Jain Renu N, Samuelson Linda C
Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, Michigan 48109-2200, USA.
Physiol Genomics. 2007 Mar 14;29(1):1-12. doi: 10.1152/physiolgenomics.00176.2006. Epub 2006 Nov 14.
Gastrin, a potent stimulator of gastric acid secretion, primarily targets the acid-secreting parietal cells and histamine-secreting enterochromaffin-like (ECL) cells in the stomach. Accordingly, gastrin-deficient (GAS-KO) mice have a severe impairment in acid secretion. The aim of this study was to characterize changes in gene expression in GAS-KO mice to identify gastrin-regulated genes and to gain insight into how gastric cell types are regulated by gastrin and acid secretion. Affymetrix microarray analysis of GAS-KO and wild-type mice identified numerous differentially expressed transcripts. The results were compared with GAS-KO mice treated with gastrin to identify genes that were gastrin responsive. Finally, genes that were primarily changed due to gastrin and not hypochlorhydria were identified by comparison to mice that are deficient in both gastrin and cholecystokinin (GAS/CCK-KO), since these mice have restored basal acid secretion. The data were validated by quantitative reverse transcriptase polymerase chain reaction analysis. Interestingly, a number of inflammatory response genes were induced in GAS-KO mice and normalized in GAS/CCK-KO mice, suggesting that they were increased in response to low gastric acid. Moreover, a number of parietal cell transcripts that were downregulated in GAS-KO mice were similarly restored in GAS/CCK-KO mice, suggesting that parietal cell changes were also primarily associated with hypochlorhydria. In contrast, ECL cell genes that were markedly downregulated in GAS-KO mice continued to be reduced in GAS/CCK-KO mice, demonstrating that gastrin coordinately regulates a number of ECL cell genes, including several involved in histamine synthesis and secretion.
胃泌素是胃酸分泌的强效刺激物，主要作用于胃中分泌酸的壁细胞和分泌组胺的肠嗜铬样（ECL）细胞。因此，胃泌素缺陷（GAS-KO）小鼠的胃酸分泌严重受损。本研究的目的是表征GAS-KO小鼠基因表达的变化，以鉴定胃泌素调节的基因，并深入了解胃细胞类型如何受到胃泌素和胃酸分泌的调节。对GAS-KO小鼠和野生型小鼠进行Affymetrix微阵列分析，鉴定出许多差异表达的转录本。将结果与用胃泌素处理的GAS-KO小鼠进行比较，以鉴定对胃泌素反应的基因。最后，通过与胃泌素和胆囊收缩素均缺乏的小鼠（GAS/CCK-KO）比较，鉴定出主要因胃泌素而非胃酸过少而发生变化的基因，因为这些小鼠的基础胃酸分泌已恢复。数据通过定量逆转录聚合酶链反应分析进行验证。有趣的是，GAS-KO小鼠中诱导了许多炎症反应基因，而在GAS/CCK-KO小鼠中这些基因恢复正常，这表明它们是对低胃酸的反应而增加。此外，GAS-KO小鼠中下调的许多壁细胞转录本在GAS/CCK-KO小鼠中也同样恢复，这表明壁细胞的变化也主要与胃酸过少有关。相比之下，GAS-KO小鼠中明显下调的ECL细胞基因在GAS/CCK-KO小鼠中继续减少，这表明胃泌素协同调节许多ECL细胞基因，包括一些参与组胺合成和分泌的基因。
