Accumulation of 1,2-sn-diradylglycerol with increased membrane-associated protein kinase C may be the mechanism for spontaneous hepatocarcinogenesis in choline-deficient rats.
Choline deficiency, via deprivation of labile methyl groups, is associated with a greatly increased incidence of hepatocarcinoma in experimental animals. This dietary deficiency also causes fatty liver, because choline is needed for hepatic secretion of lipoproteins. We hypothesized that fatty liver might be associated with the accumulation of 1,2-sn-diradylglycerol and subsequent activation of protein kinase C. Several lines of evidence indicate that cancers might develop secondary to abnormalities in protein kinase C-mediated signal transduction. We observed that rats fed a choline-deficient diet for 1, 6, or 27 weeks had increased hepatic concentrations of 1,2-diradylglycerol. At 1 and 6 weeks, hepatic plasma membrane from choline-deficient rats had increased concentrations of 1,2-sn-diacylglycerol and 1-alkyl, 2-acylglycerol, with the latter accounting for 20-26% of membrane 1,2-sn-diradylglycerol (as compared with only 2-5% in controls). Protein kinase C activity was increased in hepatic plasma membrane at 1 week of choline deficiency. By Western blotting there was an increase in the amount of protein kinase C zeta and a decrease in the amount of protein kinase C delta in liver at 1 week. By 6 weeks of choline deficiency, hepatic plasma membrane and cytosolic protein kinase C (PKC) activities were increased significantly, with increased amounts of hepatic plasma membrane protein kinase C alpha, and delta detected by Western blotting. Glycogen synthase activity in liver was diminished after 1 week of choline deficiency; this enzyme is inhibited by PKC-mediated phosphorylation. We suggest that choline deficiency perturbed PKC-mediated transmembrane signaling within liver and that this contributed to the development of hepatic cancer in these animals.
da Costa
K A
KA
Department of Nutrition, School of Public Health and School of Medicine, University of North Carolina, Chapel Hill 27599-7400.
Cochary
E F
EF
Blusztajn
J K
JK
Garner
S C
SC
Zeisel
S H
SH
D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000201:enzymology*; D002794:Choline / Q000008:administration & dosage; D002796:Choline Deficiency / Q000150:complications / Q000201:enzymology*; D004032:Diet; D004075:Diglycerides / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology; D006006:Glycogen Synthase / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D008297:Male; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism
D004075:Diglycerides; D014280:Triglycerides; C035561:diarachidonyl diglyceride; D006006:Glycogen Synthase; D011493:Protein Kinase C; D002794:Choline