Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice

Abstract

Parietal cells of the gastric mucosa contain a complex and extensive secretory membrane system that harbors gastric H+, K+-adenosine triphosphatase (ATPase), the enzyme primarily responsible for gastric lumen acidification. Here, we describe the characterization of mice deficient in the H+, K+-ATPase α subunit (Atp4a−/−) to determine the role of this protein in the biosynthesis of this membrane system and the biology of the gastric mucosa. Atp4a−/− mice were produced by gene targeting. Wild-type (WT) and Atp4a−/− mice, paired for age, were examined at 10, 12, 14 and 16 weeks for histopathology, and the expression of mucin 2 (MUC2), α-methylacyl-CoA racemase (AMACR), Ki-67 and p53 proteins was analyzed by immunohistochemistry. For further information, phosphoinositide 3-kinase (PI3K), phosphorylated-protein kinase B (p-AKT), mechanistic target of rapamycin (mTOR), hypoxia-inducible factor 1α (HIF-1α), lactate dehydrogenase A (LDHA) and sirtuin 6 (SIRT6) were detected by Western blotting. Compared with the WT mice, hypochlorhydric Atp4a−/− mice developed parietal cell atrophy and significant antral inflammation (lymphocyte infiltration) and intestinal metaplasia (IM) with elevated MUC2 expression. Areas of dysplasia in the Atp4a−/− mouse stomach showed increased AMACR and Ki-67 expression. Consistent with elevated antral proliferation, tissue isolated from Atp4a−/− mice showed elevated p53 expression. Next, we examined the mechanism by which the deficiency of the H+, K+-ATPase α subunit has an effect on the gastric mucosa. We found that the expression of phosphorylated-PI3K, p-AKT, phosphorylated-mTOR, HIF-1α, LDHA and SIRT6 was significantly higher in tissue from the Atp4a−/− mice compared with the WT mice (P<0.05). The H+, K+-ATPase α subunit is required for acid-secretory activity of parietal cells in vivo, the normal development and cellular homeostasis of the gastric mucosa, and attainment of the normal structure of the secretory membranes. Chronic achlorhydria and hypergastrinemia in aged Atp4a−/− mice produced progressive hyperplasia and mucolytic and IM, and activated the Warburg effect via PI3K/AKT/mTOR signaling.

The role of Glut-1 and H+/K+-ATPase expression in hyperplasia of mice laryngeal epithelium induced by pepsin

“…H + accumulation upregulated H +/ K + -ATPase to maintain homeostasis by exporting H + . During high-level glycolysis, Glut-1 (encoded by a hypoxia-response gene) is overexpressed in inflamed tissues, enhancing glucose transport into cells, glycolysis, and lactate production [15]. The intracellular H + of lactate accumulates, increasing the expression of the H + transporters H + /K + -ATPase and H ± ATPase, which shuttle H + out of the cells to maintain homeostasis.…”

“…Hypoxia-inducible factor (HIF)-2α plays a major role in this process [14]. Hypoxiainduced transcription factors such as HIF-2α upregulate hypoxia-response genes in Barrett's esophagus (BE) tissue, including that encoding the glucose transporter Glut-1 [15]. High-level expression of Glut-1 may increase glycolysis.…”

“…High-level expression of Glut-1 may increase glycolysis. H + /K + -ATPase may be associated with aerobic glycolysis (the Warburg effect) during intestinal metaplasia of the gastric corpus mucosa, as PI3K/AKT/mTOR signaling is activated [16] and then AKT directly increases the surface translocation of glucose transporters (including Glut-1), enhancing aerobic glycolysis [15]. In patients with LPRD, large amounts of energy are required during H + secretion by H + /K + ATPase.…”

Tumor suppressor ATP4B serve as a promising biomarker for worsening of gastric atrophy and poor differentiation

“…Acid secretory activity of H+ , K+ -ATPase is essential for the viability and normal development of parietal cells [10,20]. The inhibition of H+ , K+ -ATPase using PPIs results in the suppressing production of gastric acid, which may promote parietal cell degeneration worsen gastric atrophy [21,22].…”

“…Gastric H, K-ATPase (ATP4) is a membrane-bound P-type ATPase enzyme on the surface of gastric parietal cells which is responsible for gastric acid secretion [9]. This enzyme consists of α-subunit and β-subunits; α-subunit (ATP4A) contains the catalytic site for ATP hydrolysis [10]. ATP4B gene is located on human chromosome 13q34, encoding β subunit of H, K-ATPase that is associated with the stabilization of the catalytic α-subunit and mediating the last step in acid secretion [11].…”