Loss of Parietal Cell Tubulovesicles and Hypertrophic Gastritis in Hip1r Knockout Mice

Huntingtin‐interacting protein‐1 related (Hip1r) is a clathrin and F‐actin binding protein proposed to play an important role in endocytosis. Hip1r is abundantly expressed in the stomach. We used cell fractionation and immunostaining to demonstrate its predominant expression in parietal cells coincident with the F‐actin rich intracellular canaliculus. In resting parietal cells the proton pump is stored in intracellular tubulovesicles, which fuse with the apical canalicular membrane when stimulated to secrete acid. Cessation of acid secretion involves endocytosis and regeneration of tubulovesicles. We hypothesized that Hip1r is crucial for endocytosis of the parietal apical membrane to form tubulovesicles. We analyzed the stomachs of Hip1r knockout mice (Hip1r‐KO) with and without histamine stimulation. Hip1r‐KO mice had markedly reduced acid secretion, suggesting a parietal cell defect. Histological analysis showed reduced numbers of parietal and chief cells, and increased inflammatory cell infiltrates. However, expansion of both an abnormal mucous neck cell population as well as surface mucous cells resulted in a marked thickening of the oxyntic mucosa in the mutant. Electron microscopic studies showed that Hip1r‐KO parietal cells have grossly altered morphology with loss of tubulovesicles and expansion of the canalicular membrane. These results suggest that Hip1r is required for clathrin‐mediated endocytosis of the apical membrane to form tubulovesicles in the parietal cell. We speculate that abnormal membrane dynamics in the Hip1r‐KO causes parietal cell death leading to low acid and cellular transformation of the gastric mucosa. Support: DK56882(LCS) & DK31900 (CSC).