The effect of two periods of short-term fasting during the promotion stage of hepatocarcinogenesis in rats: the role of apoptosis and cell proliferation

The loss of body and liver weight caused by chronic caloric restriction andits effects on carcinogenesis are well known; however, the effects of acutefasting on carcinogenesis have not been intensively investigated. We havestudied some parameters of rat liver during short- term fasting and itseffect on the stage of promotion in hepatocarcinogenesis in rats. Duringtwo fasting periods, body and liver weight decreased remarkably.Bromodeoxyuridine (BrdU) labeling indices (LI) decreased, and cell densityincreased prominently in liver sections. Hematoxylin and eosin-stained andnick end labeling (TUNEL)- stained sections showed an increase of apoptoticbodies in the absence of necrosis during the fasting period. Moreover, gelelectrophoresis of DNA isolated from whole liver revealed ladder formationindicative of nucleosomal DNA cleavage. At the beginning of the fastingperiod livers exhibited a small but definite number of altered hepatic foci(AHF) expressing glutathione S-transferase, placental form (GST-P), but atthe end of the fasting period no AHF were discernible in all livers ofanimals subjected to the fasting period. After refeeding, cell density andthe incidence of apoptotic bodies decreased prior to a transient increaseof BrdU LI. The percentage volume of liver occupied by AHF of fasted ratswas significantly greater than that of control rats at 140 days afterinitiation. These results suggest that both the liver weight loss and thecomplete loss of discernible AHF from short-term fasting was caused by (i)decrease of cell volume, (ii) cell loss by apoptosis, and (iii) a decreaseof hepatocyte proliferation. Furthermore, this relatively transient liverweight loss enhanced the promotion of hepatocarcinogenesis, possibly byenhanced cell proliferation compensatory to the fasting cycles.