An enzymatic explanation of the differential effects of oleate and gemfibrozil on cultured hepatocyte triacylglycerol and phosphatidylcholine biosynthesis and secretion.
Incubation (1-4 h) of primary cultures of adult rat hepatocytes with gemfibrozil (0.1-1.0 mM) significantly decreased the: (1) incorporation of [1,3-14C]glycerol into cellular triacylglycerol (30%); (2) secretion of labeled (VLDL) triacylglycerol (4-fold); and (3) oleate-induced rise in triacylglycerol biosynthesis and secretion. Gemfibrozil also increased the: (1) incorporation of labeled glycerol into cellular phosphatidylcholine (2-fold); and (2) secretion of labeled (HDL) phosphatidylcholine (10-fold). The gemfibrozil-dependent increase in the flux of labeled diacylglycerol into phosphatidylcholine is rapid (15 min) and associated with a 2-fold increase in membrane-bound phosphocholine cytidylyltransferase activity. A phosphocholine cytidylyltransferase-mediated rise in cellular CDP choline content may explain the gemfibrozil-dependent rise in phosphatidylcholine biosynthesis since homogenates of monolayers incubated with CDP choline preferentially incorporate labeled diacylglycerol into phosphatidylcholine rather than triacylglycerol. Therefore, the triacylglycerol-lowering potential of gemfibrozil may be due in part to its ability to shunt liver cell diacylglycerol into phosphatidylcholine rather than triacylglycerol. These results suggest that CDP choline may be a key regulator of the diacylglycerol branchpoint, since diacylglycerol is primarily incorporated into phosphatidylcholine or triacylglycerol depending on whether CDP choline is or is not available.
Lamb
R G
RG
Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond 23298-0613.
Koch
J C
JC
Bush
S R
SR
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015248:Gemfibrozil / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology*; D010711:Phosphatidate Phosphatase / Q000378:metabolism; D010713:Phosphatidylcholines / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000096:biosynthesis* / Q000378:metabolism
D001647:Bile Acids and Salts; D009829:Oleic Acids; D010713:Phosphatidylcholines; D014280:Triglycerides; D019301:Oleic Acid; D010711:Phosphatidate Phosphatase; D015248:Gemfibrozil