title: A Carboxyl Ester Lipase (CEL) Mutant Causes Chronic Pancreatitis by Forming Intracellular Aggregates That Activate Apoptosis.
abstract: Patients with chronic pancreatitis (CP) frequently have genetic risk factors for disease. Many of the identified genes have been connected to trypsinogen activation or trypsin inactivation. The description of CP in patients with mutations in the variable number of tandem repeat (VNTR) domain of carboxyl ester lipase (CEL) presents an opportunity to study the pathogenesis of CP independently of trypsin pathways. We tested the hypothesis that a deletion and frameshift mutation (C563fsX673) in the CEL VNTR causes CP through proteotoxic gain-of-function activation of maladaptive cell signaling pathways including cell death pathways. HEK293 or AR42J cells were transfected with constructs expressing CEL with 14 repeats in the VNTR (CEL14R) or C563fsX673 CEL (CEL maturity onset diabetes of youth with a deletion mutation in the VNTR (MODY)). In both cell types, CEL MODY formed intracellular aggregates. Secretion of CEL MODY was decreased compared with that of CEL14R. Expression of CEL MODY increased endoplasmic reticulum stress, activated the unfolded protein response, and caused cell death by apoptosis. Our results demonstrate that disorders of protein homeostasis can lead to CP and suggest that novel therapies to decrease the intracellular accumulation of misfolded protein may be successful in some patients with CP.
authors.affiliation: From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
authors.forename: Xunjun
authors.initials: X
authors.lastname: Xiao
authors.affiliation: From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Jones
authors.affiliation: From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
authors.forename: Wednesday A
authors.initials: WA
authors.lastname: Sevilla
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Magee
authors.affiliation: From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
authors.forename: Margaret
authors.initials: M
authors.lastname: Haughney
authors.affiliation: From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
authors.forename: Amitava
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and loweme2@upmc.edu.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lowe
mesh_terms: D017209:Apoptosis; D043182:Carboxylesterase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006801:Humans; D018598:Minisatellite Repeats; D009154:Mutation; D046790:Pancreas, Exocrine / Q000201:enzymology; D050500:Pancreatitis, Chronic / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology*; D066329:Protein Aggregates
chemical_list: D066329:Protein Aggregates; D043182:Carboxylesterase
keywords: apoptosis; carboxyl ester lipase; chronic pancreatitis; disulfide; disulfide bonds; endoplasmic reticulum stress (ER stress); lipase; unfolded protein response (UPR)