Studies on the mechanism of hypertriglyceridemia in Tangier disease. Determination of plasma lipolytic activities, k1 values and apolipoprotein composition of the major lipoprotein density classes

Abstract

Mechanisms responsible for hypertriglyceridemia in Tangier disease were elucidated by an analysis of the plasma post-heparin lipolytic activities and the structural and metabolic properties of very low (VLDL) and low (LDL) density lipoproteins. The levels of lipoprotein lipase activity in six Tangier patients were significantly lower ( P < 0.001) than in 40 control subjects (8.1 ± 3.3 (± S. D.) vs. 14.1 ± 3.7 units/ml). In contrast, the levels of hepatic triacylglycerol lipase were higher ( P < 0.01) than in normal controls (14.4 ± 3.9 vs. 9.3 ± 4.0 units/ml). Because kinetic parameters such as K m or V max cannot be obtained with naturally occurring triacylglycerol-rich lipoproteins, the pseudo-first-order rate constant ( k 1) of triacylglycerol hydrolysis was used to assess the effectiveness of triacylglycerol-rich lipoproteins as substrates for lipoprotein lipase. The k 1 values for Tangier VLDL ( k 1 = 0.017 ± 0.002 min −1) were significantly lower ( P < 0.001) than the k 1 values (0.036 ±0.008 min −1) for control VLDL. Both the Tangier and control LDL 2 are similar in their resistance to the action of lipoprotein lipase, as shown by their low k 1 values (0.002 ± 0.001 and 0.001 ± 0.001 mm −1, respectively). The major compositional difference between the lipoproteins of Tangier disease and normal subjects was a significant increase in the percent content of apolipoprotein A-II in all lipoprotein particles with d < 1.063 g/ml, with the greatest increase occurring in VLDL and the lowest in LDL 2. These results were interpreted as indicating that, in Tangier disease, there is a lower reactivity of VLDL with lipoprotein lipase which may in part be attributed to the abnormal apolipoprotein composition. This finding, in conjunction with the reduced levels of lipoprotein lipase activity, may explain the hypertriglyceridemia in Tangier disease.