Effects of prolonged (1 year) choline deficiency and subsequent re-feeding 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 hepatocytes with subsequent formation of hepatic tumors. They also develop fatty livers, because choline is needed for hepatic secretion of lipoproteins. We have previously reported that 1,2-sn-diradylglycerol accumulates in the livers of rats fed a choline-deficient diet for 1-27 weeks, and that protein kinase C activity in the hepatic plasma membrane is elevated during that time (da Costa et al., J. Biol. Chem., 268, 2100-2105, 1993). In the present study, we examined the changes that occur in rat liver at 52 weeks of choline deficiency and determined whether 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 liver samples from the experimental animals had increased 1,2-sn-diradylglycerol concentrations in the lipid droplets compared with control animals. Plasma membrane 1,2-sn-diradylglycerol levels in the liver did not differ between the two groups, but an age-related increase in membrane 1,2-sn-diradylglycerol concentrations was observed. Unsaturated free fatty acids, another activator of protein kinase C, accumulated in the deficient livers. Protein kinase C activity associated with the plasma membrane remained significantly elevated at 52 weeks in deficient livers. Hepatic foci expressing gamma-glutamyltranspeptidase were detected only in the deficient rats (0.83% of liver volume) and 15% of these rats had hepatocellular carcinoma at 1 year on the diet. At 53 weeks (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 re-feeding choline), the membrane protein kinase C activity had returned to normal. At this time, 14% of the experimental animals had hepatocellular carcinoma. We suggest that choline deficiency altered the protein kinase C-mediated signal transduction within liver and this contributed to hepatic carcinogenesis in these animals.
da Costa
K A
KA
Department of Nutrition, School of Public Health, University of North Carolina at Chapel Hill, 27599.
Garner
S C
SC
Chang
J
J
Zeisel
S H
SH
D000375:Aging / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D002794:Choline / Q000494:pharmacology*; D002796:Choline Deficiency / Q000150:complications* / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000737:chemistry / Q000209:etiology* / Q000473:pathology; D008297:Male; D010767:Phosphorylcholine / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D004075:Diglycerides; D005227:Fatty Acids; D010767:Phosphorylcholine; C035561:diarachidonyl diglyceride; D005723:gamma-Glutamyltransferase; D011493:Protein Kinase C; D002794:Choline