Biochemical Models of Hereditary Pancreatitis

Abstract

The past decade has witnessed remarkable progress in the genetics of chronic pancreatitis. Mutations of the PRSS1 gene encoding cationic trypsinogen and the SPINK1 gene encoding pancreatic secretory trypsin inhibitor were found in association with hereditary, familial or sporadic chronic pancreatitis; and the genotype -phenotype correlations have been characterized at the clinical level. Despite these accomplishments, our understanding of the molecular mechanism(s) through which PRSS1 and SPINK1 mutations cause chronic pancreatitis has remained sketchy. Pancreatitis-associated gene mutations are believed to result in uncontrolled trypsin activity in the pancreas. Thus, PRSS1 mutations would cause a gain of (trypsin) function, while SPINK1 mutations would result in the loss of a (trypsin inhibitor) function. However, experimental identification of the disease-relevant functional alterations caused by PRSS1 or SPINK1 mutations proved to be challenging, as results of biochemical analyses lent themselves to different interpretations. The present review focuses on PRSS1 mutations and summarizes the salient biochemical findings in the context of the mechanistic models that attempt to explain the connection between mutations and hereditary pancreatitis. Human Trypsinogens and Pancreatitis-Associated Trypsinogen MutationsThe human pancreas produces the digestive pro-enzyme trypsinogen in three isoforms. On the basis of their relative isoelectric points and electrophoretic mobility, these are commonly referred to as cationic trypsinogen, anionic trypsinogen, and mesotrypsinogen. The isoenzymes are encoded by separate genes, the PRSS1 (protease, serine, 1), PRSS2 and PRSS3 genes (for a recent review see [1] and references therein). Cationic trypsinogen (PRSS1) and anionic trypsinogen (PRSS2) make up the bulk of secreted trypsinogens in the pancreatic juice, while mesotrypsinogen (PRSS3) accounts for 2-10 % [2-6]. Typically, there is approximately twice as much cationic trypsinogen as anionic trypsinogen, but this ratio is reversed in chronic alcoholism or chronic pancreatitis [3,5]. The significance of the "isoform reversal" is unknown [7]. Human trypsinogens are synthesized as pre-pro-enzymes with a signal peptide of 15 amino acids, followed by the 8 amino acid long pro-peptide, the trypsinogen activation peptide. The signal-peptide is removed upon entry into the endoplasmic reticulum lumen and the proenzymes are packaged into zymogen granules and eventually secreted into the pancreatic juice. Physiological activation of trypsinogen to trypsin takes place in the duodenum by enteropeptidase (enterokinase), a highly specialized serine protease in the brush-border membrane of enterocytes. Trypsin can also activate trypsinogen, a process termed autoactivation, which in the duodenum may have a physiological role in facilitating zymogen activation, whereas inappropriate autoactivation in the pancreas might cause pancreatitis. Mutations in the PRSS1 gene have been identified in patients with hereditary pancreatitis, fam...

Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis

“…To examine this issue, we assessed the effects of pancreatitis and fasting on the processing and activities of CatL and CatB, which are important for autophagic function (3). CatB is relevant for the mechanism of pancreatitis, because there is compelling evidence (19,21,22,24,38,39) that it is a key activator of the pathological, intra-acinar conversion of trypsinogen to trypsin. Although CatL is present in human and rodent pancreas, there is little known on its role in pancreatitis (40)(41)(42).…”

“…Another early response of pancreatitis is the pathological, intra-acinar cell activation of digestive enzymes, especially trypsinogen. Trypsinogen activation (i.e., its conversion from inactive zymogen to trypsin) has been found clinically and in experimental models of acute pancreatitis and is considered a critical disease-initiating event (19)(20)(21)(22)(23)(24). The mechanism of the intraacinar trypsinogen activation remains poorly understood.…”

Cigarette smoke-induced pancreatic damage—experimental data

“…A cigarette smoke-induced increase in the rate of trypsin autoactivation or a reduction in anti-protease activity in pancreatic juice is also likely. The importance of the equilibrium of trypsin activity to anti-protease activity has been underlined by the understanding of genetic mutations in hereditary pancreatitis where both mutations of cationic trypsinogen gene (PRSS1) and mutations of its anti-protease serine protease inhibitor, Kazal type 1 (SPINK1), result in increased pancreatic trypsin activity, and where both mutations are associated with disease [29][30]. Biochemical analysis of PRSS1 mutations revealed, for the two most common mutations, an increased trypsin activity.…”

Intracellular Autoactivation of Human Cationic Trypsinogen Mutants Causes Reduced Trypsinogen Secretion and Acinar Cell Death

“…Compared with trypsinogens from other species, human cationic trypsinogen exhibits an unusually high propensity for autoactivation, which may result in an increased risk for pancreatitis in humans (8,9). This notion is supported by a number of biochemical studies demonstrating that the majority of hereditary pancreatitis-associated mutations increase autoactivation of cationic trypsinogen (10 -12, 5) The stimulatory effect is particularly strong in the case of the activation peptide mutations p.D19A, p.D22G, and p.K23R ( Fig.…”