Selective left-lobe atrophy by nodularin treatment accompanied by reduced protein phosphatase 1/2A and increased peroxisome proliferation in rat liver.

Abstract

The effect of nodularin on selective atrophy of left lobes in the liver was investigated in F344 rats. Nodularin was injected for 10 weeks from the third week of initiation with saline or N-nitrosodiethylamine (DEN), grouped as S/N and D/N, respectively. Nodularin significantly decreased weights of left (LL) and caudate (CL) lobes but increased right (RL) and middle (ML) lobes in S/N rats. Activity of protein phosphatases [types 1 (PPI) and 2A (PP2A)] was more severely reduced in S/N than D/N rats; moreover, in LL compared with RL of S/N rats, activity was significantly inhibited by nodularin treatment from week 4, which corresponded to 2 weeks after nodularin injection. However, nodularin significantly induced peroxisomal palmitoyl-CoA oxidase and cytochrome P-450 4A1 expression in S/N compared with D/N rats. An effect of nodularin on apoptosis was evident since expression of Bcl-Xs was clearly induced in LL of S/N rats as opposed to various inductions of Bcl-XL. However, Bcl-XL in RL was persistently induced, with undetectable Bcl-Xs expression. These results demonstrate biochemical evidence of selective atrophy of LL by inhibition of PP1 and PP2A activity, increase of peroxisomal enzymes and induction of Bcl-Xs expression, in contrast to proliferation of RL in rats treated with nodularin alone. However, nodularin endowed DEN-altered hepatocytes with regenerating power and concomitant restoration of phosphatase activity as well as persistent expression of Bcl-XL in D/N rats.