Individuals with genetic disorders of lipoproteins offer a unique means by which lipoprotein metabolism can be investigated. Recent studies have focused on the metabolism of Lp(a), a new independent risk factor for premature cardiovascular disease. Lp(a) is an atherogenic lipoprotein formed by a covalent linkage of apo(a) to apoB-100 on LDL. Both Lp(a) and free apo(a) are present in plasma, as well as 80-240 kDa apo(a) fragments in plasma and urine. The present study compares the in vivo metabolism of Lp(a) and free apo(a). Lp(a) and apo(a) were purified by zonal rate ultracentrifugation followed by lysine-Sepharose chromatography from a control and a single isoform of 391 kDa was used in the kinetic studies. Purified 125| apo(a) and 131|Lp(a) from the normal were injected into two control subjects and the plasma decay curve obtained over 14 days. The FCR of Lp(a) and apo(a) were 0.49 plus/minus 0.01 d -1 and 0.20 plus/minus 0.01d -1 respectively establishing that the plasma catabolism of apo(a) was much slower that Lp(a). At 10 min 38% of the injected 125| apo(a) was found in the Lp(a) fraction (d1.05-1.10g/ml) and 50% free in the bottom (d>1.21g/ml). The plasma percentage of 125| apo(a) progressively increased in Lp(a) and decreased in the d>1.21 bottom fraction; after 24 hrs 80% and 20% of 125| apo(a) was in the Lp(a) and d>1.21 fraction respectively. In contrast, at 10 min 95% of 131 Lp(a) was present in Lp(a) (1.05-1.10 g/ml) after which there was a progressive shift with 20% of the 131| found in the free apo(a) (d<1.21 g/ml) fraction and 10% in the LDL (1.019-1.05 g/ml) fraction after 36 hrs. Over the 14 days study >99% of the urinary radioactivity was either free iodine or TCA soluble indicating that only a very small fraction of apo(a) is catabolized and secreted as large fragments in the urine. The combined results from these studies have indicated that free apo(a) can form Lp(a) in plasma, and during metabolism Lp(a) can be converted to apo(a) and LDL. Catabolism and urinary secretion of large apo(a) fragments generated from free apo(a) or Lp(a) is a minor catabolic pathway in man.
