GO:0034364 high-density lipoprotein particle: Components, Assembly and Research Methods, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0034364 describes the high-density lipoprotein (HDL) particle, a 5-10 nm lipoprotein of density 1.063-1.21 g/ml that contains APOAs and may contain APOCs and APOE and functions in reverse cholesterol transport.
• HDL particles are heterogeneous, with subfractions such as HDL2 and HDL3 that differ in size, density, and composition.
• HDL particle number and function, not only cholesterol content, are increasingly recognized as determinants of atherosclerotic cardiovascular disease risk.
• The HDL surfaceome and its interactions with cells regulate cholesterol efflux, mitochondrial function, and macrophage biology.
• HDL dysfunction has been linked to carotid artery stenosis and other vascular pathologies.
• Accurate quantification of HDL particles requires careful methodology because proton NMR-based particle number estimates can be misleading.
Description
The high-density lipoprotein (HDL) particle, annotated as GO:0034364, is a circulating lipoprotein complex defined by its high density (typically 1.063-1.21 g/ml) and small diameter of 5-10 nm. It contains apolipoprotein A (APOA) as its major structural protein and may also contain APOC and APOE, and it mediates the transport of lipids from peripheral tissues to the liver as part of reverse cholesterol transport. Because of this central role in cholesterol homeostasis, the HDL particle is a major focus in cardiovascular research and a target for therapeutic and diagnostic development. HDL particles are not a single uniform entity but a heterogeneous population of subfractions, historically separated into HDL2 and HDL3 by density and size. This heterogeneity underlies the diverse functional properties of HDL, including cholesterol efflux capacity, antioxidant and anti-inflammatory activities, and interactions with cellular receptors and mitochondria. Recent work has emphasized that HDL particle composition and functionality, rather than simply HDL cholesterol concentration, are critical for understanding its relationship with atherosclerotic cardiovascular disease. For researchers, GO:0034364 provides a standardized ontology term to annotate genes, proteins, and cellular components involved in HDL biology. Studies of the HDL surfaceome, HDL-specific phospholipid efflux, and HDL-based nanoplatforms all rely on a precise definition of the HDL particle to interpret experimental results. This article reviews the structure, assembly, molecular mechanisms, key genes, disease associations, and research methods relevant to the HDL particle, based on published literature.
high-density lipoprotein particle At A Glance
| GO ID | GO:0034364 |
|---|---|
| GO term | high-density lipoprotein particle |
| Ontology | cellular_component |
| Synonym | HDL2, HDL3, HDL complex, HDL particle, high-density lipoprotein class complex |
| Major function | Reverse cholesterol transport: carries lipids from body tissues to the liver |
| Density | Typically 1.063-1.21 g/ml |
| Diameter | 5-10 nm |
| Major apolipoproteins | Contains APOAs; may contain APOCs and APOE |
| Location | Found in blood |
What Is GO:0034364?
GO:0034364 (high-density lipoprotein particle) is a cellular component term describing a lipoprotein particle with high density (typically 1.063-1.21 g/ml) and a diameter of 5-10 nm. It contains APOAs and may contain APOCs and APOE, is found in blood, and carries lipids from body tissues to the liver as part of the reverse cholesterol transport process.
Why Is high-density lipoprotein particle Important in Cell Biology?
The HDL particle is central to reverse cholesterol transport, the process by which excess cholesterol is removed from peripheral tissues and delivered to the liver for excretion. Because impaired reverse cholesterol transport contributes to atherosclerosis, HDL particle composition and functionality are key determinants of cardiovascular risk. Moreover, HDL particles interact with macrophages and other cells through their surface proteins, influencing mitochondrial function, inflammation, and plaque stability. Understanding HDL particle biology at the molecular level is therefore essential for developing diagnostics and therapeutics for atherosclerotic cardiovascular disease and related vascular disorders.
• HDL particles mediate reverse cholesterol transport, protecting against atherosclerosis.
• HDL particle number and function are emerging biomarkers for cardiovascular risk beyond HDL cholesterol.
• HDL subfractions (HDL2, HDL3) have distinct functional properties relevant to disease.
• The HDL surfaceome regulates interactions with cells and influences cholesterol efflux.
• HDL dysfunction is associated with carotid artery stenosis.
• HDL regulates mitochondrial function, linking lipoprotein metabolism to cellular energetics.
• HDL-based nanoplatforms are being developed for macrophage-targeted diagnosis and therapy of atherosclerosis.
• Assays for HDL-specific phospholipid efflux provide functional readouts of HDL quality.
• HDL particles may contain APOE and APOCs, expanding their functional repertoire.
• Accurate quantification of HDL particle number is critical for clinical and research applications.
