Lipoprotein(a) Particle Core Remodeling and Apolipoprotein C-III Inhibition

Corresponding Author

Lipoprotein(a) (Lp(a)) is an established, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD), myocardial infarction, and calcific aortic valve stenosis.¹ Its atherogenicity is multifaceted, primarily driven by elevated particle numbers and the structural properties of apolipoprotein(a) (apo(a)), including high content of proinflammatory oxidized phospholipids (OxPLs).¹ Although human Lp(a) metabolism remains incompletely understood, emerging evidence highlights complex metabolic and structural interactions of Lp(a) with triglyceride-rich lipoproteins (TRLs), including very-low-density lipoprotein (VLDL), chylomicrons, and their remnants.² Understanding the metabolism of Lp(a) in hypertriglyceridemic states is important to advancing our understanding of its role in ASCVD.

Standard lipid-lowering therapies for hypertriglyceridemia (HTG), including fibrates and omega-3 fatty acid supplementation, can reduce plasma triglyceride concentrations by up to 30%, whereas insulin sensitizers (eg, pioglitazone) and GLP-1 receptor agonists exert more modest effects (10%-20% reduction).³ Each of these agents lowers apolipoprotein C-III (apoC-III) to varying degrees via distinct mechanisms. Emerging therapies targeting APOC3 achieve far greater triglyceride reductions and lower the risk of acute pancreatitis.³ Among these, olezarsen is a subcutaneously administered antisense oligonucleotide that selectively inhibits hepatic APOC3 mRNA in the liver. By reducing apoC-III synthesis, olezarsen enhances triglyceride clearance through both lipoprotein lipase (LPL)–dependent and LPL-independent pathways, reducing plasma triglycerides by approximately 50%.

In this issue of JACC: Basic to Translational Science, Lin et al⁴ investigate the effects of olezarsen on Lp(a) particle concentration and its core lipid cargo (triglycerides and cholesterol) in patients with moderate HTG. This Phase 2, dose-ranging, randomized, double-blind, placebo-controlled trial enrolled patients with established ASCVD or high ASCVD risk (mean body mass index: 32.1 kg/m²; 67.5% with type 2 diabetes), most of whom had diabetes and were already on low-density lipoprotein (LDL) cholesterol–lowering therapy with LDL cholesterol adequately controlled, but who had moderately elevated fasting triglyceride concentrations of 200 to 500 mg/dL (2.26-5.65 mmol/L). Earlier data from this cohort showed that olezarsen beneficially reduced TRL levels and shifted LDL toward larger particle sizes without affecting total LDL particle concentration.⁵ Using a novel validated immune-isolation assay,⁶ the authors measured Lp(a)-associated triglyceride (Lp(a)-TG) and cholesterol (Lp(a)-C) content. Lin et al⁴ report 2 novel findings. First, Lp(a) particles in patients with moderate HTG were substantially enriched with triglycerides (16%-21%) and cholesterol (9%-11%) compared with normotriglyceridemic individuals (<5% for both). Second, olezarsen treatment produced dose-dependent, marked reductions in Lp(a)-TG (62.9%-69.8%) and Lp(a)-C (55.7%-64.6%) at higher monthly equivalent doses (15 mg every 2 weeks to 50 mg every 4 weeks). Importantly, this occurred without decreasing plasma Lp(a) particle concentrations or significantly altering OxPL levels relative to placebo.

These findings demonstrate that the lipid composition of Lp(a) particles can be dynamically remodeled independent of total particle number or surface OxPL content. These findings should be interpreted within the broader context of the bioregulation of Lp(a) and their potential clinical implications.

Lp(a) Metabolism and Hypertriglyceridemia

Lp(a) is a polymorphic particle consisting of an LDL-like particle in which apoB-100 is covalently linked to apo(a) via a disulfide bond. This structure encapsulates a core rich in triglycerides and cholesteryl esters, enveloped by a surface layer of unesterified cholesterol and phospholipids.^1,2 Both apo(a) and apoB-100 are synthesized in hepatocytes and assembled intracellularly, acquiring their core lipids via microsomal triglyceride transfer protein in the endoplasmic reticulum. Emerging evidence also suggests that apo(a) may associate with apoB-100 particles at the hepatocyte surface, providing an additional site for the assembly of Lp(a) and remodeling of its lipid cargo remodeling.² However, whether the apoC-III content of these particles influences this extracellular remodeling process, particularly under hypertriglyceridemic conditions, remains unclear.

