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 and its effects on carcinogenesis are well known; however, the effects of acute fasting on carcinogenesis have not been intensively investigated. We have studied some parameters of rat liver during short-term fasting and its effect on the stage of promotion in hepatocarcinogenesis in rats. During two fasting periods, body and liver weight decreased remarkably. Bromodeoxyuridine (BrdU) labeling indices (LI) decreased, and cell density increased prominently in liver sections. Hematoxylin and eosin-stained and nick end labeling (TUNEL)-stained sections showed an increase of apoptotic bodies in the absence of necrosis during the fasting period. Moreover, gel electrophoresis of DNA isolated from whole liver revealed ladder formation indicative of nucleosomal DNA cleavage. At the beginning of the fasting period livers exhibited a small but definite number of altered hepatic foci (AHF) expressing glutathione S-transferase, placental form (GST-P), but at the end of the fasting period no AHF were discernible in all livers of animals subjected to the fasting period. After refeeding, cell density and the incidence of apoptotic bodies decreased prior to a transient increase of BrdU LI. The percentage volume of liver occupied by AHF of fasted rats was significantly greater than that of control rats at 140 days after initiation. These results suggest that both the liver weight loss and the complete loss of discernible AHF from short-term fasting was caused by (i) decrease of cell volume, (ii) cell loss by apoptosis, and (iii) a decrease of hepatocyte proliferation. Furthermore, this relatively transient liver weight loss enhanced the promotion of hepatocarcinogenesis, possibly by enhanced cell proliferation compensatory to the fasting cycles.