What Happens During high-density lipoprotein particle?
Assembly and Biogenesis
In simple terms: HDL particles are built in the blood from lipid-poor apolipoprotein A-I and lipids.
HDL particles are assembled through the lipidation of lipid-poor APOA-I, primarily by the ATP-binding cassette transporter A1 (ABCA1) in the liver and intestine, forming nascent discoidal HDL. These particles then mature through the action of lecithin-cholesterol acyltransferase (LCAT), which esterifies cholesterol and drives the formation of spherical HDL particles. The heterogeneity of HDL particles arises from differences in apolipoprotein composition, lipid content, and size, giving rise to subfractions such as HDL2 and HDL3.
Reverse Cholesterol Transport
In simple terms: HDL picks up cholesterol from tissues and carries it to the liver for disposal.
The primary function of HDL particles is reverse cholesterol transport, in which they accept cholesterol from peripheral cells, including macrophages, and transport it to the liver for excretion into bile. This process involves interactions with cellular receptors such as SR-BI and the efflux of cholesterol and phospholipids. The efficiency of reverse cholesterol transport is a key determinant of HDL's protective effects against atherosclerosis.
HDL Surfaceome Interactions
In simple terms: Proteins on the HDL surface interact with cells and other molecules to carry out HDL functions.
The HDL surfaceome comprises proteins and lipids on the particle surface that mediate interactions with cells, enzymes, and other lipoproteins. These interactions regulate cholesterol efflux, inflammation, and mitochondrial function. Decoding the HDL surfaceome has revealed that HDL functionality is influenced by its protein cargo, which can vary in health and disease.
HDL Subfractions and Heterogeneity
In simple terms: HDL particles come in different sizes and densities, which affect what they do.
HDL particles are heterogeneous and can be separated into subfractions such as HDL2 (larger, less dense) and HDL3 (smaller, denser). These subfractions differ in their apolipoprotein and lipid composition, and in their functional properties, including cholesterol efflux capacity and antioxidant activity. The distribution of HDL subfractions is altered in various disease states, including cardiovascular disease.
Regulation of HDL Particle Number and Function
In simple terms: The number and quality of HDL particles are controlled by many factors.
HDL particle number and functionality are regulated by genetic, metabolic, and environmental factors. Accurate quantification of HDL particle number is challenging, and proton NMR-based estimates may not reflect true particle numbers. Functional assays, such as HDL-specific phospholipid efflux, provide complementary information about HDL quality. Dysfunctional HDL particles have been observed in conditions such as carotid artery stenosis.
Key Genes Involved in GO:0034364 high-density lipoprotein particle
The following genes and proteins are central to the structure, assembly, and function of the high-density lipoprotein particle (GO:0034364).
| Gene | Major Role | Research Relevance |
|---|---|---|
| APOA1 | Major structural apolipoprotein of HDL; acceptor for cholesterol efflux | Central to HDL assembly and reverse cholesterol transport |
| APOA2 | Second most abundant HDL apolipoprotein; modulates HDL function | Influences HDL subfraction distribution and function |
| APOE | May be present on HDL; involved in lipid transport | Modulates HDL metabolism and reverse cholesterol transport |
| APOC1 | May be present on HDL; regulates lipoprotein metabolism | Affects HDL composition and function |
| APOC2 | May be present on HDL; cofactor for lipoprotein lipase | Impacts HDL remodeling and triglyceride metabolism |
| APOC3 | May be present on HDL; inhibits lipoprotein lipase | Linked to HDL dysfunction and cardiovascular risk |
| ABCA1 | Mediates lipidation of APOA1 to form nascent HDL | Key regulator of HDL biogenesis |
| LCAT | Esterifies cholesterol on HDL, driving maturation | Essential for spherical HDL formation |
| SR-BI | Receptor for HDL; mediates selective cholesterol uptake | Critical for reverse cholesterol transport |
| CETP | Transfers cholesteryl esters between HDL and other lipoproteins | Modulates HDL cholesterol levels and function |
| PLTP | Phospholipid transfer protein; remodels HDL | Affects HDL particle size and composition |
| LIPC | Hepatic lipase; hydrolyzes HDL lipids | Influences HDL subfraction distribution |
| MPO | Myeloperoxidase; oxidizes HDL components | Contributes to HDL dysfunction |
| PON1 | Paraoxonase 1; associated with HDL, antioxidant | Protects HDL from oxidation |
| SAA | Serum amyloid A; acute-phase protein that can associate with HDL | Alters HDL function during inflammation |
| ApoM | Apolipoprotein M; associated with HDL | Carries sphingosine-1-phosphate and affects HDL function |
How Is high-density lipoprotein particle Regulated?
