EFFECTS OF PROLONGED (1 YEAR) CHOLINE DEFICIENCY AND SUBSEQUENT REFEEDING OF CHOLINE ON 1,2-SN-DIRADYLGLYCEROL, FATTY-ACIDS AND PROTEIN-KINASE-C IN RAT-LIVER

Rats fed a choline-deficient diet develop foci of enzyme-altered hepat ocytes with subsequent formation of hepatic tumors. They also develop fatty livers, because choline is needed for hepatic secretion of lipop roteins. We have previously reported that 1,2-sn-diradylglycerol accum ulates in the livers of rats fed a choline-deficient diet for 1-27 wee ks, and that protein kinase C activity in the hepatic plasma membrane is elevated during that time (da Costa et al., J. Biol. Chem., 268, 21 00-2105, 1993). In the present study, we examined the changes that occ ur in rat liver at 52 weeks of choline deficiency and determined wheth er these changes were reversible when choline was returned to the diet of the deficient animals for 1 or 16 weeks. At 52 weeks, non-tumor li ver samples from the experimental animals had increased 1,2-sn-diradyl glycerol concentrations in the lipid droplets compared with control an imals. Plasma membrane 1,2-sn-diradylglycerol levels in the liver did not differ between the two groups, but an age-related increase in memb rane 1,2-sn-diradylglycerol concentrations was observed. Unsaturated f ree fatty acids, another activator of protein kinase C, accumulated in the deficient livers. Protein kinase C activity associated with the p lasma membrane remained significantly elevated at 52 weeks in deficien t livers. Hepatic foci expressing gamma-glutamyltranspeptidase were de tected only in the deficient rats (0.83% of liver volume) and 15% of t hese rats had hepatocellular carcinoma at 1 year on the diet. At 53 we eks (1 week after choline was returned to the deficient group), 1,2-sn -diradylglycerol concentrations in the lipid droplets and hepatic free fatty acids had dropped to control levels. By 68 weeks (16 weeks of r e-feeding choline), the membrane protein kinase C activity had returne d to normal. At this time, 14% of the experimental animals had hepatoc ellular carcinoma. We suggest that choline deficiency altered the prot ein kinase C-mediated signal transduction within liver and this contri buted to hepatic carcinogenesis in these animals.