Cardiovascular disease remains the leading cause of death worldwide. While most people have heard of LDL cholesterol—the so-called “bad cholesterol”—fewer are familiar with its close molecular relative, Lipoprotein(a), or Lp(a). Yet elevated Lp(a) is now recognized as a causal, independent risk factor for both atherosclerotic cardiovascular disease and calcific aortic valve stenosis, a serious form of heart failure.
What makes Lp(a) particularly challenging is that your levels are largely determined by your genes. Unlike standard LDL cholesterol, which responds to diet, exercise, and medications, Lp(a) levels are highly heritable and can vary enormously across the population—from less than 1 mg/dL to over 200 mg/dL. Research in European ancestry populations has estimated that each two-fold increase in Lp(a) is associated with a roughly 22% greater risk of heart attack.1
Despite decades of research, one fundamental question has stubbornly resisted a clear answer: which receptor is responsible for clearing Lp(a) from the bloodstream? A 2025 study published in the journal Atherosclerosis by researchers at the University of Michigan now provides compelling evidence that the answer has been hiding in plain sight.2
The Clearance Question
Your liver is the primary organ responsible for removing lipoproteins from circulation. For standard LDL particles, this process is well understood: the LDL receptor (LDLR) on the surface of liver cells binds LDL, pulls it inside the cell, and breaks it down. This is the mechanism that statins and PCSK9 inhibitors so effectively exploit to lower LDL cholesterol.
But Lp(a) is not ordinary LDL. It consists of an LDL-like particle linked by a chemical bond to a unique protein called apolipoprotein(a), or apo(a). This additional protein component makes Lp(a) structurally distinct—and has made its clearance pathway difficult to pin down.
Over the years, researchers have proposed numerous candidate receptors for Lp(a) uptake, including the VLDL receptor, scavenger receptors, toll-like receptors, lectins, and plasminogen receptors. Studies of the LDL receptor itself have produced inconsistent and sometimes contradictory results across different cell types, animal models, and human populations. Much of this inconsistency reflects differences in experimental systems, cell types, and—critically—the purity and characterization of Lp(a) preparations used across studies.Until now, no study had conducted a systematic, unbiased search across all potential receptors in a single experimental system.
An Unbiased Search: Genome-Scale CRISPR Screening
To resolve the controversy, the Michigan team employed a powerful approach called genome-scale CRISPR screening. CRISPR technology allows researchers to selectively disable, or “knock out,” individual genes in living cells. In a genome-scale screen, this is done simultaneously across nearly every gene in the human genome—approximately 19,000 genes—in a single experiment.
Here is how it works in practice. The researchers introduced a CRISPR knockout library into roughly 60 million HuH7 cells, a well-established human liver cell line commonly used to model hepatocyte biology. Each cell received a guide RNA targeting a different gene, effectively creating a massive pool where every gene in the genome was disabled in some subset of cells. After allowing two weeks for the gene knockouts to take effect, the team exposed these cells to fluorescently labeled, purified Lp(a) and used flow cytometry to sort cells into two groups: those that took up the most Lp(a) and those that took up the least. By comparing which gene knockouts were enriched in each group, the researchers could identify which genes promote or inhibit Lp(a) uptake.
The results were striking. The gene whose disruption caused the greatest reduction in Lp(a) uptake was LDLR—the LDL receptor. The gene whose disruption caused the greatest increase was MYLIP, which encodes a protein called IDOL that normally triggers LDLR degradation. In other words, removing the brake on LDLR caused Lp(a) uptake to go up. At the most stringent statistical threshold—a false discovery rate below 5%—these were the only two genes with a significant effect.
Notably, none of the other receptors previously proposed in the scientific literature—including the VLDL receptor, scavenger receptor B1, toll-like receptors, and plasminogen receptors—showed a significant impact on Lp(a) uptake in this screen.
Why Protein Purity Mattered
A critical challenge in Lp(a) research is ensuring that experimental results reflect genuine Lp(a) biology rather than artifacts from contaminating lipoproteins. If an Lp(a) preparation contains even trace amounts of LDL, any observed interaction with LDLR could be a false positive—driven by LDL contamination rather than Lp(a) itself.
The researchers addressed this challenge by sourcing their lipoproteins from Athens Bioscience, Inc. (formerly known as Athens Research & Technology, Inc.). The purified native Lp(a) used in the study (Cat# 12-16-121601) was isolated from single-donor human plasma through sequential density ultracentrifugation followed by size exclusion chromatography and verified to lack detectable contaminating lipoproteins. Purified native LDL (Cat# 12-16-120412) and HDL (Cat# 12-16-080412) served as essential positive and negative controls throughout the study.
To further guard against artifacts, the team used an independent detection method for validation. Rather than relying solely on the fluorescent labeling used in the initial screen, they measured Lp(a) uptake using an ELISA specific to the apo(a) component of Lp(a)—a protein that is entirely absent in LDL particles. This confirmed the screen results: disrupting LDLR eliminated Lp(a) uptake, and this effect was rescued by re-introducing LDLR through a separate genetic construct.