HDL particle number and function are regulated at multiple levels, including transcriptional control of apolipoprotein genes, post-translational modification of HDL-associated proteins, and remodeling by enzymes such as LCAT, CETP, and PLTP. Metabolic and inflammatory states can alter HDL composition and functionality, leading to dysfunctional HDL. Accurate assessment of HDL particle number requires careful methodology, as proton NMR-based estimates may not reliably reflect true particle numbers. Functional assays, such as HDL-specific phospholipid efflux, provide insights into HDL quality and its regulation.
high-density lipoprotein particle and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| APOA1 | Atherosclerotic cardiovascular disease; HDL deficiency | APOA1 knockout and knock-in cell models |
| ABCA1 | Tangier disease; impaired HDL biogenesis | ABCA1 knockout cell lines |
| LCAT | Fish-eye disease; HDL maturation defect | LCAT knockout and point-mutation models |
| SR-BI | Altered reverse cholesterol transport; cardiovascular risk | SR-BI knockout and overexpression models |
| APOE | Alzheimer's disease; cardiovascular disease | APOE isoform knock-in cell models |
Atherosclerotic Cardiovascular Disease
Low HDL cholesterol levels and dysfunctional HDL particles are associated with increased risk of atherosclerotic cardiovascular disease. HDL particle composition and functionality, rather than simply cholesterol content, are critical determinants of cardiovascular risk. Impaired reverse cholesterol transport contributes to plaque formation and progression.
Carotid Artery Stenosis
HDL dysfunction has been observed in patients with carotid artery stenosis, suggesting that qualitative HDL abnormalities may contribute to cerebrovascular disease. Oxidative modification of HDL components, such as by myeloperoxidase, may impair HDL function in this context.
Mitochondrial Dysfunction and Metabolic Disease
HDL particles regulate mitochondrial function in cells, and impaired HDL signaling may contribute to metabolic and cardiovascular pathologies. The interaction between HDL and mitochondria highlights a broader role for HDL beyond cholesterol transport.
Macrophage Biology and Inflammation
HDL particles interact with macrophages and influence inflammatory responses, making them attractive targets for macrophage-targeted therapies. HDL-based nanoplatforms are being developed for diagnosis and therapy of atherosclerosis by exploiting these interactions.
From high-density lipoprotein particle-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of APOA1 impair HDL assembly? | APOA1 knockout cell line |
| Does a specific ABCA1 mutation affect cholesterol efflux? | ABCA1 point-mutation knock-in |
| Can tagged APOA1 track HDL particle trafficking? | Tagged APOA1 knock-in |
| Does LCAT overexpression increase spherical HDL? | LCAT overexpression cell model |
| Which genes regulate HDL particle number? | CRISPR library screening |
| How does APOE isoform affect HDL function? | APOE isoform knock-in |
How to Study the high-density lipoprotein particle Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Ultracentrifugation | HDL density and subfraction distribution | Isolation of HDL2 and HDL3 |
| NMR spectroscopy | HDL particle number and size | Cardiovascular risk assessment |
| Cholesterol efflux assay | Functional capacity of HDL to accept cholesterol | Evaluating HDL quality |
| Phospholipid efflux assay | HDL-specific phospholipid efflux | Assessing HDL function |
| Mass spectrometry proteomics | HDL protein composition (surfaceome) | Identifying HDL-associated proteins |
| CRISPR screening | Genes regulating HDL particle number/function | Discovery of novel HDL regulators |
| HDL-based nanoplatform imaging | Macrophage targeting and plaque imaging | Atherosclerosis diagnosis |
Lipid and Lipoprotein Profiling
HDL particles can be separated and quantified using ultracentrifugation, gel electrophoresis, and nuclear magnetic resonance (NMR) spectroscopy. However, NMR-based particle number estimates should be interpreted with caution. These methods are used to characterize HDL subfractions and assess cardiovascular risk.
Functional Assays
HDL function is assessed using assays such as HDL-specific phospholipid efflux, cholesterol efflux capacity, and antioxidant activity. These assays provide functional readouts that complement compositional measurements.
Proteomics and Surfaceome Analysis
Mass spectrometry-based proteomics can characterize the HDL surfaceome and identify proteins associated with HDL particles. This approach reveals how HDL composition changes in disease and provides insights into HDL functionality.
Imaging and Nanoplatforms
HDL-based nanoplatforms can be used for macrophage-targeted imaging and therapy, allowing visualization of HDL interactions in atherosclerosis. These tools are valuable for studying HDL biology in vivo.
How CRISPR Can Be Used to Study GO:0034364 high-density lipoprotein particle
Knockout
CRISPR knockout of genes such as APOA1, ABCA1, or LCAT in cell models can reveal their essential roles in HDL assembly and function. Knockout studies help determine whether a candidate gene is required for HDL particle formation or reverse cholesterol transport.
