High-fat diet accelerates pancreas pathology in the Cel-HYB1 mouse model

Introduction The CEL gene encodes the pancreatic enzyme carboxyl ester lipase. The human CEL-HYB1 allele, a hybrid variant of CEL and its adjacent pseudogene CELP , is associated with a five-fold increased risk for chronic pancreatitis in European cohorts. Humanized Cel-HYB1 mice develop chronic pancreatitis spontaneously albeit with a relatively mild presentation. The aim of this study was to further characterize the pancreatic phenotype in Cel-HYB1 mice. Methods We investigated Cel-HYB1 animals by two complementary approaches. First, we analyzed compound heterozygous Cel-16R/HYB1 mice where the second Cel allele carries the 16-repeat ( 16R ) VNTR of the normal human CEL gene. Second, heterozygous and homozygous Cel-HYB1 animals were fed either a high-fat diet or standard chow for 3 months. All animals were characterized with respect to growth, organ weights, pancreas pathology and glucose metabolism. Results In the Cel-16R/HYB1 model, body weight, pancreas weight and pancreatic histology were comparable to those of heterozygous Cel-HYB1 mice. However, within each genotype female mice generally exhibited more pronounced pancreatic histopathological changes than males. Male Cel-16R/HYB1 mice had larger fat depots at 6 months of age, and Cel-16R/HYB1 animals of both sexes showed slightly improved glucose tolerance relative to heterozygous Cel-HYB1 mice. When fed a high-fat diet, increased body weights were seen across all mouse groups without genotype-dependent differences. Under this condition, Cel-HYB1 animals displayed more pronounced pancreatic histopathology than littermate controls. Notably, no consistent genotype-dependent differences in glucose tolerance were observed in Cel-HYB1 mice under either high-fat diet or standard chow conditions. Conclusion The humanized Cel-16R allele did not substantially modify the pancreatic phenotype of Cel-HYB1 mice, although Cel-16R/HYB1 animals exhibited somewhat improved glucose tolerance compared with heterozygous Cel-HYB1 mice. In contrast, high-fat diet promoted exocrine pancreatic pathology, supporting a role for dietary factors as potential modifiers of disease severity in CEL-HYB1 -associated chronic pancreatitis.