Isolation, quantitation, and characterization of a stable complex formed by Lp[a] binding to triglyceride-rich lipoproteins

Abstract

Lipoprotein [a] (Lp[a]) is a cholesterol-rich lipoprotein resembling LDL to which a large polymorphic glycoprotein, apolipoprotein [a] (apo[a]), is covalently coupled. Lp[a] usually exists as a free-standing particle in normolipidemic subjects; however, it can associate noncovalently with triglyceride-rich lipoproteins in hypertriglyceridemic (HTG) subjects. In this study, 10-78% of the Lp[a] present in five HTG subjects was found in the triglyceride-rich lipoprotein (TRL) fraction. The Lp[a]-TRL complex was resistant to dissociation by ultracentrifugation (UCF) alone, but was quantitatively dissociated by UCF in the presence of 100 mM proline. Of this dissociated Lp[a], 70-88% was in the form of a lipoprotein resembling conventional Lp[a]. Incubation of Lp[a]-depleted TRL with native Lp[a] resulted in a reconstituted Lp[a]-TRL complex that closely resembled the native isolates in all examined properties. Complex formation was inhibited by several compounds in the order proline Ͼ tranexamate Ͼ -aminocaproate ϾϾ arginine Ͼ lysine. Neither plasminogen nor LDL inhibited binding of Lp[a] to TRL. We observed the preferential binding of Lp[a] containing higher apparent molecular weight apo[a] polymorphs to TRL both in native and reconstituted Lp[a]-TRL complexes. A disproportionate amount of Lp[a] was bound to the larger TRL particles. Although most apo[a] bound to TRL was in the form of conventional Lp[a] particles, lipidfree recombinant apo[a] was observed to bind TRL. These results provide unequivocal evidence of the existence of an Lp[a]-TRL complex under pathophysiologic conditions. The metabolic fate of the Lp[a]-TRL complex, which is more abundant in hypertriglyceridemia, may be different from that of conventional Lp[a], and may contribute uniquely to the progression or severity of cardiovascular disease.

Sortilin enhances secretion of apolipoprotein(a) through effects on apolipoprotein B secretion and promotes uptake of lipoprotein(a)

“…The noncovalent interaction of Lp(a) with triglyceride-rich lipoproteins has been noted in postprandial triglyceridemia and/or in hypertriglyceridemic subjects in several studies ( 68 , 69 , 70 ), and Lp(a) binding to VLDL has also been described ( 71 , 72 ). The Lp(a)/triglyceride-rich lipoprotein or Lp(a)/LDL complexes can be disrupted by lysine analogs ( 70 , 72 ), consistent with our observation that the lysine analog ε-ACA eliminated the stimulatory effect of sortilin on Lp(a) internalization. On the other hand, the internalization of apo(a), which also can be taken up by lysine-dependent interactions with plasminogen receptors, was not affected by sortilin.…”

“…On the other hand, the internalization of apo(a), which also can be taken up by lysine-dependent interactions with plasminogen receptors, was not affected by sortilin. Although apo(a) can also bind to triglyceride-rich lipoproteins ( 70 ), it is possible that since apo(a) can interact with lysine-dependent plasminogen receptors ( 26 , 28 ) through as many as five different lysine-binding kringles, versus one for Lp(a) ( 73 ), that enhanced expression of sortilin would not be sufficient to overcome this “noise”.…”

Correlation of lipoprotein (a) levels and plaque morphology in very young acute coronary syndrome patients using optical coherence tomography

“…It was measured by ELISA technique using monoclonal antibodies based on immunoturbidimetric principle against apo-a moiety of Lp(a) in fasting state because of its falsely elevated level after meals. 13 …”

Effect of Omega-3 Fatty Acid Supplementation on the Postprandial Metabolism of Apolipoprotein(a) in Familial Hypercholesterolemia

“…Experimental evidence suggests that the apoB-100-apo(a) complex within Lp(a) particles has high affinity for TRL particles 10,11) . A significant proportion of Lp(a) particles can bind noncovalently to TRLs in the hypertriglyceridemic state 19) . The Lp(a)-TRL complex may aggravate the pathogenesis of ASCVD in FH.…”