BIGLYCAN AND DECORIN GENE-EXPRESSION IN NORMAL AND FIBROTIC RAT-LIVER - CELLULAR-LOCALIZATION AND REGULATORY FACTORS

The expression of genes encoding the core proteins of the novel small chondroitin/dermatan sulfate proteoglycans decorin and biglycan was studied in the livers of normal rats and in liver tissue during fibrogenesis induced by prolonged bile-duct ligation and thioacetamide poisoning. The cell types responsible for the expression of these transcripts and some key regulatory factors were identified. Both biglycan and decorin messenger RNAs were detected in normal liver tissue. Their relative abundance increased strongly during liver fibrogenesis, reaching highest levels in cirrhotic tissue 8 wk after common bile-duct ligation and after 12 wk of peroral thioacetamide administration, respectively. Specific proteoglycan transcripts were almost absent in hepatocytes from normal and regenerating liver, and only trace amounts were observed in freshly isolated and cultured Kupffer cells. Fat-storing cells clearly expressed both biglycan and decorin transcripts. The steady-state levels of their messenger RNAs increased threefold (biglycan) and fourfold (decorin) during primary culture. Myofibroblastlike cells (transformed fat-storing cells after the second passage) contained dramatically reduced levels of decorin messenger RNA and also lower levels of biglycan messenger RNA compared with primary cultures. These changes of core protein messenger RNA expression were not reflected by the synthesis rates, of medium proteoglycans labeled with S-35 as Na2SO4, in particular that of medium chondroitin sulfate. Transiently acidified (but not native) conditioned media from Kupffer cells and myofibroblastlike cells,and trans forming growth factor-beta-1 enhanced the relative abundances of biglycan and decorin messenger RNAs up to five times in primary-pultured fat-storing cells. Biglycan and decorin in myofibroblastlike cells did not respond to these stimuli. Instead, transforming growth factor-alpha-conditioned and native conditioned media, both inefficient in primary cultures, were most effective in the elevation of the steady-state levels of these proteoglycan transcripts in transformed fat-storing cells. The data provide evidence for the expression of both biglycan and decorin in normal and fibrotic liver, which is a property of fat-storing cells and myofibroblastlike cells. Biglycan and decorin transcript levels are differentially regulated by transforming growth factor-beta-1, transforming growth factor-alpha, Kupffer cell-conditioned medium and myofibroblastlike cell-conditioned medium in fat-storing cells and their transformed counterparts.