Pnlip, pancreatic lipase, is an essential enzyme in the hydrolysis of dietary fat [5]. Dietary fat, especially polyunsaturated fatty acids (PUFA), can regulate PNLIP, and this regulation might be mediated by PPARγ, as PPARγ transcriptionally regulates PNLIP gene expression [5].

Mutations in PNLIP are associated with various pancreatic diseases. For instance, novel PNLIP variants (c.305G > A, p.(W102∗); c.562C > T, p.(R188C); and c.1257G > A, p.(W419∗)) in congenital pancreatic lipase deficiency (CPLD) lead to a loss-of-function through impaired secretion, and p.R188C and p.W419∗ variants may induce proteotoxicity through misfolding and potentially increase the risk for pancreatic acinar cell injury [1]. Missense PNLIP mutations impeding pancreatic lipase secretion cause protein misfolding and endoplasmic reticulum (ER) stress, potentially increasing the risk for chronic pancreatitis [2]. The Pnlip p.T221M mouse model exhibits hallmarks of human chronic pancreatitis (CP), including pancreatic atrophy, acinar cell loss, fibrosis, etc., caused by ER stress and proteotoxicity of misfolded mutant PNLIP [3]. Also, protease-sensitive PNLIP variants are associated with pancreatitis, often characterized by early-onset disease and recurrent acute pancreatitis [4].

In conclusion, Pnlip is crucial for dietary fat hydrolysis. Studies on Pnlip-related mouse models have revealed its significance in pancreatic diseases such as congenital pancreatic lipase deficiency and chronic pancreatitis, highlighting its role in disease mechanisms like protein misfolding, ER stress, and proteotoxicity.