BIOGENESIS OF LP(A) IN TRANSGENIC MOUSE HEPATOCYTES

Lipoprotein(a) [Lp(a)] biogenesis was examined in primary cultures of hepatocytes isolated from mice transgenic for both human apolipoprotei n(a) [apo(a)] and human apoB. Steady-state and pulse-chase labeling ex periments demonstrated that newly synthesized human apo(a) had a prolo nged residence time (similar to 60 min) in the endoplasmic reticulum ( ER) before maturation and secretion. Apo(a) was inefficiently secreted by the hepatocytes and a large portion of the protein was retained an d degraded intracellularly. Apo(a) exhibited a prolonged and complex f olding pathway in the ER, which included incorporation of apo(a) into high molecular weight, disulfide-linked aggregates. These folding char acteristics could account for long ER residence time and inefficient s ecretion of apo(a). Mature apo(a) bound via its kringle domains to the hepatocyte cell surface before appearing in the culture medium. Apo(a ) could be released from the cell surface by apoB-containing lipoprote ins. These studies are consistent with a model in which the efficiency of post-translational processing of apo(a) strongly influences human plasma Lp(a) levels, and suggest that cell surface assembly may be one pathway of human Lp(a) production in vivo. Transgenic mouse hepatocyt es thus provide a valuable model system with which to study factors re gulating human Lp(a) biogenesis.