ASAP3 regulates microvilli structure in parietal cells and presents intervention target for gastric acidity

Jin Qian,Ye Hu,Luoyan Ai,Huanbin Wang,Lunxi Liang,Yueyuan Li,Jing-Yuan Fang,Jilin Wang,Jiayin Tang,Han Yao,Yingxuan Chen,Jie Xu,Yuanhong Xie,Haiying Tian,Chushu Li,Yao Zhang,Yujie Bao

doi:10.1038/sigtrans.2017.3

Jin Qian, Ye Hu + Show 15 more

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https://doi.org/10.1038/sigtrans.2017.3

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Abstract

Gastric acidity-associated disorders such as peptic ulcer and reflux diseases are widespread, and the reported resistance and side effects of currently used medicines suggest an urgent requirement for alternative therapeutic approaches. Here we demonstrate a critical role of ASAP3 in regulating the microvilli structure of parietal cells in vivo, and reveal the feasibility of controlling gastric acidity by targeting ASAP3. Conditional knockout of ASAP3 in mice caused elongation and stacking of microvilli in parietal cells, and substantially decreased gastric acid secretion. These were associated with active assembly of F-actin caused by a higher level of GTP-bound Arf6 GTPase. Consistently, a small molecular compound QS11 inhibited ASAP3 function and significantly reduced gastric acidity in vivo. Of note, the expression of ASAP3 was positively correlated with gastric acid secretion in 90 human cases, and high expression of ASAP3 was associated with reflux disease and peptic ulcer. These results reveal for the first time that ASAP3 regulates the microvilli structures in parietal cells. Our data also suggest ASAP3 as a feasible and drugable therapeutic target for gastric acidity-associated diseases.

Highlights

Gastric acid secretion is required for the digestion of protein, absorption of vitamin B12, iron and calcium,[1] as well as the prevention of bacterial overgrowth
Insufficient gastric acidity may increase the risks of osteoporosis,[2] rheumatoid arthritis,[3] infectious diseases[4] and malignancy,[5] whereas excess acid secretion may lead to widespread diseases such as peptic ulcer[6] and gastroesophageal reflux disease (GERD).[7,8,9,10]
The single amplicon size for each condition indicated the homozygous status of ASAP3loxP/loxP and ASAP3− / − mice. (e) The messenger RNA level of ASAP3 in ASAP3loxP/loxP-UBC-cre/ERT2 mice which were induced with tamoxifen was barely detected by quantitative Polymerase chain reaction (PCR), compared to that in ASAP3WT mice (n = 7 per genotype)

Summary

Introduction

Gastric acid secretion is required for the digestion of protein, absorption of vitamin B12, iron and calcium,[1] as well as the prevention of bacterial overgrowth. The PPIs are among the most widely sold drugs in the world and are in general well tolerated, but resistance and adverse effects such headache, nausea, diarrhea, abdominal pain, fatigue and dizziness have been reported.[11] there is a need for discovering alternative approaches for controlling gastric acidity, which may provide therapeutic opportunity for patients who have unsatisfactory response to PPIs. The gastric parietal cells contain extensive apical membrane on the surface of microvilli, constituting a structural basis for transient proton pumping. The gastric parietal cells contain extensive apical membrane on the surface of microvilli, constituting a structural basis for transient proton pumping It is poorly understood how the structure of microvilli is regulated. An in vitro study based on isolated rabbit parietal cells indicated that ASAP3, an Arf

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