Beta‐glucosidase 2 knockout mice with increased glucosylceramide show impaired liver regeneration
Beta‐glucosidase 2 knockout mice with increased glucosylceramide show impaired liver regeneration
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葡萄糖神经酰胺增加的 β-葡萄糖苷酶 2 敲除小鼠表现出肝再生受损
DOI：
10.1111/j.1478-3231.2012.02841.x
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发表时间：
2012
影响因子：
6.7
通讯作者：
Canbay AE
中科院分区：
文献类型：
--
作者：
Gonzalez-Carmona MA;Sandhoff R;Tacke F;Vogt A;Weber S;Canbay AE
背景和目的糖脂已被证明在细胞信号、增殖和分化过程中具有特殊的功能，这些过程在肝脏再生过程中都是重要的。我们之前产生了β-葡萄糖苷酶2(GBA2)基因敲除小鼠，它在包括肝脏在内的各种组织中积累糖脂葡萄糖神经酰胺。本研究探讨了GBA2缺乏和随后的葡萄糖神经酰胺积累在肝再生中的作用。方法Gba2基因敲除和野生型小鼠接受三分之二的肝部分切除。在不同时间点处死小鼠，采血，取残肝。用质谱仪对全肝和分离肝细胞中的葡萄糖神经酰胺和神经酰胺进行定量。用双抗体夹心法检测血清和肝细胞培养上清液中IL-6、肿瘤坏死因子-α和转化生长因子-β的水平。免疫印迹分析细胞信号蛋白。结果肝部分切除后，GBA2基因缺陷小鼠肝组织中葡萄糖神经酰胺含量明显高于对照组。葡萄糖神经酰胺的蓄积与肝脏再生的延迟和血清IL-6和肿瘤坏死因子-α水平的降低有关。此外，IL-6的降低导致信号转导和转录激活因子3(P-STAT3)磷酸化形式的表达减少。结论葡萄糖神经酰胺的增加影响了肝再生过程中细胞因子和生长因子介导的信号转导通路。因此，抑制IL-6/STAT3信号通路可能是GBA2基因缺陷小鼠肝再生延迟的机制之一。
Background and aimsGlycolipids have been shown to serve specialized functions in cell signalling, proliferation and differentiation processes, which are all important during liver regeneration. We previously generated beta‐glucosidase 2 (GBA2) knockout mice that accumulate the glycolipid glucosylceramide in various tissues, including the liver. The present study addressed the role of GBA2‐deficiency and subsequent glucosylceramide accumulation in liver regeneration.MethodsGba2knockout and wild‐type mice were subjected to two‐third partial hepatectomy. Mice were sacrificed at different time points, blood was collected, and the remnant liver was removed. Glucosylceramide and ceramide were quantified using mass spectrometry from whole liver and isolated hepatocytes. Serum and hepatocytic supernatant of IL‐6, TNF‐α and TGF‐β levels were measured using ELISA. Cell signalling proteins were analysed using immunoblots.ResultsRegenerating liver after partial hepatectomy showed a significant increase of hepatic glucosylceramide in GBA2‐deficient mice compared to controls. Accumulation of glucosylceramide was associated with a delay in liver regeneration and reduced serum levels of IL‐6 and TNF‐α. Furthermore, reduced IL‐6 led to decreased expression of the phosphorylated form of the signal transducer and activator of transcription 3 (P‐STAT3).ConclusionsWe conclude that increased glucosylceramide affects cytokine‐ and growth factor‐mediated signalling pathways during liver regeneration. Thus, the repression of IL‐6/STAT3 signalling pathway seems to be one of the mechanisms for the delay of liver regeneration in GBA2‐deficient mice.
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β-糖脂对细胞内机制的调节与 NKT 脂筏的改变和刀豆球蛋白诱导的肝炎的改善有关。
影响因子：
3.6
作者：
G. Lalazar;A. Ben Ya’acov;A. Lador;D. Livovsky;O. Pappo;S. Preston;Menahem Hareati;Y. Ilan
通讯作者：
Y. Ilan
部分肝切除术后，大鼠肝脏中的特定神经节苷脂迅速增加。
DOI：
10.1016/0006-291x(91)91465-o
发表时间：
1991
影响因子：
3.1
作者：
Fishman,JB;Cahill,M;Morin,P;McCrory,M;Bucher,NL;Ullman,MD
通讯作者：
Ullman,MD
影响因子：
4.6
作者：
Weici Zhang;Y. Moritoki;Koichi Tsuneyama;G‐X. Yang;G‐X. Yang;Yaron Ilan;Zhe‐Xiong Lian;Zhe‐Xiong Lian;M. E. Gershwin
通讯作者：
Weici Zhang;Y. Moritoki;Koichi Tsuneyama;G‐X. Yang;G‐X. Yang;Yaron Ilan;Zhe‐Xiong Lian;Zhe‐Xiong Lian;M. E. Gershwin
肝再生过程中大鼠肝神经节苷脂的含量、模式和代谢过程。
DOI：
--
发表时间：
1990
期刊：
European Journal of Biochemistry
影响因子：
--
作者：
L. Riboni;R. Ghidoni;A. Benevento;G. Tettamanti
通讯作者：
G. Tettamanti
DOI：
10.1074/jbc.m110641200
发表时间：
2002-06
期刊：
The Journal of Biological Chemistry
影响因子：
--
作者：
R. Sandhoff;Stefan T. Hepbildikler;R. Jennemann;R. Geyer;V. Gieselmann;R. Proia;H. Wiegandt;H. Gröne
通讯作者：
R. Sandhoff;Stefan T. Hepbildikler;R. Jennemann;R. Geyer;V. Gieselmann;R. Proia;H. Wiegandt;H. Gröne