The team also used biolayer interferometry (BLI), a technique that measures molecular binding interactions in real time, to demonstrate direct, concentration-dependent binding between purified Lp(a) and the LDLR extracellular domain. Importantly, while Lp(a) did bind LDLR, the binding was of lesser magnitude than that observed for LDL—consistent with the structural differences between the two particles and with the clinical reality that Lp(a) is harder to clear from circulation than LDL.
Validation in Nearly 360,000 People
Laboratory findings, no matter how rigorous, require validation in human populations. To test the real-world relevance of their results, the researchers analyzed data from 359,090 individuals in the UK Biobank, a large-scale biomedical database with whole exome sequencing and serum lipoprotein measurements.
They identified 225 carriers of 25 different pathogenic LDLR gene variants—the kinds of mutations responsible for Familial Hypercholesterolemia, a genetic condition characterized by dangerously elevated cholesterol. As expected, these individuals had significantly elevated LDL cholesterol, with levels approximately 32% higher than non-carriers. Critically, the same individuals also had significantly elevated Lp(a) levels—approximately 9% higher than non-carriers.
The smaller magnitude of the Lp(a) effect relative to LDL is itself informative. It aligns with the laboratory data showing weaker Lp(a)–LDLR binding and suggests that while LDLR plays a central role in Lp(a) clearance, other factors may also contribute. Across a broader set of individual LDLR variants, the team found a statistically significant correlation between each variant’s effect on LDL levels and its effect on Lp(a) levels. Variants classified as “Pathogenic” were associated with increased Lp(a); those classified as “Benign” were not.
A Therapeutic Paradox—and What It Might Mean
One of the most intriguing implications of this research relates to a longstanding puzzle in cardiology. PCSK9 inhibitors—a relatively newer class of cholesterol-lowering drugs—have been shown to reduce both LDL and Lp(a). Statins, the most widely prescribed cholesterol medications in the world, effectively lower LDL but do not lower Lp(a). Both drug classes work in part by increasing LDLR expression on liver cells, so why do they have such different effects on Lp(a)?
Several hypotheses have been proposed. One possibility discussed by the study authors is that statins may simultaneously stimulate expression of the LPA gene, which encodes the apo(a) component of Lp(a). If statins boost Lp(a) production at the same time they increase its clearance through LDLR, the two effects could cancel each other out.3 PCSK9 inhibitors may not trigger this compensatory increase, allowing the clearance benefit to predominate.
This is directly relevant to the ongoing development of next-generation Lp(a)-targeted therapies. Several pharmaceutical programs are advancing antisense oligonucleotide and small interfering RNA approaches designed to reduce Lp(a) production at its genetic source. Understanding the complete lifecycle of Lp(a)—from synthesis through receptor-mediated clearance—will be essential for optimizing these therapies and potentially combining them with existing treatments to address cardiovascular risk more comprehensively.
The Proteins Behind the Science
Athens Bioscience, Inc. (formerly known as Athens Research & Technology) has manufactured high-purity native human proteins from its facility in Athens, Georgia for four decades. The lipoproteins used in this study—purified native Lp(a), LDL, and HDL—are part of a comprehensive portfolio of more than 20 lipoprotein and apolipoprotein products, available in Standard, Low Endotoxin Level (LEL), and Immunogen Grade (IMM) formats to serve research, diagnostic, and pharmaceutical applications.
For researchers investigating cardiovascular disease mechanisms, IVD manufacturers developing Lp(a) diagnostic assays, and pharmaceutical companies advancing next-generation lipid-lowering therapies, protein purity is not a luxury —it is essential for drawing valid biological conclusions. When a genome-scale screen depends on distinguishing genuine receptor-mediated uptake from contamination artifacts, the quality of the starting material determines whether results are meaningful or misleading.
References:
1. Kamstrup, P.R., Tybjaerg-Hansen, A., Steffensen, R., Nordestgaard, B.G. (2009). “Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.” JAMA, 301, 2331–2339.
2. Khan, T.G., Bragazzi Cunha, J., Raut, C., et al. (2025). “Functional interrogation of cellular Lp(a) uptake by genome-scale CRISPR screening.” Atherosclerosis, 403, 119174. https://doi.org/10.1016/j.atherosclerosis.2025.119174
3. Tsimikas, S., Gordts, P., Nora, C., Yeang, C., Witztum, J.L. (2020). “Statin therapy increases lipoprotein(a) levels.” European Heart Journal, 41, 2275–2284.
Athens Products Referenced in This Study:
Lipoprotein(a), Human Plasma (Cat# 12-16-121601)
Lipoproteins, Low Density, Human Plasma (Cat# 12-16-120412)
Lipoproteins, High Density, Human Plasma (Cat# 12-16-080412)
Explore Athens' full portfolio of lipoproteins and apolipoproteins at www.athensbioscience.com.