While hypertriglyceridemic states often exhibit an inverse correlation between plasma Lp(a) particle concentration and triglyceride levels, data regarding Lp(a) lipid composition under these conditions are limited. Lin et al⁶ recently also demonstrated that Lp(a) particles become markedly enriched in both triglyceride and cholesterol in the hypertriglyceridemic state. This altered lipid composition may render Lp(a) particles more susceptible to lipolysis and lipid oxidation, potentially generating bioactive lipid mediators that aggregate vascular inflammation. Interestingly, this lipid profile differs markedly from that of LDL in HTG and type 2 diabetes, where particles are typically triglyceride enriched but cholesterol depleted. These findings suggest that Lp(a) and LDL undergo distinct pathways of postsecretory remodeling under hypertriglyceridemic conditions. Further support for this concept comes from kinetic studies of the CETP (cholesteryl ester transfer protein) inhibitor anacetrapib, which lowers Lp(a) predominantly by reducing particle production, whereas LDL concentrations are reduced through enhanced clearance.² These divergent kinetic responses indicate that CETP may influence Lp(a) and LDL metabolism through different mechanisms. One possible explanation is that the distinct lipid composition and structural features (the presence of apo(a)) of Lp(a) renders it a less efficient substrate for CETP-mediated lipid exchange than LDL, but this is speculative and needs further investigation.

Lp(a) Remodeling via ApoC-III Inhibition

Unlike therapies that reduce plasma Lp(a) concentrations by 25% to 50%, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, CETP inhibitors, and apoB antisense oligonucleotides, apoC-III–targeted agents (eg, volanesorsen, olezarsen, and plozasiran) do not lower circulating Lp(a) particle concentrations. This suggests that Lp(a) particle clearance is largely independent of apoC-III–mediated lipolysis and hepatic remnant receptor pathways. Nevertheless, apoC-III inhibition can markedly remodel Lp(a) composition. In patients with familial chylomicronemia syndrome (FCS), high-dose olezarsen (80 mg) lowered Lp(a)-associated apoC-III by 39%.⁷ Because apoC-III exchanges dynamically across TRLs, LDL, high-density lipoprotein, and Lp(a), its depletion from the Lp(a) surface would be expected to extend to a reduction in Lp(a)-associated triglyceride content as well, particularly given that Lp(a)-TG enrichment appears to track circulating TRL burden. The findings by Lin et al⁴ are consistent with apoC-III depletion as a mechanism for Lp(a) core remodeling. Depletion of apoC-III from Lp(a) may restore local LPL-mediated lipolysis, thereby reducing the triglyceride content of Lp(a). The resulting depletion of core triglycerides may also attenuate CETP-mediated lipid exchange between Lp(a) and other lipoproteins, limiting further enrichment of the Lp(a) core with triglycerides and cholesteryl esters. Although it remains unproven whether these core lipid changes make Lp(a) less atherogenic and confer vascular benefit in the absence of reduced particle concentrations, reducing the apoC-III content on Lp(a) may directly mitigate its pathogenicity, mirroring the reduction in toxicity observed when apoC-III is cleared from LDL particles.

Surface OxPLs and Bioactive Lipids

Lp(a) carries approximately 80% to 85% of circulating OxPLs in human plasma, which drive monocyte adhesion, macrophage foam cell formation, endothelial activation, and vascular calcification.¹ Notably, plasma OxPL content on apoB and apo(a) predicts cardiovascular events independent of total Lp(a) mass. Because most OxPLs are covalently bound to apo(a), OxPL-apo(a) and OxPL-apoB levels are tightly correlated with Lp(a) particle concentration, a relationship confirmed by Lin et al.⁴ While olezarsen markedly cleared core lipids, its effect on Lp(a)-associated OxPL levels remained variable and showed no significant difference compared to placebo. This demonstrates that the core lipid cargo of Lp(a) and its surface OxPL moieties are governed by divergent metabolic pathways.

Beyond OxPLs, recent lipidomic profiling by Dzobo et al⁸ demonstrated that Lp(a) particles are enriched in diacylglycerols (DAGs) and lysophosphatidic acid (LPA). Specific DAG subspecies promote monocyte migration and proinflammatory NF-κB signaling, whereas pelacarsen, an apo(a)-targeted antisense oligonucleotide, substantially reduces circulating DAG species in parallel with lowering Lp(a).⁸ Interestingly, apoC-III inhibition with volanesorsen also significantly reduces total plasma DAG levels by more than 50%.⁹ Together, this marked reduction in proinflammatory DAG species, along with the accompanying decline in Lp(a)-associated triglyceride and cholesterol content, raises the possibility that apoC-III inhibition alters Lp(a) particle size, density, or atherogenicity even without changes in Lp(a) particle concentration or OxPL content. Whether olezarsen selectively depletes DAG species specifically associated with Lp(a) remains unanswered.

