The effect of the peroxisome proliferator ciprofibrate on the gastric mucosa and particularly the gastrin cell

Im, Kvetnoĭ; Sylte, R; Schulze, B; Martinsen, TC; Sandvik, A. K.

doi:10.1677/jme.0.0200111

Cited by 10 publications

(10 citation statements)

References 24 publications

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“…Normally, there is a reciprocal relationship between the activity of the antral G and D cells (6,76). During ciprofibrate dosing, we found a concomitant increase in gastrin and somatostatin mRNA abundance in the antral mucosa (3,70). To our knowledge, this had not been reported previously.…”

supporting

confidence: 47%

“…Studies have shown that ciprofibrate induces transcription of gastrin mRNA, hypergastrinemia, and hyperplasia of antral G cells (3,27,43,70). The effect is not mediated by reduced gastric acidity (43) but is potentiated by administration of the proton pump inhibitor omeprazole (27).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, G cell hyperfunction is not reversed by the normally suppressive somatostatin analog octreotide, indicating a unique and direct effect of ciprofibrate on the G cell (3) independent of gastric acidity and somatostatin. Continuous dosing of ciprofibrate for 2 wk induces significant hypergastrinemia in rats (27), and the effect is not restricted to a particular rat strain or gender (70). The mechanism by which ciprofibrate stimulates antral G cells in the rat has so far been unknown.…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, this had not been reported previously. In contrast, the abundance of somatostatin mRNA in the oxyntic mucosa was decreased during ciprofibrate dosing (70) (70). Induction of the peroxisomal enzyme CoA oxidase (ACO) is one of the most frequently used markers of PP action and PPAR-␣ stimulation (49,67).…”

mentioning

confidence: 99%

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Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-α

Martinsen¹,

Bakke²,

Chen³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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dum. Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-␣. Am J Physiol Gastrointest Liver Physiol 289: G1052-G1062, 2005. First published August 11, 2005; doi:10.1152/ajpgi.00268.2005.-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-␣ (PPAR-␣), the mechanism is still not fully elucidated. Gastric bypass was surgically prepared in male Sprague-Dawley rats. Gastric-bypassed and shamoperated rats were either given ciprofibrate (50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in methocel) or vehicle alone for 7 wk. PPAR-␣ knockout (KO) and wild-type (WT) mice were either given ciprofibrate (500 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 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-␣ 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-␣ 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-␣. The results indicate that PPAR-␣ may have a role in the physiological regulation of gastrin release.peroxisome proliferator-activated receptor-␣; hypergastrinemia; gastric bypass; peroxisome proliferator-activated receptor-␣ knockout mice IN 1905, EDKINS (19) postulated the presence of a humoral gastric acid secretagogue being released from the antral mucosa. This was confirmed by Gregory et al. (24) in 1966, who identified this secretagogue as gastrin. Gastrin is still the only known gut hormone released from the stomach that mediates gastric acid secretion. The secretagogue effect of gastrin is mediated by the gastrin receptor on the histamine-containing ECL cells (25,56,72). When activated, the ECL cells respond with increased production (55) and release of histamine (56), which stimulates acid secretion from parietal cells by acting on histamine-2 receptors (38,39,71). In addition, gastrin is acknowledged to be the most important growth factor in the oxyntic mucosa (26,73,77). The trophic effect of gastrin is also mediated by the gastrin receptor (77). Consequently, the ECL cell constitutes the main target of gastrin in the regulation of both function and growth of the oxyntic mucosa (7). Long-term hypergastrinemia leads to ...

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supporting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-α

Martinsen¹,

Bakke²,

Chen³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Neuroendocrine tumors are rare in rodents. They are most commonly caused by antisecretory drugs (3,7,12,27,31,34) and are more common in rats than mice. This higher incidence in rats is probably because rats are more endowed with ECL cells, the cell type constituting the tumors (9).…”

Section: Discussionmentioning

confidence: 99%

Gastric Neuroendocrine Tumors in a 2-Year Oncogenicity Study With CD-1 Mice

et al. 2002

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Descriptions of two rare gastric neuroendocrin e tumors (carcinoids) of enterochromaf n (ECL) cells in CD-1 mice (2/50) from a 104-week oncogenicity study of a serotonergic/dopaminergi c compoun d are presented. These tumors were detected at necropsy and con rmed by histopathology in hematoxyli n and eosin-and Chromogranin A-stained slides. ECL cell counts of the glandular stomachs were determined by quantitative image analysis and did not reveal any hyperplasti c changes as possible predisposing lesions for carcinoid formation. To investigate the possibility of druginduced hypergastrinemi a as the cause of tumor formation of ECL cells, gastrin blood levels were measured after treating mice for 7 days with the test substance. In this study, Omeprazole, the positive control, raised gastrin levels, while the test material did not. It was concluded that these two tumors were an example of "late-life"-occurring, spontaneous neuroendocrin e tumors in the stomachs of aged CD-1 mice.

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Antral G cells in rats during dosing with a PPAR? agonist: a morphometric and immunocytochemical study

Martinsen

Skogaker

Bendheim

2003

Medical Electron Microscopy

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Gastrin-producing G cells constitute one of the major populations of neuroendocrine cells in the antral mucosa of the stomach. The peroxisome proliferator-activated receptor (PPAR) alpha-agonist ciprofibrate is used as a lipid-lowering drug. Recently, ciprofibrate has been shown to induce hypergastrinemia in rats without reducing gastric acidity, which indicates a direct stimulatory effect on the G cell. Gastrin probably plays an important role in gastric tumorgenesis, and long-term dosing with ciprofibrate results in enterochromaffin-like (ECL) cell carcinoids in the oxyntic mucosa of rats. In this study, we aimed to examine changes of neuroendocrine granules in G cells following ciprofibrate dosing and relate them to changes induced by the proton pump inhibitor pantoprazole. Furthermore, we wanted to study peroxisomes in G cells. Rats received ciprofibrate 80 mg/kg/day or pantoprazole 200 mg/kg/day in 4 weeks. Antral mucosal specimens were processed for conventional staining procedures and immunocytochemistry for both the light and electron micro-scope. Specimens were immunolabeled for gastrin and peroxisome-specific proteins. Electron micrographs were analyzed planimetrically. This study shows that hypergastrinemia induced by ciprofibrate is accompanied by a decrease in granule number per cell and a relative increase in electron-dense granules. These changes were quite similar to those induced by pantoprazole, indicating signs of G-cell activation in general. However, distinctions concerning granule size and composition and both hypertrophy and hyperplasia of G cells are presented. Finally, demonstration of peroxisomes in G cells was only achieved by using the highly sensitive tyramide signal amplification technique in immunostaining for the peroxisome-specific protein PMP-70. Therefore, neither morphological nor quantitative changes of peroxisomes in G cells were detected.

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The effect of the peroxisome proliferator ciprofibrate on the gastric mucosa and particularly the gastrin cell

Cited by 10 publications

References 24 publications

Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-α

Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-α

Gastric Neuroendocrine Tumors in a 2-Year Oncogenicity Study With CD-1 Mice

Antral G cells in rats during dosing with a PPAR? agonist: a morphometric and immunocytochemical study

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