MOLECULAR MECHANISMS OF LIVER FIBROGENESIS - A HOMAGE TO THE ROLE OF ACTIVATED FAT-STORING CELLS

During the last few years, considerable progress has been made in the dissection of cellular and molecular mechanisms of hepatic fibrogenesi s. The disease, initiated by hepatocellular damage and perpetuated by inflammatory reactions, results not only in an overall increase in ext racellular matrix (ECM) but also in molecular and histological rearran gement of virtually all matrix molecules including collagens, structur al glycoproteins, proteoglycans and hyaluronan. These alterations of E CM cause severe clinical (e.g. hemodynamic) complications and further metabolic changes in the whole organ. Perisinusoidal fat (retinoid)-st oring cells have been identified as the (precursor) cell type mainly r esponsible for matrix production in the diseased liver. However, these cells have to be activated, i.e. stimulated to proliferate, to transf orm phenotypically to myofibroblasts and to express matrix genes befor e full competency for fibrogenesis is reached. Multiple cell interacti ons with Kupffer cells, platelets, endothelial cells and hepatocytes m ediated by various cytokines and growth factors (e.g. TGF-beta(1), TGF -alpha, PDGF, FGF, IGF-1) are involved in the mechanism of fat-storing cell activation which is the common and central pathogenetic mechanis m in fibrogenesis. A three-step cascade model of fat-storing cell acti vation is proposed, which offers target mechanisms for possible anti-f ibrotic interventions.