Somatostatin Is an Essential Paracrine Link in Acid Inhibition of Gastrin Secretion

Holst, Jens J.; Ørskov, Cathrine; Seier-Poulsen, S

doi:10.1159/000200882

Cited by 30 publications

(15 citation statements)

References 22 publications

(32 reference statements)

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“…In sham-operated animals dosed with ciprofibrate, there was a 50% increase in the number of immunoreactive G cells per millimeter mucosa. This level of hyperplasia is quite similar to observations in previous rat studies with ciprofibrate (3,70) and in studies with inhibitors of gastric acid secretion (29,65). No further increase in G cell density is found in long-term studies (10); thus, close to a doubling of G cell density seems to be the maximal level of G cell hyperplasia independent of cause.…”

Section: Effect Of Ciprofibrate On the Antral G Cell: A Local Mechanisupporting

confidence: 90%

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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Section: Effect Of Ciprofibrate On the Antral G Cell: A Local Mechanisupporting

confidence: 90%

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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“…Gastrin and somatostatin have opposing effects on stomach acid release: gastrin induces HCl secretion, while somatostatin inhibits it (10,39,42). In pathological or drug-induced states of sustained hypochlorhydria, G-cell numbers increase at the expense of D cells (36).…”

Section: Resultsmentioning

confidence: 99%

Requirement of the Tissue-Restricted Homeodomain Transcription Factor Nkx6.3 in Differentiation of Gastrin-Producing G Cells in the Stomach Antrum

Choi

Romer

Wang

et al. 2008

Molecular and Cellular Biology

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Many homeodomain transcription factors function in organogenesis and cell differentiation. The Nkx family illustrates these functions especially well, and the Nkx6 subfamily controls differentiation in the central nervous system and pancreas. Nkx6.3, a recent addition to this subfamily, overlaps Nkx6.1 and Nkx6.2 in expression in the hindbrain and stomach. Nkx6.3 transcripts localize in the epithelium of the most distal stomach region, the antrum and pylorus; expression in the adult intestine is lower and confined to the proximal duodenum. Nkx6.3 ؊/؊ mice develop and grow normally, with a grossly intact stomach and duodenum. These mice show markedly reduced gastrin mRNA, many fewer gastrin-producing (G) cells in the stomach antrum, hypogastrinemia, and increased stomach luminal pH, with a corresponding increase in somatostatin mRNA levels and antral somatostatin-producing (D) cells. They express normal levels of other transcription factors required for gastric endocrine cell differentiation, Pdx1, Pax6, and Ngn3; conversely, Ngn3 ؊/؊ mice, which also show reduced gastrin levels, express Nkx6.3 normally. These studies implicate Nkx6.3 as a selective regulator of G-and D-cell lineages, which are believed to derive from a common progenitor, and suggest that it operates in parallel with Ngn3.

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“…Whether ciprofibrate has a direct effect on both cells or the effect on the D cell is secondary to the increase in gastric acidity (Martinsen et al 1996) provoked by the hypergastrinemic effect, cannot be settled by the present study. It is, however, well known that an increase in gastric acidity stimulates the antral D cell (Holst et al 1992). Since the degree of increase in mRNA abundance was quite similar for gastrin and somatostatin mRNA in the antral mucosa, a direct effect by ciprofibrate on both the G and D cell seems most probable.…”

Section: Discussionmentioning

confidence: 98%

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

Im¹,

Sylte²,

Schulze³

et al. 1998

Journal of Molecular Endocrinology

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The peroxisome proliferator ciprofibrate induces hypergastrinemia without inhibiting acid secretion. The present study was carried out to assess the effect of ciprofibrate on serum gastrin and gastrin (G) cells in different strains of rats and to compare the effect of ciprofibrate with other lipid-reducing agents (lovastatin and simvastatin) which have a different mechanism of action.Serum gastrin was determined by a radioimmunoassay method, G cell density by histomorphometry after immunostaining for G cells, and gastrin, somatostatin and histidine decarboxylase (HDC) mRNA abundance by Northern blot analysis.Ciprofibrate (100 mg/kg/day for three weeks) induced a marked hypergastrinemia (P<0·01) in male and female Fischer rats as well as in female Wistar rats. Simvastatin and lovastatin did not affect serum gastrin. Antral G cell density increased significantly in female Wistar rats (P<0·05) and non-significantly in the other rats after ciprofibrate. Both gastrin and somatostatin mRNA abundance in antral mucosa increased markedly and significantly (P<0·01) after ciprofibrate treatment.The present study shows that the peroxisome proliferator ciprofibrate induces hypergastrinemia secondary to an increased storage and synthesis of antral gastrin. Since somatostatin mRNA abundance also increased, the present study suggests that ciprofibrate and possibly other peroxisome proliferators in sufficient concentrations have a stimulatory effect on endocrine cells.

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Somatostatin Is an Essential Paracrine Link in Acid Inhibition of Gastrin Secretion

Cited by 30 publications

References 22 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

Requirement of the Tissue-Restricted Homeodomain Transcription Factor Nkx6.3 in Differentiation of Gastrin-Producing G Cells in the Stomach Antrum

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

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