The role of free fatty acids, pancreatic lipase and Ca+ signalling in injury of isolated acinar cells and pancreatitis model in lipoprotein lipase-deficient mice.
OBJECTIVE
Recurrent pancreatitis is a common complication of severe hypertriglyceridaemia (HTG) often seen in patients carrying various gene mutations in lipoprotein lipase (LPL). This study investigates a possible pathogenic mechanism of cell damage in isolated mouse pancreatic acinar cells and of pancreatitis in LPL-deficient and in wild type mice.


RESULTS
Addition of free fatty acids (FFA) or of chylomicrons to isolated pancreatic acinar cells caused stimulation of amylase release, and at higher concentrations it also caused cell damage. This effect was decreased in the presence of the lipase inhibitor orlistat. Surprisingly, pancreatic lipase whether in its active or inactive state could act like an agonist by inducing amylase secretion, increasing cellular cGMP levels and converting cell damaging sustained elevations of [Ca(2+)](cyt) to normal Ca(2+) oscillations. Caerulein increases the levels of serum amylase and caused more severe inflammation in the pancreas of LPL-deficient mice than in wild type mice.


CONCLUSIONS
We conclude that high concentrations of FFA as present in the plasma of LPL-deficient mice and in patients with HTG lead to pancreatic cell damage and are high risk factors for the development of acute pancreatitis. In addition to its enzymatic effect which leads to the generation of cell-damaging FFA from triglycerides, pancreatic lipase also prevents Ca(2+) overload in pancreatic acinar cells and, therefore, counteracts cell injury.
Yang
F
F
Physiological Institute, University of Saarland, Homburg, Saar, Germany.
Wang
Y
Y
Sternfeld
L
L
Rodriguez
J A
JA
Ross
C
C
Hayden
M R
MR
Carriere
F
F
Liu
G
G
Schulz
I
I
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D002766:Cholecystokinin; D002914:Chylomicrons / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008049:Lipase / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D010195:Pancreatitis / Q000378:metabolism*; D015398:Signal Transduction
D002914:Chylomicrons; D005230:Fatty Acids, Nonesterified; D002766:Cholecystokinin; D007770:L-Lactate Dehydrogenase; D008049:Lipase; D008071:Lipoprotein Lipase; D002118:Calcium