Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-alpha.
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 peroxisome proliferator-activated receptor-alpha (PPAR-alpha), the mechanism is still not fully elucidated. Gastric bypass was surgically prepared in male Sprague-Dawley rats. Gastric-bypassed and sham-operated rats were either given ciprofibrate (50 mg.kg(-1).day(-1) in methocel) or vehicle alone for 7 wk. PPAR-alpha knockout (KO) and wild-type (WT) mice were either given ciprofibrate (500 mg.kg(-1).day(-1) in methocel) or vehicle alone for 2 wk. The concentration of gastrin in blood was analyzed. Antral G cell density and gastrin mRNA abundance were determined by using immunostaining and Northern blot analysis. 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 threefold increase in gastrin mRNA in sham-operated rats. In PPAR-alpha 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 threefold increase in gastrin mRNA. Comparing animals dosed with vehicle only, PPAR-alpha KO mice had higher serum gastrin concentration than WT mice. We conclude that the main effects of ciprofibrate on G cells are mediated from the antrum lumen, and the mechanism is dependent on PPAR-alpha. The results indicate that PPAR-alpha may have a role in the physiological regulation of gastrin release.
Martinsen
Tom C
TC
Dept. of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, St. Olav's Hospital HF, Trondheim, Norway. tom.chr.martinsen@ntnu.no
Bakke
Ingunn
I
Chen
Duan
D
Sandvik
Arne K
AK
Zahlsen
Kolbjørn
K
Aamo
Trond
T
Waldum
Helge L
HL
D000818:Animals; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D005260:Female; D058607:Fibric Acids; D015390:Gastric Bypass; D019863:Gastrin-Secreting Cells / Q000187:drug effects*; D005755:Gastrins / Q000378:metabolism*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D047493:PPAR alpha / Q000819:agonists / Q000172:deficiency / Q000502:physiology*; D011706:Pyloric Antrum / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000096:biosynthesis
D058607:Fibric Acids; D005755:Gastrins; D047493:PPAR alpha; D013004:Somatostatin; D002995:Clofibric Acid; C019304:ciprofibrate