Despite decades of study, how the liver assembles and clears Lp(a) remains only partly understood, a comprehensive metabolism review (Atherosclerosis 2022)

Lipoprotein (a) (Lp(a)) is a strange lipoprotein species causatively independently and significantly associated with cardiovascular diseases and calcified aortic valve stenosis. Elevated plasma Lp(a) levels increase the rate of cardiovascular events at any achieved low-density lipoprotein (LDL) level. The major structural difference between Lp(a) and LDL is that Lp(a) has a second large protein, apolipoprotein (a) (apo(a)), bound to the apolipoprotein B100 moiety of an LDL sized particle by a single disulfide bond. Over the past decades, several investigators have tried to elucidate the molecular, cellular and metabolic pathways governing the production of Lp(a), the contribution of Lp(a) to lipid transport in the plasma, and the catabolic fate of Lp(a). The metabolism of this enigmatic lipoprotein nevertheless still remains poorly understood. The objectives of the present manuscript are to comprehensively review the knowns and unknowns of the complexities of Lp(a) metabolism with a focus on apo(a) biosynthesis in hepatocytes, Lp(a) assembly, and Lp(a) plasma clearance and catabolism. We also discuss the controversy surrounding the exact role of the LDL receptor in mediating Lp(a) cellular uptake by reviewing seminal in vitro and in vivo data, the metabolism of Lp(a) in familial hypercholesterolemia, as well as the divergent effects of statins and proprotein convertase subtilisin kexin type 9 inhibitors in modulating Lp(a) plasma concentrations. We also provide new insights into the physiology and pathophysiology of Lp(a) metabolism from human kinetic studies in the context of contemporary molecular and cell biological investigations.