Unravelling the regulation of insulin transport across the brain endothelial cell.
Unravelling the regulation of insulin transport across the brain endothelial cell.
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DOI：
10.1007/s00125-017-4285-4
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发表时间：
2017-08
期刊：
影响因子：
8.2
通讯作者：
Barrett EJ
中科院分区：
文献类型：
--
作者：
Gray SM;Aylor KW;Barrett EJ
为了使循环胰岛素作用于大脑，它必须穿过血脑屏障（BBB）。对于循环中的胰岛素如何穿过 BBB 高度限制性的脑内皮细胞 (BEC)，人们知之甚少。因此，我们研究了 BEC 转胞吞过程中调节 BEC 胰岛素摄取、信号传导和降解的潜在机制，以及高脂饮食 (HFD) 和星形胶质细胞活动如何影响运输。使用纯化的分离 BEC (iBEC) 进行单一培养和与星形胶质细胞共培养，测试 125I-TyrA14-胰岛素摄取和转胞吞作用，以及胰岛素受体 (IR) 阻断、胰岛素信号传导抑制、星形胶质细胞刺激和 HFD 的影响。在生理胰岛素浓度下，IR（而不是 IGF-1 受体）促进 BEC 胰岛素摄取，这需要脂筏介导的内吞作用，但不需要胰岛素对磷酸肌醇 3 激酶 (PI3K) 或丝裂原激活蛋白激酶激酶 (MEK) 的作用。给大鼠喂食 HFD 4 周可减少 iBEC 胰岛素摄取并增加 NF-κB 结合活性，而不影响胰岛素 PI3K 信号、IR 表达或含量或胰岛素降解酶表达。使用体外 BBB（iBEC 和星形胶质细胞的共培养），我们发现胰岛素在转胞吞过程中不会降解，并且用 L-谷氨酸刺激星形胶质细胞会增加转胞吞作用，而抑制一氧化氮合酶会减少胰岛素转胞吞作用。胰岛素通过 BEC 中 IR 特异性、囊泡介导的转运过程完整地穿过 BBB。 HFD 喂养、一氧化氮抑制和星形胶质细胞刺激可以调节 BEC 胰岛素摄取和转胞吞作用。
For circulating insulin to act on the brain it must cross the blood–brain barrier (BBB). Remarkably little is known about how circulating insulin crosses the BBB’s highly restrictive brain endothelial cells (BECs). Therefore, we examined potential mechanisms regulating BEC insulin uptake, signalling and degradation during BEC transcytosis, and how transport is affected by a high-fat diet (HFD) and by astrocyte activity. 125I-TyrA14-insulin uptake and transcytosis, and the effects of insulin receptor (IR) blockade, inhibition of insulin signalling, astrocyte stimulation and an HFD were tested using purified isolated BECs (iBECs) in monoculture and co-cultured with astrocytes. At physiological insulin concentrations, the IR, not the IGF-1 receptor, facilitated BEC insulin uptake, which required lipid raft-mediated endocytosis, but did not require insulin action on phosphoinositide-3-kinase (PI3K) or mitogen-activated protein kinase kinase (MEK). Feeding rats an HFD for 4 weeks decreased iBEC insulin uptake and increased NF-κB binding activity without affecting insulin PI3K signalling, IR expression or content, or insulin degrading enzyme expression. Using an in vitro BBB (co-culture of iBECs and astrocytes), we found insulin was not degraded during transcytosis, and that stimulating astrocytes with L-glutamate increased transcytosis, while inhibiting nitric oxide synthase decreased insulin transcytosis. Insulin crosses the BBB intact via an IR-specific, vesicle-mediated transport process in the BECs. HFD feeding, nitric oxide inhibition and astrocyte stimulation can regulate BEC insulin uptake and transcytosis.
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影响因子：
64.5
作者：
García-Cáceres C;Quarta C;Varela L;Gao Y;Gruber T;Legutko B;Jastroch M;Johansson P;Ninkovic J;Yi CX;Le Thuc O;Szigeti-Buck K;Cai W;Meyer CW;Pfluger PT;Fernandez AM;Luquet S;Woods SC;Torres-Alemán I;Kahn CR;Götz M;Horvath TL;Tschöp MH
通讯作者：
Tschöp MH
影响因子：
4.2
作者：
Lynch, John A.;George, Ana M.;Fine, Richard E.
通讯作者：
Fine, Richard E.
影响因子：
4
作者：
Catravas, John D.;Snead, Connie;Dimitropoulou, Christiana;Chang, Albert S. Y.;Lucas, Rudolf;Verin, Alexander D.;Black, Stephen M.
通讯作者：
Black, Stephen M.
影响因子：
17.1
作者：
Iliff JJ;Wang M;Liao Y;Plogg BA;Peng W;Gundersen GA;Benveniste H;Vates GE;Deane R;Goldman SA;Nagelhus EA;Nedergaard M
通讯作者：
Nedergaard M
影响因子：
4.4
作者：
Jessen NA;Munk AS;Lundgaard I;Nedergaard M
通讯作者：
Nedergaard M