids are preferred substrates of the mody8 protein carboxyl ester lipase. Biochemistry, 55(33):4636–4641, August 2016. URL: http://dx.doi.org/10.1021/acs.biochem.6b00565, doi:10.1021/acs.biochem.6b00565. This article has 59 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/acs.biochem.6b00565)

[11. (Torsvik2014Endocytosis) Janniche Torsvik, Bente B. Johansson, Monica Dalva, Michaël Marie, Karianne Fjeld, Stefan Johansson, Geir Bjørkøy, Jaakko Saraste, Pål R. Njølstad, and Anders Molven. Endocytosis of secreted carboxyl ester lipase in a syndrome of diabetes and pancreatic exocrine dysfunction. Journal of Biological Chemistry, 289(42):29097–29111, October 2014. URL: http://dx.doi.org/10.1074/jbc.m114.574244, doi:10.1074/jbc.m114.574244. This article has 38 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m114.574244)