Early gene expression associated with regeneration is intact after massive hepatectomy in rats.

BACKGROUND

Liver regeneration occurs promptly after partial hepatectomy, although the factors regulating this response have not been fully clarified. Molecular events in the regenerative response have been widely characterized after 70% hepatectomy which represents a model of "normal" liver regeneration in rats. More extensive resection results in hepatic failure which has been attributed to a critical loss of hepatic mass. It is not known whether the pattern of genes expressed early in regeneration remains intact after lethal hepatectomy. We hypothesize that the increased expression of selected early response genes remains intact after massive hepatectomy. The aim of this study was to compare the expression of selected genes after 70 and 85% hepatectomy.

MATERIALS AND METHODS

One hundred ten Wistar rats were divided into three groups: control group (sham laparotomy) (n = 30), 70% hepatectomy group (n = 40), and 85% hepatectomy group (n = 40). Animals were sacrificed at intervals. Livers were excised and divided into four equal specimens, snap frozen, and stored at -70 degrees C. RNA was extracted by standard methods and preparations were probed for protooncogenes, c-myc, c-fos, and for hepatocyte growth factor, and its receptor, c-met. After overnight exposure of autoradiographs, quantification was accomplished by densitometry of RNA slot blots.

RESULTS

After 70% hepatectomy, peaks of maximal expression for both c-myc and c-met were observed after 1 and 12 h. For c-fos, peak of maximal expression was observed at 6 h. For HGF, peak was observed between 12 h and Day 2. After 85% hepatectomy, rats demonstrated similar patterns including peak expression of c-myc at 1 h, but altered peak at 12 h. For c-met, the same pattern was observed between 1 and 12 h. For HGF, two peaks were noted: a first peak at 1 h, and a peak similar to the peak observed after 70% hepatectomy at 12 h.

CONCLUSIONS

These results suggest that early molecular events which are part of the regenerative response are largely intact after 85% lethal hepatectomy. We propose that liver dysfunction and the failure of regeneration observed after 85% hepatectomy is not due to alteration of early signaling. Further study will be required to define failure of the regeneration program in this model.