IN-VIVO RESPONSE OF HEPATOCYTES TO GROWTH-FACTORS REQUIRES AN INITIALPRIMING STIMULUS

Although growth factor effects have been studied in cultured hepatocyt es, little information exists as to whether these factors can trigger hepatocyte replication in vivo. In this study we infused epidermal gro wth factor, transforming growth factor-alpha and hepatocyte growth fac tor directly into the portal vein of rats for 24 hr to see whether the y could induce DNA synthesis in normal livers or in livers subjected t o one third hepatectomy. Infusion of transforming growth factor-alpha or epidermal growth factor at doses up to 80 mu g/24 hr had little eff ect on hepatic DNA synthesis in normal liver, whereas the monomeric an d heterodimeric forms of hepatocyte growth factor generally produced i ncreases of less than threefold in hepatic DNA synthesis. In contrast, after one-third hepatectomy infusion of epidermal growth factor, tran sforming growth factor-alpha or hepatocyte growth factor produced dose -dependent increases in hepatic DNA synthesis. At a dose of 40 mu g/24 hr, epidermal growth factor increased DNA synthesis threefold, wherea s transforming growth factor-alpha or hepatocyte growth factor increas ed DNA synthesis to greater than six times that in rats that had under gone hepatectomy alone. Furthermore, infusion of these growth factors, with or without one third-hepatectomy, induced the expression of tran sforming growth factor-alpha. mRNA in the liver. The pattern of protoo ncogene expression induced by one-third hepatectomy was studied to det ermine the effect of this procedure in sensitizing the liver to the gr owth factors. Compared with the well-characterized two-thirds hepatect omy system, there was a similar but smaller increase in c-myc expressi on but no induction of c-jun expression. The results suggest that a sm all functional deficit in the liver that by itself causes little DNA s ynthesis ''primes'' hepatocytes for replication and that the loss of l iver mass and growth factor infusions complement each other by providi ng essential stimuli needed for DNA synthesis.