Missense PNLIP mutations impeding pancreatic lipase secretion cause protein misfolding and endoplasmic reticulum stress.

Background/objective: Mutation-induced misfolding of digestive enzymes has been shown to cause chronic pancreatitis. Recently, heterozygous pancreatic lipase (PNLIP) mutations leading to reduced secretion were identified. The aim of the present study was to investigate whether PNLIP mutants with a secretion defect result in endoplasmic reticulum (ER) stress in cell culture models.

Methods: We introduced the coding DNA for wild-type and A174P, G233E, C254R and V454F mutant PNLIP into two mammalian cell lines and carried out functional assays to assess PNLIP expression, secretion and ER stress.

Results: We found that wild-type PNLIP was readily secreted from the investigated cell lines. In contrast, none of the lipase mutants were detectable in the conditioned media. PNLIP variants accumulated in the cells as intracellular protein aggregates probably due to misfolding in the ER. Consistent with this notion, PNLIP mutants induced ER stress, as indicated by increased mRNA levels of spliced X-box Binding Protein 1 (XBP1) and the ER chaperone Immunoglobulin Binding Protein (BiP).

Conclusion: The results indicate that PNLIP mutations associated with a lipase secretion defect cause ER stress and thereby may increase the risk for chronic pancreatitis.