Understanding the ins and outs of lipoprotein (a) metabolism

Abstract

This review summarizes our current understanding of the processes of apolipoprotein(a) secretion, assembly of the Lp(a) particle and removal of Lp(a) from the circulation. We also identify existing knowledge gaps that need to be addressed in future studies. The Lp(a) particle is assembled in two steps: a noncovalent, lysine-dependent interaction of apo(a) with apoB-100 inside hepatocytes, followed by extracellular covalent association between these two molecules to form circulating apo(a).The production rate of Lp(a) is primarily responsible for the observed inverse correlation between apo(a) isoform size and Lp(a) levels, with a contribution of catabolism restricted to larger Lp(a) isoforms.Factors that affect apoB-100 secretion from hepatocytes also affect apo(a) secretion.The identification of key hepatic receptors involved in Lp(a) clearance in vivo remains unclear, with a role for the LDL receptor seemingly restricted to conditions wherein LDL concentrations are low, Lp(a) is highly elevated and LDL receptor number is maximally upregulated. The key role for production rate of Lp(a) [including secretion and assembly of the Lp(a) particle] rather than its catabolic rate suggests that the most fruitful therapies for Lp(a) reduction should focus on approaches that inhibit production of the particle rather than its removal from circulation.