The hepatocyte is a direct target for transforming-growth factor β activation via the insulin-like growth factor II/mannose 6-phosphate receptor

Abstract

Background/Aims: The cation-independent mannose 6-phosphate receptor (CIMPR) is overexpressed in hepatocytes during liver regeneration and has been implicated in the maturation of latent pro-transforming growth factor β (TGFβ). In this study, we have: (1) kinetically characterized the changes in CIMPR expression in regenerating liver and cultured proliferating hepatocytes; and (2) assessed the contribution of hepatocyte via the CIMPR to latent pro-TGFβ activation.Methods: The expression of CIMPR protein and mRNA in livers collected after partial hepatectomy and hepatocyte primary cultures was analyzed by Western and Northern blotting. Activity of latent pro-TGFβ was assessed by inhibition of [3H] methylthymidine incorporation into DNA.Results: The expression of the CIMPR protein and/or mRNA progressively increased after 8 h in regenerating liver and 42–46 h in cultured hepatocytes, prior to the onset of DNA replication. Both mature TGFβ and latent pro-TGFβ inhibited epidermal growth factor-stimulated DNA synthesis in hepatocytes in a dose-dependent manner. The effect of latent pro-TGFβ was reversed by two ligands of the CIMPR: β-galactosidase, a mannose 6-phosphate containing protein, and a CIMPR antibody.Conclusions: (1) The induction of the CIMPR gene during liver regeneration and hepatocyte culture occurs in mid G1 phase; and (2) the CIMPR mediates latent proTGFβ activation and thus may act, by targeting TGFβ to hepatocytes, as a negative regulator of hepatocyte growth.