GENETIC REGULATION OF LPA METABOLISM

Lp(a)是一种类似ldl的脂蛋白，含有一种独特的载脂蛋白

Lp(a) is an LDL-like lipoprotein which contains a unique apolipoprotein designated apo(a) which has a high structural homology with plasminogen. Increased plasma levels of Lp(a) are associated with an increased risk of premature cardiovascular disease. Apo(a) is polymorphic and there is a series of isoforms of the apolipoprotein in the plasma ranging in molecular weight from 400K to 600K. The size and plasma levels of Lp(a) are genetically determined. Metabolic studies in subjects with different isoforms and plasma levels of Lp(a) established that the size of the apo(a) isoform does not effect Lp(a) catabolic rate but rather the rate of synthesis of the individual isoform. The larger the size of isoform the lower the rate of synthesis. These results have established that the synthesis of apo(a) is the major determinant of the plasma levels of Lp(a) and that variations in rate of catabolism does not play a major role in determining plasma levels of Lp(a). The pathway for catabolism for Lp(a) has not been established and it has been controversial if the LDL receptor is important in Lp(a) metabolism. The role of the LDL receptor in Lp(a) catabolism has been analyzed using Lp(a) kinetics in patients with familial hypercholesterolemia (FH) who lack the LDL receptor. Lp(a)levels are elevated in FH and it has been proposed that this is due to delayed catabolism secondary to the LDL receptor defect. Studies on four FH patients revealed that the catabolism of radiolabeled Lp(a) was similar in control subjects and the four FH patients indicating that the LDL receptor does not play a major role in the catabolism of Lp(a). The increased plasma levels of Lp(a) are due to increased production. In addition, it was also demonstrated for the first time that there was conversion of Lp(a) to LDL in vivo indicating that some of the Lp(a) is converted to LDL in the normal metabolic pathway of Lp(a) metabolism. Study subjects were ages 19 to 74, and 45% of the subjects were females. The studies included one Asian and two Hispanic subjects.