Effects of long-term ursodeoxycholate administration on expression levels of secretory low-molecular-weight phospholipases A and mucin genes in gallbladders and biliary composition in patients with multiple cholesterol stones

Abstract

Group IIA phospholipase A₂ (PLA₂), a secretory low-molecular-weight PLA₂, may play a critical role in the process of gallbladder mucosal inflammation in multiple cholesterol stones, which in turn may produce biliary pronucleating proteins as well as mucin. On the other hand, ursodeoxycholate (UDC) decreases biliary levels of various pronucleating proteins, possibly because of its membrane-protective effects on the inflamed gallbladder mucosa. To elucidate that beneficial effect of UDC, the expression levels of low-molecular-weight PLA₂s, group IIA PLA₂ (PLA₂-IIA), and group V PLA₂ (PLA₂-V), and mucin core polypeptide genes in the gallbladders were studied for UDC-treated patients and untreated patients with multiple cholesterol stones. Furthermore, the results were correlated with alterations in biliary composition. With long-term administration of UDC, the PLA₂-IIA protein mass (2.7 ± 0.5 vs. 5.0 ± 0.4 ng/mg · protein [mean ± SEM]; P < .01) and steady-state mRNA level, as well as the PLA₂-V mRNA level, were significantly decreased in the gallbladders, where the prostaglandin E₂ (PGE₂) level was concomitantly decreased (190.7 ± 27.9 vs. 393.6 ± 55.3 pg/mg · protein; P < .01). In the gallbladder bile, the immunoradiometrically determined PLA₂-IIA levels were significantly decreased in the UDC-treated patients (43 ± 4 ng/dL; P < .01) in comparison with untreated patients (78 ± 6 ng/dL). Significant decreases were similarly found for total protein, mucin, and free arachidonate concentrations, as well as nucleation activity in the bile. The degree of the changes was found to be rather small in solitary stones. In contrast to the decreased mucin concentration, however, there were no significant changes in the expression levels of mucin core polypeptide genes (MUC1-MUC6) between the UDC-treated and untreated patients. Long-term UDC administration was observed to lower the increased PLA₂-IIA protein mass and mRNA level, as well as the PLA₂-V mRNA level, in the gallbladders of patients with multiple cholesterol stones, which in turn may be of therapeutic importance in improving the gallbladder mucosal inflammation. Effects of UDC on secretory low-molecular-weight PLA₂s as inflammatory mediators may relate to the reported efficacy of UDC treatment in cholesterol gallstone disease.