title: 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.
authors.affiliation: A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Tiina-Liisa
authors.initials: TL
authors.lastname: Räsänen
authors.forename: Riitta
authors.initials: R
authors.lastname: Sinervirta
authors.forename: Jyrki J
authors.initials: JJ
authors.lastname: Parkkinen
authors.forename: Veli-Pekka
authors.initials: VP
authors.lastname: Korhonen
authors.forename: Marko
authors.initials: M
authors.lastname: Pietilä
authors.forename: Juhani
authors.initials: J
authors.lastname: Jänne
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015317:Biogenic Polyamines / Q000502:physiology*; D002455:Cell Division; D006498:Hepatectomy; D007150:Immunohistochemistry; D008115:Liver Regeneration / Q000502:physiology*; D009929:Organ Size; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015317:Biogenic Polyamines; D018809:Proliferating Cell Nuclear Antigen