VISUALIZING THE EXPRESSION OF A HUMAN GROWTH-HORMONE (HGH) TRANSGENE IN THE LIVER - INTRAHEPATIC REGIONAL AND INTRACELLULAR DIFFERENCES OF EXPRESSION ARE ASSOCIATED WITH MORPHOLOGICAL ALTERATIONS AND HEPATOCELLULAR PROLIFERATION

Growth hormone acts directly on liver cells; it binds to its receptor and induces a multitude of intracellular events leading, for example, to the production of insulin-like growth factor-1 (IGF-I). While much is known about the biochemical side of these events, their structural correlates are less well examined. Here, we examined livers of transge nic mice (TM) expressing human GH, in an attempt to correlate at the c ellular level the site of GH gene expression with the effects on morph ology and mitotic behavior of liver cells within the hepatic architect ure. Using in situ hybridization histochemistry we observed a striking expression pattern of the hGH gene in hepatocytes near the periportal spaces. In the same regions, the hGH protein, but no IGF-1 immunoreac tive product, was detected using immunohistochemical methods. In the s ections of TM livers, 6.8-31.9% of cells were hGH-immunoreactive. Howe ver, the cellular hGH staining pattern was not homogeneously distribut ed in the immunoreactive cells. Two main patterns became obvious. In t he majority of the immunoreactive cells a cytoplasmic stain was presen t. These cells exhibited normal liver cell features and were not enlar ged (type I). In the other group (type II), the staining was stronger and concentrated, sometimes punctuate, and often confined to cytoplasm ic compartments which were in a perinuclear position. The latter stain ing pattern was generally seen in morphologically altered cells, which were enlarged and possessed intranuclear inclusions and invaginations . In the the periportal regions, mitotically active hepatocytes were e vident, but these cells, as judged from immunocytochemistry, apparentl y did not express the transgene. In conclusion, different staining pat terns for hGH may indicate different levels of transgene expression, w hich could be associated with difficulties in the cells with regard pr ocessing and/or secreting the hormone. In addition to the endocrine ac tions implied by the high hGH levels in the peripheral circulation of these TM, intracrine actions are also suggested (type II staining patt ern), but para-and autocrine loops are possible as well (type I staini ng pattern). Whether IGF-1 is involved, and the mechanism underlying h epatocyte cell proliferation, remain to be examined.