Studies on competence factors in hepatocyte proliferation

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The studies on hepatocyte proliferation has been made great advance in recent years using primary cultures of hepatocytes. Several growth factors were anticipated that they played important roles in liver regeneration through their proliferative activities on hepatocytes., However, little is known about the "trigger" factor (s) of liver regeneration. It was reported that two kinds of growth factors acted sequentially in fibroblast proliferation : competence f-actor and progression factor. Although physiological coinpe-tence factor of hepatocytes has never been reported, it would probably be a trigger factor of liver regeneration because it can act on quiescent cells and can make them sensitive to progression factors.In the present studies, we found that the density of prostaglandin (PG) E_2 receptors on the rat hepa-Locytes in primary culture was decreased when cells were prepared from the rats received partial hepatectomy. We concluded that this decrease was the down regulation of PGE_2 receptors reflecting the direct exposure of the hepatocytes to PGE_2 in vivo after the surgery.In addition, we revealed that PGs had proliferative activities on hepatocyte in serum-free primary culture by enhancing their sensitivity to insulin plus epidermal growth factor. This activity was most prominent in PGE_2, and the action was mediated through stereo-specific PGE_2 receptor and pertusis toxin sensitive G-protein. PGF_2 alpha in higher concentration could act by cross-reacting to PGE_2 receptor. PG actions were, at least in part, mediated by the increase in the intracellular Ca^<2+> concentration. PGE_2 might be derived from sinusoldal endotherial cells, because cultured cells secreated PGE_2.In conclusion, PGE_2 was suggested to be a competence factor in hepatocyte proliferation, and to act as a trigger factor for liver regeneration.