Liver regeneration is associated with increased expression of the insulin-like growth factor-II/mannose-6-phosphate receptor

The process of liver regeneration involves the concerted action of certain growth factors, which stimulate hepatocyte proliferation, and other antiproliferative factors, which prevent uncontrolled growth of this organ. Some of the biological actions of insulin-like growth factor-II (IGF-II), a mitogenic polypeptide closely related to insulin, may be mediated by the IGF-II receptor. This receptor consists of a single chain extracellular domain and a very small cytoplasmic domain, and can bind lysosomal enzymes that contain mannose-6-phosphate (M-6-P) residues. Since these enzymes may be involved in remodelling processes in certain tisues, we measured the expression of the IGF-II/M-6-P receptor in the liver after subtotal hepatectomy. Binding of [¹²⁵I]IGF-II to crude plasma membranes from regenerating liver was maximal 2 days after hepatectomy (4.9% specific binding/60 μg protein) and subsequently decreased. Both control livers (livers removed at the time of operation) and sham-operated control livers demonstrated specific [¹²⁵I] IGF-II binding of 1.1% throughout the experimental period. This increase in binding in regenerating liver was shown to be associated with an increase in the concentration of IGF-II receptor protein by means of Western blot analysis using a polyclonal anti-IGF-II/ M-6-P receptor antiserum (3637). Similarly, steady state levels of IGF-II/M-6-P receptor mRNA, measured by solution hybridization/RNase protection assays, were significantly increased in the regenerat ing liver (2.0-fold over the control value 2 days after hepatectomy). Five and 10 days postsurgery, the levels of IGF-II receptor mRNA were markedly reduced, and they were even lower than the levels in control livers. These results suggest that high levels of expression of the IGF-II/M-6-P receptor are correlated with the process of liver regeneration. It is still unclear whether the receptor is required to bind some insulin-related growth factor, or whether the IGF-II/M-6-P receptor is mainly involved in binding lysosomal enzymes involved in the remodeling process.