Polyamines are required for the initiation of rat liver regeneration

Abstract

A large number of studies applying inhibitors of polyamine biosynthesis have indicated that these compounds are required for animal cell proliferation. Here we show, using a transgenic rat model with activated polyamine catabolism, that a certain critical concentration of the higher polyamines spermidine and spermine is required for liver regeneration. Partial hepatectomy of transgenic rats expressing spermidine/spermine N(1)-acetyltransferase (SSAT) under the control of mouse metallothionein promoter strikingly induced the enzyme at 24 h and reduced hepatic spermidine by 80%. At that time, the weight of the liver remnant was significantly increased in syngenic rats and proliferating cell nuclear antigen (PCNA) labelling index was 20%, whereas the transgenic rats showed no liver weight gain and their PCNA-positive cells accounted for 0.5% of hepatocytes. Similarly, hepatic thymidine incorporation was markedly enhanced at this time point in syngenic, but not in transgenic, animals, whereas the rate of leucine incorporation was only marginally affected in the transgenic animals. At 3 days after operation, the spermidine pool in transgenic livers had increased to the pre-operative level, the remnant weight was significantly elevated and hepatic PCNA labelling index increased to 5%. N(1),N(11)-Diethylnorspermine, a powerful inducer of SSAT, inhibited liver weight gain and proliferative activity in both syngenic and transgenic rats. We found an extremely close correlation between hepatic spermidine, and less close between spermine, concentrations and PCNA labelling index during early liver regeneration. These results indicate that spermidine and/or spermine, but apparently not putrescine, are required for liver regeneration, yet at concentrations smaller than those normally found after partial hepatectomy.

Metabolic Stability of α-Methylated Polyamine Derivatives and Their Use as Substitutes for the Natural Polyamines

“…Our earlier studies with transgenic rats overexpressing SSAT have indicated that partial hepatectomy of these animals resulted in an induction of SSAT and a profound depletion of the hepatic spermidine pool that was associated with failure to initiate liver regeneration (5,18). Liver regeneration could be fully restored with prior administration of MeSpd (5).…”

“…Liver regeneration could be fully restored with prior administration of MeSpd (5). Based on these studies and earlier work indicating that partial hepatectomy rapidly elevates the hepatic spermidine, but not spermine, pool, we assigned a critical role to spermidine in liver regeneration (5,18). However, the present results indicated that liver regeneration, as judged by thymidine incorporation, was equally well restored by Me 2 Spm, even at lower concentrations than required for MeSpd (Table III), indicating that spermidine and spermine may be fully exchangeable in this system.…”

“…As a conclusion it seems that ␣-methylation prevents polyamine derivatives from acetylation but not their oxidation. atectomy of the transgenic rats overexpressing SSAT results in a profound spermidine and spermine depletion because of SSAT induction at 24 h postoperatively and failure to initiate liver regeneration (5,18). Liver regeneration could be restored by a prior administration of MeSpd (5).…”

Cell-autonomous hepatic circadian clock regulates polyamine synthesis

“…6 Polyamines, small, aliphatic cations under physiological conditions, are highly associated with cell proliferation and are essential for the initiation of liver regeneration. 7,8 While the specific mechanisms by which they act are unclear, it seems they may include modulation of proteinprotein or protein-DNA interactions, DNA conformation or rRNA stability and trafficking. 9 Liver regeneration is circadian regulated and believed to be gated by Wee1 kinase in actively proliferating hepatocites.…”

“…2 Polyamines, however, are essential to the initiation of liver regeneration. 7 Cellautonomous circadian regulation of polyamine synthesis may, therefore, provide an additional or upstream mechanism for clock regulation.…”