EXTL2 controls liver regeneration and aortic calcification through xylose kinase-dependent regulation of glycosaminoglycan biosynthesis
EXTL2 controls liver regeneration and aortic calcification through xylose kinase-dependent regulation of glycosaminoglycan biosynthesis
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DOI：
10.1016/j.matbio.2013.10.010
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发表时间：
2014-04-01
期刊：
影响因子：
6.9
通讯作者：
Kitagawa, Hiroshi
中科院分区：
文献类型：
--
作者：
Nadanaka, Satomi;Kitagawa, Hiroshi
EXT基因家族的两个成员EXT 1和EXT 2的基因产物在硫酸乙酰肝素的生物合成中一起作为聚合酶起作用。EXTL 2是人类基因组中与EXT 1和EXT 2同源的三个EXT样基因之一，编码N-乙酰氨基己糖基转移酶。然而，EXTL 2在糖胺聚糖（GAG）生物合成中的作用和EXTL 2的生物学意义仍不清楚。有趣的是，EXTL 2可以转移一个GlcNAc残基到四糖连接区，当这个区域被木糖激酶1（FAM 20 B）磷酸化，从而终止链延伸。在EXTL 2敲除小鼠中GAG的产生显著高于野生型小鼠。EXTL 2基因敲除小鼠在发育和出生期间是可行的，并且明显健康。因此，在实验诱导两种单独的病理状况后，分析EXTL 2敲除小鼠。四氯化碳（CCl 4）用于诱导肝功能衰竭，5/6肾切除联合高磷饮食用于诱导慢性肾脏疾病（CKD）。在CCl 4诱导的肝功能衰竭的条件下，CCl 4治疗后EXTL 2敲除小鼠的肝细胞增殖低于野生型小鼠;因此，EXTL 2敲除小鼠的肝再生受损。肝细胞增殖的减少部分是因为EXTL 2基因敲除小鼠比野生型小鼠经历了更少的肝细胞生长因子介导的信号传导。在诱导CKD的条件下，EXTL 2基因敲除小鼠主动脉环血管平滑肌细胞（VSMCs）的基质矿化相对于野生型小鼠增强。在EXTL 2基因敲除小鼠中，GAG生物合成的改变影响了骨形态发生蛋白信号传导，从而增强了VSMC向成骨细胞的分化。总之，这些结果表明，调节GAG生物合成的EXTL 2依赖性机制对于在病理条件下维持组织稳态是重要的，即，缺乏EXTL 2导致GAG过度产生和与病理过程相关的GAG结构变化。(C)2013爱思唯尔有限公司版权所有。
The gene products of two members of the EXT gene family, EXT1 and EXT2, function together as a polymerase in the biosynthesis of heparan sulfate. EXTL2, one of the three EXT-like genes in the human genome that are homologous to EXT1 and EXT2, encodes an N-acetylhexosaminyltransferase. However, both the role of EXTL2 in glycosaminoglycan (GAG) biosynthesis and the biological significance of EXTL2 remain unclear. Interestingly, EXTL2 can transfer a GIcNAc residue to the tetrasaccharide linkage region when this region is phosphorylated by a xylose kinase 1 (FAM20B) and thereby terminate chain elongation. Production of GAGs was significantly higher in EXTL2-knockout mice than in wild-type mice. EXTL2-knockout mice are viable and apparently healthy during development and afterbirth. Therefore, EXTL2-knockout mice were analyzed following the experimental induction of two separate pathological conditions. Carbon tetrachloride (CCl4) was used to induce liver failure, and 5/6th nephrectomy in combination with a high-phosphate diet was used to induce chronic kidney disease (CKD). Under conditions of CCl4-induced liver failure, hepatocyte proliferation following CCl4 treatment was lower in EXTL2-knockout mice than in wild-type mice; consequently, liver regeneration was impaired in EXTL2-knockout mice. This reduction in hepatocyte proliferation resulted partially because EXTL2-knockout mice experienced less hepatocyte-growth-factor-mediated signaling than did wild-type mice. Under conditions of induced CKD, matrix mineralization in vascular smooth muscle cells (VSMCs) in aortic rings of EXTL2-knockout mice was enhanced relative to that in wild-type mice. Altered biosynthesis of GAGs in EXTL2-knockout mice affected bone-morphogenetic-protein signaling, and consequently enhanced the differentiation of VSMCs into osteoblasts. Taken together, these results indicated that the EXTL2-dependent mechanism that regulates GAG biosynthesis is important for the maintenance of tissue homeostasis under pathological conditions, that is, lack of EXTL2 causes GAG overproduction and structural changes of GAGs associated with pathological processes. (C) 2013 Elsevier B.V. All rights reserved.