title: Cerulein hyperstimulation decreases AMP-activated protein kinase levels at the site of maximal zymogen activation.
abstract: The premature activation of digestive enzyme zymogens in the pancreatic acinar cell is an important initiating event in acute pancreatitis. We have previously demonstrated that vacuolar ATPase (vATPase) activity is required for zymogen activation. Adenosine monophosphate-activated protein kinase (AMPK) regulates vATPase function in kidney and epididymal clear cells. To determine whether AMPK could affect pancreatitis responses, its effects were first examined in a cellular model of pancreatitis, cerulein-hyperstimulated (100 nM) pancreatic acini. This treatment caused a prominent increase in trypsin and chymotrypsin activities. Pretreatment with AICAR or metformin (AMPK activators) or compound C (an AMPK inhibitor) reduced or increased cerulein-induced zymogen activation, respectively. The association of the vATPase E subunit with membranes, a marker of its activation, tended to be inversely related to AMPK activity (assessed by AICAR and compound C treatments). Cerulein treatment did not change AMPK (α and β) levels but did lead to an increase in its activation (phosphorylation of Thr172) and induced the time-dependent translocation of the enzyme to a Triton-insoluble compartment. Basal in vivo studies showed that AMPK was widely distributed between membrane and soluble fractions generated by differential centrifugation. After cerulein hyperstimulation, AMPK levels selectively decreased in fractions containing the highest levels of active zymogens. These studies suggest that AMPK activity has a protective role in the pancreatic acinar cell that inhibits zymogen activation in the basal state, and this AMPK effect is reduced during pancreatitis. Therapies that prevent the selective reduction of AMPK in compartments that support zymogen activation could reduce injury during pancreatitis.
authors: Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors: Christina A
authors: CA
authors: Shugrue
authors: Martine
authors: M
authors: Alexandre
authors: Alexander
authors: A
authors: Diaz de Villalvilla
authors: Thomas R
authors: TR
authors: Kolodecik
authors: Lawrence H
authors: LH
authors: Young
authors: Fred S
authors: FS
authors: Gorelick
authors: Edwin C
authors: EC
authors: Thrower
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002108:Ceruletide / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D008687:Metformin / Q000494:pharmacology; D017830:Octoxynol; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects*; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology; D012967:Sodium Dodecyl Sulfate
chemical_list: D004792:Enzyme Precursors; D011720:Pyrazoles; D011743:Pyrimidines; D012265:Ribonucleotides; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D012967:Sodium Dodecyl Sulfate; D002108:Ceruletide; D017830:Octoxynol; D008687:Metformin; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide