KRINGLE-CONTAINING FRAGMENTS OF APOLIPOPROTEIN(A) CIRCULATE IN HUMAN PLASMA AND ARE EXCRETED INTO THE URINE

Apolipoprotein(a) [apo(a)] contains multiple kringle 4 repeats and cir culates as part of lipoprotein(a) [Lp(a)]. Apo(a) is synthesized by th e liver but its clearance mechanism is unknown. Previously, we showed that kringle 4-containing fragments of apo(a) are present in human uri ne. To probe their origin, human plasma was examined and a series of a po(a) immunoreactive peptides larger in size than urinary fragments wa s identified, The concentration of apo(a) fragments in plasma was dire ctly related to the plasma level of Lp(a) and the 24-h urinary excreti on of apo(a), Individuals with low (< 2 mg/dl) plasma levels of Lp(a) had proportionally more apo(a) circulating as fragments in their plasm a. Similar apo(a) fragments were identified in baboon plasma but not i n conditioned media from primary cultures of baboon hepatocytes, sugge sting that the apo(a) fragments are generated from circulating apo(a) or Lp(a), When apo(a) fragments purified from human plasma were inject ed intravenously into mice, a species that does not produce apo(a), ap o(a) fragments similar to those found in human urine were readily dete cted in mouse urine. Thus, we propose that apo(a) fragments in human p lasma are derived from circulating apo(a)/Lp(a) and are the source of urinary apo(a).