Gressner A M
Department of Clinical Chemistry, Philipps University, Marburg, Germany.
Eur J Clin Chem Clin Biochem. 1994 Apr;32(4):225-37.
In the past years, considerable progress has been made with the molecular dissection of proteoglycans in normal and fibrotic human and rat liver. Three main types of glycosaminoglycans are found in liver, which, in order of decreasing concentration, are: heparan sulphate (more than 0.6 of total glycosaminoglycans), dermatan sulphate and chondroitin-4,6-sulphate isomers. Keratan sulphate has not been detected in rat and human liver. In fibrotic liver matrix, there is a more than 4-fold increase of the overall concentration of glycosaminoglycans, which is most pronounced for chondroitin sulphate and dermatan sulphate and less prominent for heparan sulphate. In fact, the latter glycosaminoglycan decreases fractionally. Stimulated synthesis rather than reduced breakdown in response to liver injury has been determined as the main mechanism of enhanced deposition. Fat-storing cells, a special type of nonparenchymal liver cells located in the subendothelial space of Disse, are the principal cellular source of hepatic preoteoglycans. In areas of necroinflammation, these cells transform into myofibroblasts, which express the genes for decorin, biglycan, syndecan and presumably other proteoglycans characterized by cloned core proteins. Proteoglycan synthesis in these cells is stimulated in a paracrine way mainly by TGF-beta, which is elaborated by activated Kupffer cells/macrophages and released from disintegrated thrombocytes. Furthermore, TGF-beta is also secreted by myofibroblasts, which are stimulated in an autocrine pathway by TGF-beta. Myofibroblasts can also activate resting (non-transformed) fat-storing cells in a paracrine way. In addition to TGF-beta, significant roles are also played by TNF-alpha, TGF-alpha/EGF, PDGF and FGF. Their effects depend on expression of the respective growth factor receptor that determines the stage of fat-storing cell transformation, on the interaction with other cytokines/growth factors, and on the extracellular matrix supporting these cells. Available data point to a potentially significant role which proteoglycans might fulfil in the regulation of cellular functions and in the maintenance of the supramolecular organization of the extracellular matrix in normal and diseased liver, in particular during the process of liver fibrogenesis.
在过去几年中，对正常及纤维化的人肝和大鼠肝中蛋白聚糖的分子剖析取得了显著进展。肝脏中发现三种主要类型的糖胺聚糖，按浓度递减顺序依次为：硫酸乙酰肝素（占总糖胺聚糖的0.6以上）、硫酸皮肤素和硫酸软骨素-4,6-硫酸酯异构体。大鼠和人肝脏中未检测到硫酸角质素。在纤维化肝基质中，糖胺聚糖的总浓度增加了4倍多，其中硫酸软骨素和硫酸皮肤素最为明显，硫酸乙酰肝素则不太显著。事实上，后一种糖胺聚糖略有减少。已确定肝损伤时糖胺聚糖沉积增加的主要机制是合成受刺激而非降解减少。贮脂细胞是位于狄氏间隙内皮下空间的一种特殊类型的非实质肝细胞，是肝蛋白聚糖的主要细胞来源。在坏死性炎症区域，这些细胞转化为肌成纤维细胞，后者表达核心蛋白聚糖、双糖链蛋白聚糖、多功能蛋白聚糖的基因以及可能由克隆核心蛋白所表征的其他蛋白聚糖的基因。这些细胞中的蛋白聚糖合成主要通过旁分泌方式被转化生长因子-β（TGF-β）刺激，TGF-β由活化的库普弗细胞/巨噬细胞产生并从解体的血小板中释放。此外，TGF-β也由肌成纤维细胞分泌，肌成纤维细胞通过TGF-β的自分泌途径被刺激。肌成纤维细胞也能以旁分泌方式激活静止（未转化）的贮脂细胞。除TGF-β外，肿瘤坏死因子-α、转化生长因子-α/表皮生长因子、血小板衍生生长因子和成纤维细胞生长因子也发挥重要作用。它们的作用取决于决定贮脂细胞转化阶段的各自生长因子受体的表达、与其他细胞因子/生长因子的相互作用以及支持这些细胞的细胞外基质。现有数据表明，蛋白聚糖在正常和患病肝脏中，特别是在肝纤维化形成过程中，可能在调节细胞功能和维持细胞外基质的超分子组织方面发挥潜在的重要作用。
