TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response.
TRPV6 channel mediates alcohol-induced gut barrier dysfunction and systemic response.
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DOI：
10.1016/j.celrep.2022.110937
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发表时间：
2022-06-14
期刊：
影响因子：
8.8
通讯作者：
Rao, RadhaKrishna
中科院分区：
文献类型：
--
作者：
Meena, Avtar S.;Shukla, Pradeep K.;Bell, Briar;Giorgianni, Francesco;Caires, Rebeca;Fernandez-Pena, Carlos;Beranova, Sarka;Aihara, Eitaro;Montrose, Marshall H.;Chaib, Mehdi;Makowski, Liza;Neeli, Indira;Radic, Marko Z.;Vasquez, Valeria;Jaggar, Jonathan H.;Cordero-Morales, Julio F.;Rao, RadhaKrishna
肠上皮紧密连接破坏是酒精相关性内毒素血症、全身性炎症和多器官损伤的主要因素。乙醇和乙醛通过升高细胞内钙离子来破坏紧密连接。在这里，我们确定了TRPV6，一种钙离子通透通道，与酒精诱导的细胞内钙离子升高、肠屏障功能障碍和全身炎症有关。乙醇和乙醛对Caco-2细胞产生TRPV6离子电流。对Caco-2细胞单层和小鼠肠道器官的研究表明，TRPV6缺乏或抑制可减弱乙醇和乙醛诱导的钙内流、紧密连接中断和屏障功能障碍。此外，TRPV6−/−小鼠对酒精诱导的肠屏障功能障碍具有抵抗力。3-氮杂丁醇的光亲和标记确定了组氨酸是TRPV6中潜在的酒精结合部位。这种组氨酸和附近的一种精氨酸的替代，减少了乙醇激活的电流。我们的发现表明，TRPV6对于酒精诱导的肠道屏障功能障碍和炎症是必需的。降低TRPV6功能的分子有可能减轻酒精相关的组织损伤。Meena等人。表明酒精诱导的肠道通透性、内毒素血症和全身炎症的机制需要TRPV6通道。他们表明，乙醇激活TRPV6，诱导钙内流，并破坏肠上皮紧密连接。此外，N末端特定的组氨酸和精氨酸残基微调酒精诱导的TRPV6的激活。
Intestinal epithelial tight junction disruption is a primary contributing factor in alcohol-associated endotoxemia, systemic inflammation, and multiple organ damage. Ethanol and acetaldehyde disrupt tight junctions by elevating intracellular Ca2+. Here we identify TRPV6, a Ca2+-permeable channel, as responsible for alcohol-induced elevation of intracellular Ca2+, intestinal barrier dysfunction, and systemic inflammation. Ethanol and acetaldehyde elicit TRPV6 ionic currents in Caco-2 cells. Studies in Caco-2 cell monolayers and mouse intestinal organoids show that TRPV6 deficiency or inhibition attenuates ethanol- and acetaldehyde-induced Ca2+ influx, tight junction disruption, and barrier dysfunction. Moreover, Trpv6−/− mice are resistant to alcohol-induced intestinal barrier dysfunction. Photoaffinity labeling of 3-azibutanol identifies a histidine as a potential alcohol-binding site in TRPV6. The substitution of this histidine, and a nearby arginine, reduces ethanol-activated currents. Our findings reveal that TRPV6 is required for alcohol-induced gut barrier dysfunction and inflammation. Molecules that decrease TRPV6 function have the potential to attenuate alcohol-associated tissue injury. Meena et al. show that the mechanism of alcohol-induced gut permeability, endotoxemia, and systemic inflammation requires the TRPV6 channel. They show that ethanol activates TRPV6, induces calcium influx, and disrupts intestinal epithelial tight junctions. Furthermore, specific histidine and arginine residues at the N terminus fine-tune the alcohol-induced activation of TRPV6.
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影响因子：
24.5
作者：
Gao Y;Zhou Z;Ren T;Kim SJ;He Y;Seo W;Guillot A;Ding Y;Wu R;Shao S;Wang X;Zhang H;Wang W;Feng D;Xu M;Han E;Zhong W;Zhou Z;Pacher P;Niu J;Gao B
通讯作者：
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影响因子：
7.2
作者：
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通讯作者：
Van Itallie, Christina M.