Parietal cells of the gastric mucosa contain a complex and extensive secretory membrane system that harbors gastric H+, K+-adenosine triphosphatase, 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. Wild-type and Atp4a-/- mice, paired for age, were examined at 10, 12, 14 and 16 weeks for histopathology, and the expression of MUC2, AMACR, Ki-67, and p53 proteins was analyzed by immunohistochemistry. For further information, PI3K, AKT, mTOR, HIF-1α, LDHA, and SIRT6 were detected by western blotting. Compared to the WT mice, Atp4a-/- mice developed parietal cell atrophy and significant antral inflammation and intestinal metaplasia 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. The expression of P-PI3K, P-AKT, P-mTOR, HIF-1α, LDHA, and SIRT6 was significantly higher in tissue from the Atp4a-/- mice compared with the WT mice. 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 intestinal metaplasia and activated the Warburg effect via PI3K/AKT/mTOR signaling.
Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice
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Wei Liu, Liang-jun jun Yang, Yuan-liang liang Liu, Dong-sheng sheng Yuan, Zi-ming ming Zhao, Qi Wang, Yan Yan, Hua-feng feng Pan; Dynamic characterization of intestinal metaplasia in the gastric corpus mucosa of Atp4a-deficient mice. Biosci Rep BSR20181881. doi: https://doi.org/10.1042/BSR20181881
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