The objective of the proposal is to understand the mechanisms whereby dietary w3 fatty acids when substituted for w6 fatty acids lower plasma lipids. The central hypothesis is that w3 fatty acids when substituted for w6 fatty acids in membranes enhance the activity of lipoprotein lipase (LPL) and hepatic lipase (HL). Because of the enhanced peripheral delivery of chylomicron and VLDL fatty acids and cholesterol. The influx of these constituents to the liver is deceased. The decreased hepatic input would account for the deceased VLDL production. An increased hepatic lipase activity with w3 fatty acid feeding would enhance the uptake of chylomicron and VLDL remnant. Finally it is hypothesized that enrichment of w3 fatty acids in hepatic membranes enhances LDL receptor activity. VLDL secretion rates, VLDL to LDL fluxes, and fractional removal rates will be measured in roosters fed 0.5% cholesterol and either 10% fish oil or 10% corn oil. VLDL protein and lipid secretion rates by hepatocytes prepared from animals fed the experimental diets will be compared. LPL synthesis, degradation, and secretion by adipocytes incubated with w3 or w6 fatty acids will be determined. The effect of w3 series on HL synthesis, degradation, and secretion will also be determined in hepatocytes in culture. Binding constants of lipolytic enzymes for endothelial cells will be measured. The fractional removal rate and the sites of degradation of LDL and IDL by receptor and receptor independent pathways will be determined with the two diets. The fractional removal rate of (14C) sucrose IDL and (14C) sucrose methylated IDL will be determined in animals where LPL is inhibited by antiserum to prevent conversion of IDL to LDL. Recycling of plasma membrane sialoglycoproteins and heparan sulfate will be determined in cells enriched with w6 or w3 fatty acids. Finally hepatic LDL receptor activity will be assessed by binding studies of (123I) LDL, IDL, and chylomicron remnants to liver membranes.
| Montalto, M B; Bensadoun, A (1993) Lipoprotein lipase synthesis and secretion: effects of concentration and type of fatty acids in adipocyte cell culture. J Lipid Res 34:397-407 |
