The beta secretase BACE1 regulates the expression of insulin receptor in the liver.
The beta secretase BACE1 regulates the expression of insulin receptor in the liver.
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DOI：
10.1038/s41467-018-03755-2
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发表时间：
2018-04-03
影响因子：
16.6
通讯作者：
Peiretti F
中科院分区：
文献类型：
--
作者：
Meakin PJ;Mezzapesa A;Benabou E;Haas ME;Bonardo B;Grino M;Brunel JM;Desbois-Mouthon C;Biddinger SB;Govers R;Ashford MLJ;Peiretti F
胰岛素受体（IR）在控制葡萄糖稳态中起着关键作用，然而，其细胞表达的调控仍然知之甚少。在这里，我们表明，生物活性IR的量是由β-位点淀粉样前体蛋白裂解酶1（BACE 1）以葡萄糖浓度依赖性方式对其胞外域的裂解来调节的。体内研究表明，BACE 1调节肝脏中IR和胰岛素信号的量。在糖尿病期间，BACE 1依赖性裂解IR增加，肝脏中的IR量减少，而BACE 1抑制剂的输注部分恢复肝脏IR。我们建议在糖尿病期间使用BACE 1抑制剂来增强胰岛素信号传导。此外，我们发现，血浆中的裂解IR水平反映了肝脏肿瘤中IR亚型A的表达水平，这促使我们提出循环裂解IR的测量可能有助于肝癌的检测和管理。先前已经报道了人血浆中胰岛素受体的可溶形式。在这里，作者证明了胰岛素受体被BACE 1切割，BACE 1可以在生理和糖尿病条件下以葡萄糖浓度依赖性方式调节生物活性胰岛素受体水平。
Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the β-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management. A soluble form of insulin receptor in human plasma has been previously reported. Here the authors demonstrate that insulin receptor is cleaved by BACE1 that can regulate biological active insulin receptor levels in a glucose concentration-dependent manner, both in physiological and diabetic conditions.
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DOI：
10.1042/bj20110512
发表时间：
2012-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Meakin PJ;Harper AJ;Hamilton DL;Gallagher J;McNeilly AD;Burgess LA;Vaanholt LM;Bannon KA;Latcham J;Hussain I;Speakman JR;Howlett DR;Ashford ML
通讯作者：
Ashford ML
影响因子：
2.3
作者：
El Mesallamy, Hala O.;Hamdy, Nadia M.;Amin, Ashraf I.
通讯作者：
Amin, Ashraf I.
影响因子：
29
作者：
Haas JT;Miao J;Chanda D;Wang Y;Zhao E;Haas ME;Hirschey M;Vaitheesvaran B;Farese RV Jr;Kurland IJ;Graham M;Crooke R;Foufelle F;Biddinger SB
通讯作者：
Biddinger SB
影响因子：
4.6
作者：
Meakin PJ;Jalicy SM;Montagut G;Allsop DJP;Cavellini DL;Irvine SW;McGinley C;Liddell MK;McNeilly AD;Parmionova K;Liu YR;Bailey CLS;Dale JK;Heisler LK;McCrimmon RJ;Ashford MLJ
通讯作者：
Ashford MLJ
影响因子：
3.3
作者：
Maesako, M.;Uemura, K.;Kinoshita, A.
通讯作者：
Kinoshita, A.