Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]

Abstract

[a] have been described in humans, ranging in size from Ͻ 300 kDa to Ͼ 800 kDa (2).Plasma levels of Lp[a] vary greatly between individuals, from Ͻ 1 mg/dl to Ͼ 100 mg/dl (2). The source of most of this variability in plasma concentrations is variability in the production rate of Lp[a] (3, 4), which, in turn, is controlled largely by the apo[a] gene locus (5). Apo[a] is synthesized by hepatocytes and rapidly associates with LDL after secretion to form Lp[a] in the sinusoids of the liver (2, 6). Although the steps involved in Lp[a] production are known, the major mechanisms involved in Lp [a] clearance from plasma are not currently known. It has been suggested that the kidney might play a major role in Lp[a] clearance, after several clinical studies reported increased plasma Lp[a] levels in patients with renal failure (7,8). In addition, Kronenberg et al. (9) Several receptors that mediate the binding and uptake of lipoproteins containing apoB-100 have been proposed as receptors for Lp [a] catabolism. These include the LDL receptor (LDLR) (10-15), megalin/gp330 (16), the LDL receptor-related protein (LRP) (17), and the VLDL receptor (18). The latter two receptors can mediate binding to lipoproteins through apoE. According to the secretioncapture model, apoE that is secreted by the liver rapidly

HDL-C, ABCA1-mediated cholesterol efflux, and lipoprotein(a): insights into a potential novel physiologic role of lipoprotein(a)

“…This is consistent with in vivo data demonstrating that apo(a) competitively inhibits the plasma clearance of Lp(a) in mice ( 35 ). Although it has been more than 50 years since the discovery of Lp(a) ( 36 ), the receptor(s) involved in Lp(a) uptake are still not well defi ned.…”

“…The LDL-R has been implicated in Lp(a) clearance in HepG2 cells ( 37 ) and LDL-R overexpressing mice ( 38 ), possibly through a bystander effect where apoB-100 of Lp(a) is recognized by LDL-R leading to internalization of Lp(a). However, Lp(a) clearance is unaffected by LDL-R defi ciency in humans ( 39 ) or mice ( 35 ), suggesting that the overall magnitude of this pathway appears to be modest in vivo, and it is likely that the apo(a) moiety is mostly responsible for receptor-mediated catabolism of Lp(a), as suggested by this study.…”

“…Although it has been more than 50 years since the discovery of Lp(a) ( 36 ), the receptor(s) involved in Lp(a) uptake are still not well defi ned. Using [ 131 I]tyramine cellobiose labeled Lp(a), which tracks the clearance of the protein of Lp(a), Cain et al ( 35 ) showed that this lipoprotein is predominately cleared by the liver in vivo. Given that LDL is an essential component of Lp(a), the LDL receptor (LDL-R) has been an attractive candidate for the Lp(a) receptor.…”

Recent advances in physiological lipoprotein metabolism

“…ApoE and the receptors that mediate the binding and uptake of apoB100 containing lipoproteins have been proposed as having a role in Lp(a) catabolism. However, the nature of the major receptor(s) that mediate the plasma clearance and tissue uptake of Lp(a) remains to be determined [182]. Clearance of Lp(a) is not well understood, but the LDL receptor or apo(a) size does not appear to be the main determinant of clearance [183].…”

Lipoprotein(a) accelerates atherosclerosis in uremic mice

“…The mechanism may include an increased turnover-time of plasma Lp(a) ( 29 ), and the uremia-induced increase of plasma Lp(a) may be isoform-dependent (30)(31)(32). It has been suggested that the increase of Lp(a) in uremic individuals refl ects decreased clearance in the kidney ( 28,33,34 ), although kinetic studies in rabbits and mice using radiolabeled Lp(a) indicate that the liver is the major organ for clearance of plasma Lp(a) in nonuremic animals ( 35,36 ). Elevated Lp(a) has been associated with increased risk of cardiovascular disease in relatively small studies of uremic patients ( 37,38 ).…”