MOLECULAR-BASIS FOR NULL LIPOPROTEIN(A) PHENOTYPES AND THE INFLUENCE OF APOLIPOPROTEIN(A) SIZE ON PLASMA LIPOPROTEIN(A) LEVEL IN THE BABOON

High plasma levels of lipoprotein(a) (Lp(a)) and its unique apolipopro tein, apo(a), are an independent risk factor for cardiovascular diseas e. Plasma Lp(a) levels vary over a 1000-fold range and are determined by the apo(a) locus, which has at least 34 alleles expressing apo(a) i soforms with molecular weights from <300,000 to >800,000. In addition, ''null'' apo(a) alleles produce no detectable plasma apo(a). We used primary cultures of baboon hepatocytes to investigate the molecular ba sis for null apo(a) phenotypes. Immunoprecipitation of apo(a) after ra diolabeling of hepatocytes revealed that some null alleles gave rise t o intracellular protein products that were not secreted. Pulse chase a nalysis and endoglycosidase digests demonstrated that these proteins w ere retained in the endoplasmic reticulum. We also examined the molecu lar basis for the documented inverse correlation between apo(a) size a nd plasma Lp(a) concentration. Steady-state labeling and pulse-chase a nalysis of hepatocytes from animals expressing two isoforms of apo(a) revealed that the endoplasmic reticulum residence time of secreted apo (a) isoforms was determined by their size. This accounted for the inve rse relationship between isoform size and level of secretion. We concl ude that the efficiency of post-translational processing of apo(a) is a major determinant of plasma Lp(a) concentration.