Understanding the ins and outs of lipoprotein (a) metabolism

Abstract

Purpose of reviewThis 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.Recent findingsThe 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.SummaryThe 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.

Sex-Specific Differences in Lipoprotein Production and Clearance

“…Three of these studies provided data for Lp(a) in women before and after bilateral oophorectomy, and these found no difference between them. 12,65,66 The authors conclude that transition to menopause may increase Lp(a) concentrations, but the process of aging could not be excluded. 71…”

“…Both apo(a) clearance and production have been associated with regulating small isoforms; however, larger isoforms have only been linked to apo(a) production. 12,65,66 Importantly, Lp(a) levels are higher in black individuals and women, but the mechanisms behind these differences are not well understood. Changes in the expression of the LPA gene have been proposed as regulators of the production of Lp(a) and these transcriptional gene changes could be responsible for the higher Lp(a) levels in women when compared with men.…”

“…Although there have been important advancements in understanding its biology and pathophysiology, the complete synthetic pathway, and regulators of Lp(a) production and clearance have not been fully elucidated. 12,13…”

“…Although there have been important advancements in understanding its biology and pathophysiology, the complete synthetic pathway, and regulators of Lp(a) production and clearance have not been fully elucidated. 12,13 Apo AI and High-Density Lipoprotein Hepatocytes are also the main cells implicated in the production of apoA 1 (apo AI) and apo AII, the main structural components of HDL (high-density lipoprotein). HDL can deliver cholesterol and other lipids to extrahepatic tissues, although its main role is to remove free cholesterol accumulated in cells such as those present in atherosclerotic lesions by cholesterol efflux, which is a key component of cholesterol elimination by reverse cholesterol transport.…”

Estimation of serum levels of Lipoprotein(a) might help to resolve the dilemma of differentiation between Unstable Angina and Non-ST-elevation Myocardial Infarction

“…medications were provided and this stability could be attributed to multiple facts; Lp(a) is synthesized in the liver and so has no relation to dietary lipid intake, metabolism or diet restriction (24) . Lp(a) differs from LDL in having two protein moieties, apoB100 and apo(a), so could not metabolize through binding to LDL receptors (25) . Furthermore, apo(a) protein is encoded by the LPA gene in the long arm of chromosome 6 within region 6q2.6-2.7, so it is a conserved protein (26) with steady production rate that is only affected by liver diseases (27) and not by statin therapy (28) .…”