Human plasma fibrinogen is synthesized in the liver
Human plasma fibrinogen is synthesized in the liver
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DOI：
10.1182/blood-2006-08-040956
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发表时间：
2007-03-01
期刊：
影响因子：
20.3
通讯作者：
Pepys, Mark B.
中科院分区：
文献类型：
--
作者：
Tennent, Glenys A.;Brennan, Stephen O.;Pepys, Mark B.
由纤维蛋白原A α链基因突变引起的遗传性系统性淀粉样变性是一种常染色体显性遗传病，外显率不同，通常晚发，典型表现为肾病导致肾功能衰竭。淀粉样蛋白沉积通常在移植的肾脏中迅速形成，最近在一些患者中进行了同时的原位肝移植，希望能阻止淀粉样蛋白沉积。纤维蛋白原在体外由肝细胞产生，但也由其他人类细胞类型产生，尽管肝脏是大鼠体内血浆纤维蛋白原的来源，但在人类中尚不清楚。将表达野生型纤维蛋白原的肝脏移植到变异纤维蛋白原淀粉样变患者体内，为确定人血浆纤维蛋白原的来源提供了一个独特的机会。因此，我们通过电喷雾电离质谱法测定肝移植前后胰蛋白酶消化的特征，来表征血浆纤维蛋白原A α链异体。肝移植前，具有GIu526Val A α -链变异的纤维蛋白原淀粉样变性患者与野生型序列TFPGFFSPMLGEFVSETESR和淀粉样变性序列TFPGFFSPMLGEFVSVTESR的肽比例大致相等，这与突变杂合个体的预期一致。移植后，仅检测到野生型序列，因此肝脏是至少98%循环纤维蛋白原的来源。
Hereditary systemic amyloidosis caused by fibrinogen A alpha-chain gene mutations is an autosomal dominant condition with variable penetrance, usually of late onset, and typically presents with nephropathy leading to renal failure. Amyloid deposits often develop rapidly in transplanted kidneys, and concomitant orthotopic liver transplantation has lately been performed in several patients with the hope of halting amyloid deposition. Fibrinogen is produced in vitro by hepatocytes but also by other human cell types, and although the liver is the source of plasma fibrinogen in vivo in rats, this is not known in humans. Transplantation of livers expressing wildtype fibrinogen into patients with variant fibrinogen amyloidosis provides a unique opportunity to establish the source of human plasma fibrinogen. We therefore characterized plasma fibrinogen A alpha-chain allotypes by electrospray ionization mass spectrometry mapping of tryptic digests before and after liver transplantation. Before liver transplantation, fibrinogen amyloidosis patients with the GIu526Val A alpha- chain variant had approximately equal proportions of peptide with the wild-type sequence TFPGFFSPMLGEFVSETESR, and with the amyloidogenic variant sequence TFPGFFSPMLGEFVSVTESR, as expected for individuals heterozygous for the mutation. After transplantation, only the wild-type sequence was detected, and the liver is thus the source of at least 98% of the circulation fibrinogen.