4-Phenylbutyric acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini.
OBJECTIVE
Endoplasmic reticulum (ER) stress leads to misfolded proteins inside the ER and initiates unfolded protein response (UPR). Unfolded protein response components are involved in pancreatic function and activated during pancreatitis. However, the exact role of ER stress in the exocrine pancreas is unclear. The present study examined the effects of 4-phenylbutyric acid (4-PBA), an ER chaperone, on acini and UPR components.


METHODS
Rat acini were stimulated with cholecystokinin (10 pmol/L to 10 nmol/L) with or without preincubation of 4-PBA. The UPR components were analyzed, including chaperone-binding protein, protein kinaselike ER kinase, X-box-binding protein 1, c-Jun NH(2)-terminal kinase, CCAAT/enhancer-binding protein homologous protein, caspase 3, and apoptosis. Effects of 4-PBA were measured on secretion, calcium, and trypsin activation.


RESULTS
4-Phenylbutyric acid led to an increase of secretion, whereas trypsin activation with supraphysiological cholecystokinin was significantly reduced. 4-Phenylbutyric acid prevented chaperone-binding protein up-regulation, diminished protein kinaselike ER kinase, and c-Jun NH2-terminal kinase phosphorylation, prohibited X-box-binding protein 1 splicing and CCAAT/enhancer-binding protein homologous protein expression, caspase 3 activation, and apoptosis caused by supraphysiological cholecystokinin.


CONCLUSIONS
By incubation with 4-PBA, beneficial in urea cycle deficiency, it was possible to enhance enzyme secretion to suppress trypsin activation, UPR activation, and proapoptotic pathways. The data hint new perspectives for the use of chemical chaperones in pancreatic diseases.
Department of Medicine II, Campus Groβhadern, University of Munich, Munich, Germany.
Antje
A
Malo
Burkhard
B
Krüger
Burkhard
B
Göke
Constanze H
CH
Kubisch
D000681:Amylases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002766:Cholecystokinin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D046790:Pancreas, Exocrine / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; D010654:Phenylbutyrates; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; C075773:4-phenylbutyric acid; D002766:Cholecystokinin; D000681:Amylases; D014357:Trypsin; D002118:Calcium