NASCENT VLDL PHOSPHOLIPID-COMPOSITION IS ALTERED WHEN PHOSPHATIDYLCHOLINE BIOSYNTHESIS IS INHIBITED - EVIDENCE FOR A NOVEL MECHANISM THAT REGULATES VLDL SECRETION

Previous work has shown that inhibition of phosphatidylcholine biosynt hesis inhibits very low density lipoprotein (VLDL) secretion by causin g a decrease in the number of particles in the Golgi but not in the en doplasmic reticulum of rat liver (Verkade et al. (1993) J. Biol. Chem. 268, 24990-24996). One explanation for this observation was that VLDL from choline deficient Livers was degraded in a post-endoplasmic reti culum compartment. This hypothesis was supported by experiments in whi ch choline deficient (CD) or choline supplemented (CS) rat hepatocytes were incubated +/- Brefeldin A. In the presence of Brefeldin A, VLDL secretion was blocked, but no difference was observed in the degradati on of apolipoprotein B (apoB) within the CD or CS cells. If increased catabolism of apoB were occurring in the endoplasmic reticulum of CD h epatocytes, enhanced degradation of apoB in CD cells might have been e xpected. Inhibition of phosphatidylcholine biosynthesis also caused de creases in the phosphatidylcholine content of membranes of the secreto ry pathway. The lipids of nascent VLDLs from the lumina of endoplasmic reticulum and Golgi prepared from CD rat liver were relatively enrich ed in phosphatidylethanolamine and depleted of phosphatidylcholine whe n compared to samples from CS liver. The changes in nascent VLDL phosp holipid composition mimicked that of the organelle membranes from whic h the VLDLs were isolated. Possibly the phospholipid composition of th e organelles is a factor in determining the final phospholipid composi tion of VLDLs. One hypothesis is that when phosphatidylcholine biosynt hesis is impaired, nascent VLDL is assembled incorrectly and degraded by a quality control protease in a post-endoplasmic reticulum compartm ent.