Point Mutation
Introducing disease-associated point mutations (e.g., in ABCA1 or LCAT) using CRISPR base editing or homology-directed repair allows researchers to study the functional consequences of specific variants on HDL biology.
Knock-in
Knock-in of tagged APOA1 or APOE isoforms enables tracking of HDL particles and analysis of isoform-specific effects on HDL function.
Overexpression
Overexpression of genes such as LCAT or SR-BI can enhance HDL maturation or cholesterol uptake, providing models to study gain-of-function effects on HDL particles.
How EDITGENE Supports high-density lipoprotein particle Research
Researchers studying high-density lipoprotein particle-related genes often need to determine whether a candidate gene is causally involved in HDL assembly, function, or disease. EDITGENE provides CRISPR-based cell model services to enable precise genetic manipulation and functional validation of HDL-related targets.
Contact EDITGENE today to design your custom CRISPR model for high-density lipoprotein particle research.
Frequently Asked Questions About high-density lipoprotein particle
What is GO:0034364?
GO:0034364 is the Gene Ontology term for high-density lipoprotein particle, a lipoprotein complex of density 1.063-1.21 g/ml and diameter 5-10 nm that contains APOAs and functions in reverse cholesterol transport.
What is a high-density lipoprotein particle?
A high-density lipoprotein (HDL) particle is a small, dense lipoprotein found in blood that carries lipids from body tissues to the liver as part of reverse cholesterol transport.
What genes are involved in high-density lipoprotein particle?
Key genes include APOA1, APOA2, APOE, ABCA1, LCAT, SR-BI, CETP, and PLTP, among others.
What is the function of high-density lipoprotein particle?
Its major function is reverse cholesterol transport, removing cholesterol from peripheral tissues and delivering it to the liver.
How are HDL particles measured?
HDL particles can be measured by ultracentrifugation, NMR spectroscopy, and functional assays such as cholesterol efflux.
What diseases are associated with HDL particles?
Dysfunctional HDL particles are associated with atherosclerotic cardiovascular disease, carotid artery stenosis, and metabolic disorders.
What are HDL subfractions?
HDL subfractions such as HDL2 and HDL3 are distinct populations of HDL particles that differ in size, density, and composition.
Can CRISPR be used to study HDL particles?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models can be used to study genes involved in HDL biology.
What is the HDL surfaceome?
The HDL surfaceome is the collection of proteins and lipids on the HDL particle surface that mediate interactions with cells and other molecules.
Why is HDL particle number important?
HDL particle number, in addition to cholesterol content, is increasingly recognized as a determinant of cardiovascular risk, though accurate measurement is challenging.
Conclusion
The high-density lipoprotein particle (GO:0034364) is a central component of lipid metabolism and reverse cholesterol transport, with critical roles in cardiovascular health and disease. Its heterogeneity, functional diversity, and interactions with cells and other lipoproteins make it a rich subject for research. Advances in CRISPR-based models and functional assays continue to illuminate the molecular mechanisms underlying HDL biology, offering new opportunities for therapeutic intervention.
References
- 1. Schaefer EJ et al.. 2025. High Density Lipoprotein Particle Composition, Functionality, Deficiency, and Atherosclerotic Cardiovascular Disease Risk: A Review.. Curr Atheroscler Rep 27(1):62 PMID: 40489011
- 2. Vaisar T et al.. 2024. Quantification of high-density lipoprotein particle number by proton nuclear magnetic resonance: don't believe the numbers.. Curr Opin Lipidol 35(5):228-233 PMID: 39162237
- 3. Neufeld EB et al.. 2025. High-Density Lipoprotein-Specific Phospholipid Efflux Assay.. J Vis Exp PMID: 41115105
- 4. Silverman DI et al.. 1993. High-density lipoprotein subfractions.. Am J Med 94(6):636-45 PMID: 8506891
- 5. Frey K et al.. 2022. Decoding Functional High-Density Lipoprotein Particle Surfaceome Interactions.. Int J Mol Sci 23(16) PMID: 36012766
- 6. Senat A et al.. 2023. High-density lipoprotein dysfunction in carotid artery stenosis.. Vasa 52(5):342-348 PMID: 37622201
- 7. White CR et al.. 2017. High-Density Lipoprotein Regulation of Mitochondrial Function.. Adv Exp Med Biol 982:407-429 PMID: 28551800
- 8. He J et al.. 2025. High-density lipoprotein-based nanoplatforms for macrophage-targeted diagnosis and therapy of atherosclerosis.. Int J Biol Macromol 306(Pt 3):140826 PMID: 40010459
