Expression of glutamine:fructose-6-phosphate amidotransferase in human tissues - Evidence for high variability and distinct regulation in diabetes
Expression of glutamine:fructose-6-phosphate amidotransferase in human tissues - Evidence for high variability and distinct regulation in diabetes
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DOI：
10.2337/diabetes.47.2.170
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发表时间：
1998-02-01
期刊：
影响因子：
7.7
通讯作者：
Schleicher, ED
中科院分区：
文献类型：
--
作者：
Nerlich, AG;Sauer, U;Schleicher, ED
最近的体外和体内研究表明，葡萄糖通过己糖胺生物合成途径的通量增加可能有助于葡萄糖诱导的胰岛素抵抗和诱导生长因子的合成。由于谷氨酰胺：果糖-6-磷酸氨基转移酶（GFAT）催化了己糖胺产物形成的第一步和限制性步骤，因此，tills酶是该途径的关键调节因子，因此可能也参与了临床前或显性糖尿病患者发生的改变。为了研究GFAT在人体组织中的表达，我们制作并鉴定了一种特异性识别GFAT蛋白的消化性抗血清和一种检测GFAT mRNA的核糖核酸探测器。免疫组织化学和非放射性原位杂交分析显示，脂肪细胞和骨骼肌中GFAT蛋白和mRNA的表达水平较高。此外，显著的GFAT表达战；在血管平滑肌细胞中发现的GFAT具有出乎意料的高变异性，而在其他细胞（如外周神经鞘细胞或内分泌活性细胞，包括胰岛细胞）中的表达水平较低，内皮细胞、骨细胞、淋巴细胞、粒细胞和大多数静止成纤维细胞中的表达低于检测水平。在肾组织中，GFAT在小管上皮细胞中表达，而肾小球细胞基本未染色。糖尿病肾病患者的肾切片显示GFAT在部分肾小球上皮细胞和系膜细胞中显著表达，表明GFAT的表达可能是由显性糖尿病诱导的。我们的数据表明GFAT在大多数参与糖尿病晚期并发症发生的组织中表达。此外，结果表明GFAT基因表达受到高度调控。
Recent in vitro and in vivo studies suggested that the increased flux of glucose through the hexosamine biosynthetic pathway may contribute to glucose-induced insulin resistance and to the induction of the synthesis of growth factors. Because glutamine:fructose-6-phosphate amidotransferase (GFAT) catalyzes the first and rate-limiting step in the formation of hexosamine products, tills enzyme is the key regulator in this pathway and is therefore possibly also involved in the alterations occurring in preclinical or manifest diabetic patients, To study the expression of GFAT in human tissues, we produced and characterized a peptic antiserum specifically recognizing GFAT protein and a riboprobe for the detection of GFAT mRNA. Immunohistochemical and nonradioactive in situ hybridization analysis revealed high levels of expression of GFAT protein and mRNA in adipocytes and skeletal muscle. Furthermore, a marked GFAT expression war; found in vascular smooth muscle cells with unexpectedly high variability and lower levels in other cells, e.g., peripheral nerve sheath cells or endocrine-active cells, including the pancreatic islet cell, GFAT protein expression was below detection level in endothelium, osteocytes, lymphocytes, granulocytes, and in most quiescent fibroblasts, In renal tissue, GFAT was expressed ins tubular epithelial cells, while glomerular cells remained essentially unstained, Renal sections obtained from patients with diabetic nephropathy showed significant GFAT expression in some glomerular epithelial and mesangial cells, indicating that GFAT expression may be induced by manifest diabetes, Our data indicate that GFAT is expressed in most tissues involved in the development of diabetic late complications. Furthermore, the results suggest that GFAT gene expression is highly regulated.