Activation of proteoglycan synthesis in injured liver--a brief review of molecular and cellular aspects.

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.