The metabolism of apolipoprotein B in subjects with hypertriglyceridemia and polydisperse LDL

Abstract

This research concerns the metabolism of apolipoprotein B (apoB) in hypertriglyceridemic subjects with polydisperse or heterogeneous LDL. Five subjects maintained under constant dietary control had blood samples fractionated into very low density lipoprotein (VLDL), Sf 20, Sf 10, and Sf 4 LDL, and plasma free leucine, and in three subjects VLDL was further fractionated by size. Apo B was isolated, and the masses of the plasma apo B pools were measured for these lipoproteins. Following injection of [3H]leucine as a metabolic tracer the specific activity of apo B in these lipoproteins and of plasma leucine were measured over 7 or 14 days. The kinetic data were examined using multicompartmental analysis and interpreted in terms of our previous model of apo B metabolism (1975. Federation Proc. 24: 2263.). Newly synthesized apo B, secreted as large VLDL, is metabolized by a delipidation chain yielding intermediate density lipoprotein (IDL), consisting of small VLDL and Sf 20 LDL, and eventually forms small, Sf4 LDL. LDL is metabolized in a steplike process from Sf 20 to Sf 10 and Sf 4 LDL. A second major biosynthetic input in apo B enters directly into IDL and 1/4 to 2/3 of newly synthesized apo B enters plasma by this route. Total apo B synthesis in these subjects is 5- to 10-fold greater than reported for normals. The rate of transport of VLDL apo B and IDL is slower than normal with a residence time which is increased about twofold; however, the VLDL apo B pool is enlarged 5- to 10-fold, and thus the quantity of apo B entering and leaving this pool per hour is much greater than in the normal. Two major pathways for apo B catabolism occur. Between 1/3 and 2/3 of apo B is metabolized through LDL, disappearing from plasma as Sf 4 LDL. The remainder of apo B disappears from plasma IDL directly. The four major findings in this kinetic study of apo B metabolism in hypertriglyceridemic subjects with polydisperse LDL are: 1) The marking increase in apo B synthesis; 2) the biosynthetic input of much of this apo B directly into IDL; 3) the large catabolic pathway of apo B which leaves IDL, and 4) the stepwise metabolism of LDL by which Sf 20, Sf 10 and Sf 4 LDL are generated.