Submitted on June 9, 2005
Accepted on August 10, 2005
Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR
Tom C. Martinsen1*, Ingunn Bakke2, Duan Chen2, Arne K. Sandvik1, Kolbjorn Zahlsen3, Trond Aamo3, and Helge L. Waldum1
1 Department of Cancer Research and Molcular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Department of Medicine, St. Olav's Hospital HF, Trondheim University Hospital, Trondheim, Norway
2 Department of Cancer Research and Molcular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
3 Department of Clinical Pharmacology, St. Olav's Hospital HF, Trondheim University Hospital, Trondheim, Norway
* To whom correspondence should be addressed. E-mail: tom.chr.martinsen{at}ntnu.no.
Background: The lipid-lowering drug ciprofibrate stimulates gastrin-producing cells in the rat
stomach without lowering gastric acidity. Although suggested to be a luminal action on antral
PPAR
, the mechanism is still not fully elucidated. Methods: Gastric bypass was surgically
prepared in male Sprague-Dawley rats. Gastric bypassed and sham-operated rats were either
given ciprofibrate (50 mg/kg/day in methocel) or vehicle alone for 7 weeks. PPAR knockout
(KO) and wildtype (WT) mice were either given ciprofibrate (500 mg/kg/day in methocel) or
vehicle alone for two weeks. The concentration of gastrin in blood was analyzed. Antral G
cell density and gastrin mRNA abundance was determined by using immunostaining and
Northern blot. Results: Ciprofibrate did not raise plasma gastrin or G cell density in gastric
bypassed rats, although the gastrin mRNA level was slightly increased. In contrast,
ciprofibrate induced hypergastrinemia, a 50% increase in G cell density and a 3-fold increase
in gastrin mRNA in sham-operated rats. In PPAR KO mice, ciprofibrate did not raise G cell
density or the gastrin mRNA level. The serum gastrin level was reduced by ciprofibrate. In
WT mice, ciprofibrate induced hypergastrinemia, a doubling of G cell density and a 3-fold
increase in gastrin mRNA. Comparing animals dosed with vehicle only, PPAR KO-mice
had higher serum gastrin concentration than WT-mice. Conclusions: The main effects of
ciprofibrate on G cells are mediated from the antrum lumen and the mechanism is dependent
on the PPAR. The results indicate that the PPAR may have a role in the physiological
regulation of gastrin release.
