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J Biol Chem. 2016 Oct 28;291(44):23224-23236. Epub 2016 Sep 20.

A Carboxyl Ester Lipase (CEL) Mutant Causes Chronic Pancreatitis by Forming Intracellular Aggregates That Activate Apoptosis.

Author information

1
From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and.
2
Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
3
From the Department of Pediatrics, Children's Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224 and loweme2@upmc.edu.

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.

KEYWORDS:

apoptosis; carboxyl ester lipase; chronic pancreatitis; disulfide; disulfide bonds; endoplasmic reticulum stress (ER stress); lipase; unfolded protein response (UPR)

PMID:
27650499
PMCID:
PMC5087739
DOI:
10.1074/jbc.M116.734384
[Indexed for MEDLINE]
Free PMC Article

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