Background & Aims: Recurrent pancreatitis is a common complication of severe hypertriglyceridemia (HTG) in patients with various gene mutations in lipoprotein lipase (LPL) or Apolipoprotein CII. However, the exact pathogenetic mechanism has not yet been defined.
Methods: Susceptibility to pancreatitis in LPL deficient mice was compared with that of wild-type mice after i.p. injections of caerulein by determinations of amylase release and of pancreatic pathological scores. The effect of chylomicrons (CMs) and fatty acids was investigated on enzyme release, Ca2+ signaling and cell injury in isolated pancreatic acinar cells from wild type mice.
Results: Caerulein induced higher levels of serum amylase and more severe inflammation in the pancreas of LPL deficient than in wild type mice. Addition of free fatty acids (FFA), or of CMs to isolated pancreatic acinar cells led to release of amylase and caused cell injury at higher concentrations. The effect of CMs was partially blocked by orlistat, an inhibitor of pancreatic lipase (PL). These results suggest that increased concentrations of FFA from CM hydrolysis by PL can induce acinar cell injury. Surprisingly, PL, whether in its active or inactive state could act like an agonist by inducing amylase secretion without cell injury. It caused incease in cGMP levels and conversion of cell damaging sustained elevations of [Ca2+] to normal Ca2+ oscillations.
Conclusions: LPL deficient mice with severe HTG display enhanced susceptibility to acute pancreatitis. High levels of CMs and FFAs result in pancreatic cell injury. PL has a dual effect: generating FFA from CMs and preventing Ca2+ overload in pancreatic acinar cells.
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