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

Abstract

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 ...

Adverse Effects of Proton Pump Inhibitors—Evidence and Plausibility

“…Shortly thereafter it was realized that the competitive H2RA ranitidine also caused ECL cell tumours, when given the dose needed to achieve prolonged acid inhibition [18]. Further studies have demonstrated that ECL cell tumours in the corpus remnant may also be induced by partial corpectomy causing hypergastrinemia [19,20] or by administration of ciprofibrate, a drug that induces hypergastrinemia without altering gastric acidity [21,22,23]. Transgenic INS-GAS mice have hypergastrinemia accompanied by gastric hyperacidity and develop tumours in the gastric corpus with an adenocarcinoma phenotype [24].…”

Stomach gastrin is regulated by sodium via PPAR-α and dopamine D1 receptor

“…Ciprofibrate, a peroxisome proliferator-activated receptor α (PPAR-α) agonist, given by oral gavage, increases gastrin secretion, associated with a doubling of G cell density in the stomach antrum of Sprague-Dawley rats (Martinsen et al 2005). This did not occur in gastricbypassed rats and PPAR-α -/mice (Martinsen et al 2005).…”

“…Ciprofibrate, a peroxisome proliferator-activated receptor α (PPAR-α) agonist, given by oral gavage, increases gastrin secretion, associated with a doubling of G cell density in the stomach antrum of Sprague-Dawley rats (Martinsen et al 2005). This did not occur in gastricbypassed rats and PPAR-α -/mice (Martinsen et al 2005). PPAR-α agonists have been reported also to increase progastrin production in human colorectal carcinoma cells (Lachal et al 2004), but this mechanism has not been studied in normal human stomach G cells.…”

Animal Models to Study the Role of Long‐Term Hypergastrinemia in Gastric Carcinogenesis

“…Long-term administration of the competitive H2-blocker ranitidine also has the ability to induce ECL cell carcinoids when given in large enough doses [22]. Finally, the administration of ciprofibrate induces ECL cell carcinoids [23] in rats without gastric hypoacidity [24], but causes hypergastrinemia through a direct effect on the antral G-cell [25]. The induction of ECL cell carcinoids by ciprofibrate clearly demonstrates that it is hypergastrinemia and not hypoacidity that drives ECL cell carcinogenesis.…”