Mechanism of triglyceridemia in hypercholesterolemic rabbits.

To elucidate mechanisms responsible for the increased plasma triglyceride (TG) which occurs in diet-induced hypercholesterolemia in rabbits, albino rabbits were fed a 3% cholesterol diet for various durations, and the following determinations were carried out: plasma lipid levels; turnover rate of plasma TG (labeled very low density lipoprotein, or glycerol-2-H method); lipoprotein lipase activity of the heart and plasma; fatty acid and acetate incorporation into TG in the liver (homogenates and slices). Plasma levels of both free and esterified cholesterol and phospholipid increased rapidly, while TG increased relatively slowly during cholesterol feeding without change in hepatic TG synthesis. The fractional turnover was, on the other hand, depressed within a week. The decrease in plasma TG in response to a heparin injection was less in hypercholesterolemic rabbits than in normal animals. However, the measured activity of heart lipoprotein lipase of cholesterol-fed rabbits was higher than that of the control group. When the effects of two substrates (very low density lipoprotein from normoand from hypercholesterolemic plasma) were compared, the apparent activity was lower with the latter. The degree of this inhibition was proportional to the amount of cholesterol in the lipoproteins. The inhibition of lipoprotein lipase activity was also observed with the addition of cholesterol to activated Ediol, but not with addition of esterified cholesterol. Lineweaver-Burk plots were constructed using partially purified plasma lipoprotein lipase, and Km values for Ediol, Ediol plus protamine sulphate, and Ediol plus cholesterol were calculated. The presence of cholesterol in the substrate of lipoprotein lipase competitively inhibits the enzyme activity, and this is the mechanism of hyperglyceridemia observed in diet-induced hypercholesterolemic rabbits. ADDITIONAL