Abstract
BackgroundThe premature activation of digestive enzyme zymogens within pancreatic acinar cells is an important early feature of acute pancreatitis. Supraphysiological concentrations of cholecystokinin (CCK) cause intrapancreatic zymogen activation and acute pancreatitis. Stimulation of vacuolar ATPase (vATPase) activity is required for zymogen activation in pancreatic acinar cells. Parkin, a multiprotein E3 ubiquitin ligase complex, promotes vATPase ubiquitination and degradation, which inhibits vATPase activity. Docosahexaenoic acid (DHA), an omega-3 fatty acid, exerts anti-inflammatory effects. It is reported to bind to G-protein coupled receptor 120 (GPR120) and GPR40. DHA induces the degradation of certain proteins by activating ubiquitin-proteasome system in various cells. This study aimed to investigate whether DHA induces Parkin and inhibits vATPase activity, resulting in zymogen inactivation in pancreatic acinar AR42J cells stimulated with cerulein, a CCK analog.ResultsCerulein induced the translocation of the cytosolic V1 domain (E subunit) of vATPase to the membrane, which indicated vATPase activation, and zymogen activation in AR42J cells. DHA suppressed the association of the vATPase with membranes, and zymogen activation (increased trypsin activity and amylase release) induced by cerulein. Pretreatment with a GPR120 antagonist AH-7614, a GPR40 antagonist DC260126, or an ubiquitination inhibitor PYR-41 reduced the effect of DHA on cerulein-induced zymogen activation. Treatment with PYR-41 reversed the DHA-induced decrease in vATPase activation in cerulein-treated cells. Furthermore, DHA increased the level of Parkin in membranes of cerulein-treated cells.ConclusionsDHA upregulates Parkin which inhibits vATPase-mediated zymogen activation, via GPR120 and GPR40, in cerulein-stimulated pancreatic acinar cells.
Highlights
The premature activation of digestive enzyme zymogens within pancreatic acinar cells is an important early feature of acute pancreatitis
G-protein coupled receptor 120 (GPR120) and GPR40 antagonist suppressed the inhibitory effect of Docosahexaenoic acid (DHA) on zymogen activation in ceruleinstimulated AR42J cells To elucidate the mechanism underlying the inhibitory effect of DHA on cerulein-induced zymogen activation via the GPR120 and GPR40 signaling pathway, we investigated whether a GPR120 antagonist AH-7614 and a GPR40 antagonist DC260126 could suppress this inhibitory effect of DHA
The ubiquitination inhibitor, PYR-41, suppressed the inhibitory effect of DHA on zymogen activation in cerulein-stimulated AR42J cells To confirm the effect of DHA on the ubiquitination of vacuolar ATPase (vATPase), we investigated whether the ubiquitination inhibitor, PYR-41, could suppress the inhibitory effect of Trypsin activity was expressed as milliunits per microgram protein. b
Summary
The premature activation of digestive enzyme zymogens within pancreatic acinar cells is an important early feature of acute pancreatitis. This study aimed to investigate whether DHA induces Parkin and inhibits vATPase activity, resulting in zymogen inactivation in pancreatic acinar AR42J cells stimulated with cerulein, a CCK analog. The pancreatic acinar cell, which comprises over 90% of the exocrine pancreas, synthesizes and secretes the enzymes required to digest nutrients. Many of these digestive enzymes are stored in acinar cells as inactive zymogens that become activated only after reaching the (2020) 15:6. The worldwide incidence of acute pancreatitis remains high [11]
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