Key Unresolved Questions

The findings of Lin et al⁴ are not definite, require confirmation, and generate several new research questions.

First, HTG affects not only the composition of Lp(a), but also its physical distribution. Non–covalent binding between apo(a)/Lp(a) and TRLs increases in postprandial periods. However, high-dose omega-3 fatty acid supplementation effectively reduces postprandial TRL-bound apo(a), even though total apo(a) levels remain unchanged.¹⁰ Whether these transient Lp(a)-TRL complexes contribute disproportionately to atherogenesis, and how apoC-III inhibition alters postprandial apo(a) distribution across TRL subfractions, requires further study.

Second, apo(a) isoform size is inversely associated with Lp(a) particle concentration and is a major determinant of both Lp(a) production and clearance.^1,2 Smaller apo(a) isoforms, which are associated with higher cardiovascular risk, also carry a greater OxPL burden per particle.¹ Whether apo(a) isoform size influences the interaction of Lp(a) with TRLs or modulates the extent of Lp(a) core lipid remodeling during apoC-III inhibition remains unknown. In addition, potential differences according to sex and genetic ancestry, particularly between individuals of African and non-African ancestry, warrant investigation to better inform personalized cardiovascular risk assessment and therapeutic strategies.

Third, apoC-III inhibitors are approved for FCS and severe HTG,³ conditions driven by profound impairment of LPL-mediated TRL clearance given severe LPL deficiency or dysfunction. In contrast, moderate HTG is driven predominantly by hepatic TRL overproduction in the setting of relatively preserved LPL activity. Whether the Lp(a) core remodeling observed with olezarsen in moderate HTG also extends to severe HTG (>500 mg/dL), a condition associated with elevated ASCVD risk, or to FCS remains to be determined. Analyzing Lp(a)-triglyceride and Lp(a)-cholesterol levels across other olezarsen studies (BALANCE, CORE, CORE2) and plozasiran trials (SHASTA, PALISADE) could shed light on the exact role LPL activity plays in this process.

Clinical Implications

From a clinical perspective, the findings of Lin et al⁴ raise the important question of whether assessing Lp(a) core lipid composition, in addition to particle concentration, could improve cardiovascular risk stratification in patients with HTG and metabolic syndrome. These observations also provide a rationale for complementary therapeutic strategies that target distinct aspects of Lp(a) biology. Combining apoC-III inhibition to remodel the core lipid cargo and reduce triglyceride burden with direct Lp(a)-lowering therapies to decrease circulating particle concentrations may offer a more comprehensive approach to mitigating residual ASCVD risk in patients with HTG and elevated Lp(a). However, the neutral result of the Lp(a) HORIZON trial leaves unresolved whether lowering Lp(a) itself translates into cardiovascular benefit. The forthcoming outcomes trials of lepodisiran and zerlasiran will help establish whether more profound and durable Lp(a) lowering can achieve this.

Summary

Lp(a) particle concentration, core lipid composition (including triglycerides, cholesteryl esters, and DAG), and surface OxPL content appear to be independently regulated in patients with moderate HTG. Whether these findings extend to other metabolic conditions, including severe HTG, familial hypercholesterolemia, familial combined hyperlipidemia, and chronic kidney disease, remains unknown. Further studies evaluating the effects of established Lp(a)-modifying therapies, such as CETP inhibitors, PCSK9 inhibitors, and thyroid hormone receptor–β agonists, as well as emerging targeted Lp(a)-lowering agents, including pelacarsen, olpasiran, and the apoC-III–targeting siRNA plozasiran, on both the core lipid cargo and surface constituents of Lp(a) are important for advancing our understanding of Lp(a) metabolism and its role in ASCVD.

Funding Support and Author Disclosures

Dr Watts has received honoraria for lectures, advisory board membership, or research grants from Amgen, Arrowhead, AstraZeneca, Esperion, Novartis, Novo Nordisk Regeneron, and Sanofi. Dr Chen has reported no relationships relevant to the contents of this paper to disclose.