Liver regeneration .8. Liver regeneration versus direct hyperplasia

In this, the penultimate article to appear in the series on liver regeneration, Columbano and Shinozuka review the role of primary mitogens as inducers of hepatic growth without cell. loss. Cell proliferation by direct hyperplasia in the absence of compensatory regeneration represents another unique ability of hepatic cells to proliferate. Throughout the series we have dealt primarily with liver regeneration after two-thirds partial hepatectomy or chemical toxicity. We are now introduced to a type of hepatocyte proliferation that does not necessarily require expression of certain immediate early genes or growth factors or even exhibits the same patterns of signal transduction associated with compensatory hyperplasia. The mechanisms involved in transition through the G1 phase of the cell cycle are quite different for the two types of liver regeneration. However, once the hepatocyte is committed to replication, progression through the cell cycle appears to be the same for both types of growth. The characteristics of mitogen-induced direct hyperplasia also appear to depend on the type of mitogen involved. For example, the pattern of ploidy, the perturbation in cytokinesis, and the incidence of multinucleate cells are very different in direct hyperplasia induced by lead nitrate vs. that induced by the peroxisome proliferator nafenopin. However, one common characteristic remains intact: as soon as the mitogenic stimulus is withdrawn, liver mass and DNA content return to their original values, regressing through what appears to be the well-controlled process of apoptosis. In liver regeneration by direct hyperplasia, we become aware of a host of new players, including nuclear receptors for peroxisome proliferators such as clofibrate and the retinoid X receptor for 9-cis retinoic acid. We are also reintroduced to a set of old players including nonparenchymal cells and TNF-alpha. If it begins to seem logical, try to explain why direct hyperplasia is far less effective in initiation of chemical hepatocarcinogenesis than compensatory regeneration. The hepatic cell is truly a remarkable entity, with its myriad of ways to replicate, regress, and remain quiescent. Just when the subject of liver regeneration was beginning to make sense!.