The Function of ATPase Copper Transporter ATP7B in Intestine.
The Function of ATPase Copper Transporter ATP7B in Intestine.
复制标题
DOI：
10.1053/j.gastro.2017.09.019
复制
发表时间：
2018-01
期刊：
影响因子：
29.4
通讯作者：
Lutsenko S
中科院分区：
文献类型：
--
作者：
Pierson H;Muchenditsi A;Kim BE;Ralle M;Zachos N;Huster D;Lutsenko S
肝豆状核变性是由ATPase铜转运β基因(ATP7B)突变引起的铜(铜)失衡的疾病。ATP7B在肝组织中高表达，肝脏是肝豆状核变性患者铜蓄积的主要部位。肠道也表达ATP7B，但关于肠道ATP7B对正常肠道内环境平衡或对肝豆状核变性表现的作用知之甚少。我们研究了ATP7B在小鼠肠道器官和组织中的作用。收集ATP7B基因敲除小鼠(ATP7B-/-)和对照小鼠的肠道组织，建立三维肠小体模型。用免疫组织化学和X射线荧光方法检测ATP7B和铜在组织中的分布。用电子显微镜、组织学分析和免疫印迹法确定ATP7B缺失的影响。将正常小鼠和ATP7B基因敲除小鼠的肠道组织分别与过量铜或铜络合剂孵育，用荧光共聚焦显微镜观察对细胞脂肪含量和ATP7B水平及定位的影响。ATP7B沿十二指肠隐窝-绒毛轴维持铜的梯度，并缓冲肠细胞胞浆中的铜水平。这些功能是通过铜依赖的含有ATP7B的囊泡的快速扩大和ATP7B水平的增加来调节的。ATP7B−/−小鼠的肠道中铜储存池减少，铜耗竭，肠细胞内甘油三酯充满的囊泡积聚，载脂蛋白B错位，乳糜粒丢失。在初级三维肠样体中，过量的铜或铜螯合剂会损害乳糜粒的组装。ATP7B调节小鼠肠道铜的囊泡储存。ATP7B缓冲肠道细胞中的铜水平，以维持形成乳糜粒所必需的范围。肝豆状核变性的胃肠道表现可能与肠道铜、脂平衡失调有关。
Wilson disease is a disorder of copper (Cu) misbalance caused by mutations in the ATPase copper transporting beta gene (ATP7B). ATP7B is highly expressed in the liver—the major site of Cu accumulation in patients with Wilson disease. The intestine also expresses ATP7B, but little is known about the contribution of intestinal ATP7B to normal intestinal homeostasis or to Wilson disease manifestations. We characterized the role of ATP7B in mouse intestinal organoids and tissues. We collected intestinal tissues from ATP7B-knockout (Atp7b–/–) and control mice, and establish 3-dimensional enteroids. Immunohistochemistry and X-ray fluorescence were used to characterize the distribution of ATP7B and Cu in tissues. Electron microscopy, histologic analyses, and immunoblotting were used to determine the effects of ATP7B loss. Enteroids derived from control and ATP7B-knockout mice were incubated with excess Cu or with Cu-chelating reagents; effects on cell fat content and ATP7B levels and localization were determined by fluorescent confocal microscopy. ATP7B maintains a Cu gradient along the duodenal crypt–villus axis and buffers Cu levels in the cytosol of enterocytes. These functions are mediated by rapid Cu-dependent enlargement of ATP7B-containing vesicles and increased levels of ATP7B. Intestines of Atp7b−/− mice had reduced Cu storage pools in intestine, Cu depletion, accumulation of triglyceride-filled vesicles in enterocytes, mis-localization of apolipoprotein B, and loss of chylomicrons. In primary 3-dimensional enteroids, administration of excess Cu or Cu chelators impaired assembly of chylomicrons. ATP7B regulates vesicular storage of Cu in mouse intestine. ATP7B buffers Cu levels in enterocytes to maintain a range necessary for formation of chylomicrons. Misbalance of Cu and lipid in the intestine could account for gastrointestinal manifestations of Wilson disease.
登录
查看更多内容
影响因子：
14.5
作者：
Martinelli, Diego;Travaglini, Lorena;Dionisi-Vici, Carlo
通讯作者：
Dionisi-Vici, Carlo
I型胶原蛋白作为人类小肠上皮体外生长的细胞外基质。
影响因子：
3.7
作者：
Jabaji Z;Brinkley GJ;Khalil HA;Sears CM;Lei NY;Lewis M;Stelzner M;Martín MG;Dunn JC
通讯作者：
Dunn JC
DOI：
10.1016/j.bbalip.2016.04.012
发表时间：
2016-08
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
D'Aquila T;Hung YH;Carreiro A;Buhman KK
通讯作者：
Buhman KK
影响因子：
4.8
作者：
Barnes, N;Tsivkovskii, R;Lutsenko, S
通讯作者：
Lutsenko, S
影响因子：
4.2
作者：
Monty, JF;Llanos, RM;Kramer, DR
通讯作者：
Kramer, DR