Phosphate-dependent luminal ATP metabolism regulates transcellular calcium transport in intestinal epithelial cells
Phosphate-dependent luminal ATP metabolism regulates transcellular calcium transport in intestinal epithelial cells
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磷酸盐依赖性管腔 ATP 代谢调节肠上皮细胞中的跨细胞钙转运
DOI：
10.1096/fj.201700631r
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Masuyama Ritsuko
中科院分区：
文献类型：
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作者：
Uekawa Atsushi;Yamanaka Hitoki;Lieben Liesbet;Kimira Yoshifumi;Uehara Mariko;Yamamoto Yoko;Kato Shigeaki;Ito Kosei;Carmeliet Geert;Masuyama Ritsuko
细胞外低磷酸盐强烈增强肠钙吸收独立于活性维生素D [1，25（OH）2D 3]信号传导，但潜在的机制仍然很差的特点。为了阐明钙转运的磷酸盐依赖性调节，我们研究了参与1，25（OH）2D 3非依赖性钙吸收的肠内环境的一部分，这对缺乏肠道维生素D受体（Vdr）活性的小鼠的饮食磷酸盐水平有反应。通过饮食磷酸盐限制改善了肠道Vdr缺失小鼠的钙吸收受损。因此，培养的肠上皮细胞中的钙转运增加时，顶侧暴露于低磷酸盐水平（0.5 mM）相比，正常或高磷酸盐水平（1.0或5.0 mM，分别）。从机制上讲，低磷酸盐增加了顶侧培养基中的ATP，并允许钙通过P2 X7嘌呤受体进入上皮细胞，从而导致钙转运增加。我们发现，管腔ATP受上皮ATP释放和降解的调节，磷酸盐限制增加了上皮细胞通过连接蛋白-43半通道释放ATP。此外，外核苷酸焦磷酸酶-1的ATP降解减少，这是由MAPK级联反应的减少引起的。这些研究结果表明，管腔ATP代谢通过1，25（OH）2D 3非依赖性机制调节肠道中的跨细胞钙转运，以响应膳食磷酸盐水平。Uekawa，A.，Yamanaka，H.，利本湖，Kimira，Y.，Uehara，M.，山本，Y.，Kato，S.，伊藤，K.，Carmeliet，G.，增山河磷酸盐依赖性管腔ATP代谢调节肠上皮细胞的跨细胞钙转运。FASEB J.32，1903-1915（2018）。www.fasebj.org
Extracellular low phosphate strongly enhances intestinal calcium absorption independently of active vitamin D [1, 25(OH)2D3] signaling, but the underlying mechanisms remain poorly characterized. To elucidate the phosphate‐dependent regulation of calcium transport, we investigated part of the enteral environment that is involved in 1, 25(OH)2D3‐independent calcium absorption, which responds to dietary phosphate levels in mice that lack intestinal vitamin D receptor (Vdr) activity. Impaired calcium absorption in intestinal Vdr‐null mice was improved by dietary phosphate restriction. Accordingly, calcium transport in cultured intestinal epithelial cells was increased when the apical side was exposed to low phosphate levels (0.5 mM) compared with normal or high phosphate levels (1.0 or 5.0 mM, respectively). Mechanistically, low phosphate increased ATP in the apical side medium and allowed calcium entry into epithelial cellsviathe P2X7 purinoreceptor, which results in increased calcium transport. We found that luminal ATP was regulated by the release and degradation of ATP at the epithelium, and phosphate restriction increased ATP release from epithelial cellsviaconnexin‐43 hemichannels. Furthermore, ATP degradation by ectonucleotide pyrophosphatase‐1 was reduced, which was caused by the reduction of the MAPK cascade. These findings indicate that luminal ATP metabolism regulates transcellular calcium transport in the intestine by an 1, 25(OH)2D3‐independent mechanism in response to dietary phosphate levels.— Uekawa, A., Yamanaka, H., Lieben, L., Kimira, Y., Uehara, M., Yamamoto, Y., Kato, S., Ito, K., Carmeliet, G., Masuyama, R. Phosphate‐dependent luminal ATP metabolism regulates transcellular calcium transport in intestinal epithelial cells.FASEB J.32, 1903–1915 (2018). www.fasebj.org