Diverse Misfolding Mutant Digestive Enzymes Cause Chronic Pancreatitis Through Common Pathways
Year: 2025
Type: article
Abstract: BACKGROUND & AIMS: Increasing evidence suggests that protein misfolding and proteotoxicity is an important mechanism of chronic pancreatitis (CP) in patients with genetic variants. Two mouse models carrying misfolding digestive enzyme variants, CPA1 N256K and PNLIP T221M, recapitulate the human CP phenotype. We hypothesized that both models develop CP through similar disease mechanisms. METHODS: We conducted a comprehensive analysis of mice aged 1 to 6 months using histology, immunohistochemistry, protein immunoblotting, quantitative polymerase chain reaction (qPCR), transmission electron microscopy (TEM), and RNA sequencing (RNA-seq) analysis to characterize pancreatic pathological changes. RESULTS: Both homozygous models exhibited CP hallmarks, including progressive acinar cell loss, inflammation, fibrosis, and fatty replacement. CP progression was slower and less severe in Cpa1 N256K mice compared with Pnlip T221M mice, and heterozygous mice showed slower CP development than homozygotes. Both mutant proteins misfolded in the pancreas, inducing endoplasmic reticulum stress and activating the unfolded protein response. RNA-seq analysis revealed slight differences in altered pathways at 1 month, but these differences disappeared by 3 months. Notably, apoptosis pathways were among the top upregulated pathways, confirmed by qPCR and immunohistochemistry. Differential expression and pathway analyses indicated early activation of both intrinsic and extrinsic apoptosis pathways elicited through multiple mechanisms. CONCLUSIONS: Our study demonstrates that Cpa1 N256K and Pnlip T221M mice develop CP through similar mechanisms with slight differences in progression and severity. Both models could serve as invaluable tools for developing and testing CP therapies. Targeting cell death pathways for therapy may be unfeasible given their redundancy. Instead, effective therapeutic strategies should focus on reducing the burden of misfolded digestive enzymes in the pancreas.
Authors: Steven J. Wilhelm, Grace E. Curry, Neel Matiwala, Jianguo Lin, Tran Quach, Mark.E. Lowe, Miklós Sahin-Tóth, Xunjun K. Xiao
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
Funders: Foundation for Barnes-Jewish Hospital, Children's Discovery Institute, St. Louis Children's Hospital, National Institutes of Health, Diabetes Research Center, University of Washington, Washington University School of Medicine in St. Louis, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G2147663471, Proteotoxicity in the Pathophysiology of Chronic Pancreatitis, Molecular pathomechanism of hereditary pancreatitis, G6206179931, G6517681182, G822624359, Pathophysiology of Chronic Pancreatitis Associated with Misfolded PNLIP Risk Variants, Diabetes Research Center, Host-environment interactions in the pathophysiology of digestive disease, Does Proteotoxicity Contribute to Chronic Pancreatitis in Murine Models of Human Carboxyl Ester Lipase (CEL) Genetic Risk Variants?
OpenAlex ID: W4414419972