The role of phosphatidylcholine biosynthesis in the secretion of lipoproteins from hepatocytes.

An investigation of the role of phospholipids in lipoprotein assembly and secretion is important since phospholipids, particularly phosphatidylcholine, are prominent components of all plasma lipoproteins. The fatty acid composition of phosphatidylcholine is virtually identical in human very low (VLDL), low, and high density lipoproteins, which supports the idea that phosphatidylcholine exchanges freely among plasma lipoproteins. However, the fatty acid composition of phosphatidylcholine from cultured rat hepatocytes is different from that in the secreted lipoproteins. In addition, the composition of molecular species of phosphatidylcholine is quite different in the rat liver, plasma, and red cells. Phosphatidylcholine is made in liver by two alternate pathways, by the CDP-choline pathway and by the methylation of phosphatidylethanolamine. Regulation of phosphatidylcholine biosynthesis by the CDP-choline pathway in rat liver is well established. In most instances, the rate of phosphatidylcholine synthesis is governed by the activity of CTP:phosphocholine cytidylyltransferase, which is present in the cytosol and also associated with microsomes. The cytosolic enzyme is inactive but can be reversibly translocated to the microsomes, where it is active. Translocation of this enzyme to the microsomes can be achieved either by a dephosphorylation reaction or by the presence of fatty acids in the cytosol. Once synthesized, how is phosphatidylcholine assembled into lipoprotein particles? The sequence of assembly of phospholipids into VLDL has been investigated in several studies. In a pulse-chase experiment, there was an initial labelling (within 15 min of the pulse) of phospholipids in secreted VLDL, which probably reflected the rapid movement of the phospholipids from their site of synthesis (the endoplasmic reticulum) to the Golgi. There appears to be a rapid exchange of phospholipid between the Golgi membranes and contents. There was also a delayed labelling (after 30 min) of the phospholipids and triacylglycerols (from [3H]glycerol) and the apoproteins (from [3H]leucine) in the secreted VLDL. This lag was attributed to the time taken for the nascent VLDL particles to move from the lumen of the endoplasmic reticulum to the Golgi and into the medium. Is phosphatidylcholine biosynthesis is required for lipoprotein secretion? This question was investigated in rats maintained on a choline-deficient diet for 10 days. The total amount of plasma phosphatidylcholine decreased by approximately 40% and the rats developed fatty livers.(ABSTRACT TRUNCATED AT 400 WORDS)