The role of AMP-dependent protein kinase in acute pancreatitis
Acute pancreatitis (AP) is an inflammatory disease of the pancreas
involving premature activation of digestive enzyme zymogens. Since energy
stress and ischemia are important in the development of AP, we studied the role
of a cellular energy-sensing enzyme AMP-dependent protein kinase, AMPK, in
groups of pancreatic acinar cells (acini), which have phenotypic responses that
match those of early pancreatitis. We used the cholecystokinin orthologue,
caerulein, to stimulate acini and to induce experimental pancreatitis. Using this
system, activation of AMPK with the agonist AICAR decreased zymogen
activation, while inhibition with the antagonist compound C enhanced it; both
AMPK modulators appeared to influence a later stage of zymogen activation.
Stimulation of acini with physiologic concentrations of caerulein caused mild
changes in AMPK activity. However, when exposed to hyperstimulatory doses
which caused pancreatitis, caerulein caused a rapid and prolonged decrease in
AMPK activity. Unexpectedly, AMPK activity varied inversely with protease
activation. The hyperstimulation-induced change in AMPK activity was
accompanied by modifications in phosphorylation at the enzymes activating and
inhibitory sites. Further, a transient decrease in AMPK protein levels was
observed with hyperstimulation.
We investigated the processes involved in zymogen activation by
developing a cell-free assay using zymogen-containing compartments and
cytosol. We found that cytosolic factors were necessary to cause zymogen
activation, and that adenosine nucleotides tended to inhibit trypsinogen, and
enhance chymotrypsinogen activation. Time-course studies of secretion and cell
injury in acini in the presence of AICAR and compound C revealed no effects of
modulating AMPK on either process.
These findings suggest that AMPK activity is linked to early pathologic
protease activation in the pancreatic acinar cell. The cellular targets of AMPK
will be a subject of future studies.
School Location:USA - Connecticut
Source Type:Master's Thesis
Keywords:amp activated protein kinases enzyme precursors pancreatitis metabolism chemically induced pancreas activation caerulein
Date of Publication:02/23/2009