Enhanced susceptibility to pancreatitis in severe hypertriglyceridaemic lipoprotein lipase-deficient mice and agonist-like function of pancreatic lipase in pancreatic cells
- Y Wang1,
- L Sternfeld2,
- F Yang2,
- J A Rodriguez3,
- C Ross4,
- M R Hayden4,
- F Carriere3,
- G Liu1,
- W Hofer5,
- I Schulz2
- 1 Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Peking University, Beijing, China
- 2 Physiological Institute, University of Saarland, Homburg, Germany
- 3 Laboratory of Enzymology at Interfaces and Physiology of Lipolysis, CNRS, Marseille, France
- 4 Department of Medical Genetics, University of British Columbia, Vancouver, Canada
- 5 Department of Biology, University of Konstanz, Konstanz, Germany
- ProfessorDr I Schulz, University of Konstanz, Department of Biology, Box 648, D-78457 Konstanz, Germany; or Professor G Liu;
- Revised 21 August 2008
- Accepted 30 September 2008
- Published Online First 20 October 2008
Background and aims: Recurrent pancreatitis is a common complication of severe hypertriglyceridaemia 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 intraperitoneal injections of caerulein by determination of amylase release and pancreatic pathological scores. The effect of chylomicrons and fatty acids on enzyme release, Ca2+ signalling and cell injury in isolated pancreatic acinar cells from wild-type and LPL-deficient mice was investigated.
Results: Caerulein induced higher levels of serum amylase and more severe inflammation in the pancreas of LPL-deficient mice than in wild-type mice. Addition of free fatty acids or chylomicrons to isolated pancreatic acinar cells led to the release of amylase and caused cell injury at higher concentrations. The effect of chylomicrons was partially blocked by orlistat, an inhibitor of pancreatic lipase. These results suggest that increased concentrations of free fatty acids from chylomicron hydrolysis by pancreatic lipase can induce acinar cell injury. Surprisingly, pancreatic lipase, whether in its active or inactive state could act like an agonist by inducing amylase secretion without cell injury. It caused an increase in cGMP levels and conversion of cell-damaging sustained elevations of [Ca2+] to normal Ca2+ oscillations.
Conclusions: LPL-deficient mice with severe hypertriglyceridaemia display enhanced susceptibility to acute pancreatitis. High levels of chylomicrons and free fatty acids result in pancreatic cell injury. Pancreatic lipase has a dual effect: generating free fatty acids from chylomicrons and preventing Ca2+ overload in pancreatic acinar cells.
Supplementary methods, figures and a table are published online only at http://gut.bmj.com/content/vol58/issue3
YW, LS and FY contributed equally to this work.
Funding: The authors thank the Deutsche Forschungsgemeinschaft (DFG) for support of LS, FY and IS in the SFB 390, project 5A. They also thank the Major National Basic Research Program of the People’s Republic of China (G2006CD5o3801), Program for the Changjiang Scholars Innovative Research Team in University (PCSIRT).
Competing interests: None.
Ethics approval: The Principles of Laboratory Animal Care (NIH publication no. 85–23, revised 1996) was followed and the experimental protocol was approved by the Animal Care Committee, Peking University Health Science Center.