Regulation of proteoglycan expression in fibrotic liver and cultured fat-storing cells.

Considerable progress has been made in recent years with the molecular dissection of proteoglycans in normal and fibrotic human and rat liver. Proteoglycans constitute a major fraction of extracellular, pericellular and intracellular glycoconjugates. In former times, proteoglycans were classified nearly exclusively on the basis of the composition of their carbohydrate chain (glycosaminoglycan, GAG) attached to the core protein. Accordingly, three main types are discerned in liver, which are in order of decreasing concentrations heparan sulfate (HS, more than 60% of total GAG), dermatan sulfate and chondroitin-4,6-sulfate isomers. Keratan sulfate has not been detected in rat and human liver. Recently, proteoglycans have been characterized by sequencing and cloning of the core proteins to which a number of specific glycosaminoglycan side chains are covalently linked. Accordingly, decorin and biglycan have been identified as major chondroitin sulfate/dermatan sulfate proteoglycans in the extracellular space. In addition, evidence was obtained recently for the expression of aggrecan and lumican, both keratan sulfate bearing proteoglycans, and of syndecan in liver. Using in situ hybridization techniques the temporal and spatial pattern of expression of biglycan, decorin and aggrecan has been assessed. These studies together with Northern blot hybridizations performed with isolated parenchymal and nonparenchymal liver cells confirm that fat-storing cells (Ito cells, perisinusoidal lipocytes), are the most important, principal cellular site of proteoglycan production in diseased liver. The level of expression is regulated by a number of cytokines among which TGF beta, TNF alpha and TGF alpha play significant roles. The effects of these cytokines on proteoglycan expression are dependent on the stage of phenotypic transition of fat storing cells to the activated myofibroblast. Taken together, these data point to the 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 in diseased liver during the process of fibrogenesis.