GO:0071404 cellular response to low-density lipoprotein particle stimulus: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0071404 describes how a cell changes its state or activity in response to a low-density lipoprotein (LDL) particle stimulus, including changes in gene expression, secretion, movement, and enzyme production.
• LDL particles are not merely cholesterol carriers; they actively modulate inflammatory signaling, neutrophil stimulation, and macrophage transcriptional programs [2, 3, 5].
• Oxidized LDL (oxLDL) is recognized by T lymphocytes from human atherosclerotic plaques, linking this response to adaptive immunity in atherosclerosis.
• Key signaling nodes include NF-kappaB and IRAK-1, which are inhibited by ozonized LDL, and the EGFR-ERK cascade activated by GOLM1 in macrophages [1, 7].
• SPA promotes atherosclerosis by mediating macrophage foam cell formation, a hallmark of the cellular response to LDL.
• CRISPR knockout, knock-in, and overexpression models are essential to dissect causal genes in this pathway and to identify therapeutic targets.
Description
The Gene Ontology term GO:0071404, cellular response to low-density lipoprotein particle stimulus, defines any process that results in a change in state or activity of a cell as a result of a low-density lipoprotein particle stimulus [1, 2]. This term captures a broad range of cellular outputs, including movement, secretion, enzyme production, and gene expression, that are triggered when cells encounter LDL particles. LDL is a major carrier of cholesterol in the bloodstream, but its biological effects extend far beyond lipid transport. For example, apolipoprotein B mediates the capacity of LDL to suppress neutrophil stimulation by particulates, demonstrating that LDL can directly modulate inflammatory cell behavior. Similarly, LDL inhibits the physical interaction of phlogistic crystals with inflammatory cells, further supporting its role as a modulator of cellular responses. These early observations established that LDL particles are not passive cargo but active participants in cell signaling. In the context of atherosclerosis, oxidized LDL (oxLDL) is recognized by T lymphocytes isolated from human atherosclerotic plaques, indicating that the cellular response to LDL is linked to adaptive immunity and disease progression. More recent work has identified specific signaling cascades, such as the GOLM1-EGFR-ERK axis in macrophages, that promote atherogenesis in response to LDL. Understanding GO:0071404 is therefore critical for researchers studying cardiovascular disease, inflammation, and lipid biology, as it provides a framework to connect LDL stimuli to downstream cellular phenotypes.
cellular response to low-density lipoprotein particle stimulus At A Glance
| GO ID | GO:0071404 |
|---|---|
| GO term | cellular response to low-density lipoprotein particle stimulus |
| Ontology | biological_process |
| Synonym | response to low density lipoprotein particle; response to low-density lipoprotein particle; response to low-density lipoprotein particle stimulus |
| Major function | Mediates cellular changes in movement, secretion, enzyme production, and gene expression in response to LDL particles |
| Related stimuli | Low-density lipoprotein (LDL), oxidized LDL (oxLDL), ozonized LDL (ozLDL) |
| Key signaling pathways | NF-kappaB, IRAK-1, EGFR-ERK, inflammatory transcriptional programs |
| Associated cell types | Macrophages, neutrophils, T lymphocytes, endothelial cells |
| Disease relevance | Atherosclerosis, cardiovascular disease, endometriosis (oxidative stress context) |
What Is GO:0071404?
In our own words, GO:0071404 encompasses all cellular changes that occur when a cell senses and responds to a low-density lipoprotein particle. This includes alterations in gene expression, secretion of cytokines or enzymes, changes in cell movement, and modulation of signaling pathways. The term is intentionally broad to cover any process that results in a change in cellular state or activity due to LDL stimulation, as defined by the Gene Ontology Consortium.
Why Is cellular response to low-density lipoprotein particle stimulus Important in Cell Biology?
GO:0071404 is important because it provides a systematic way to annotate and study how cells interpret LDL signals, which is central to understanding atherosclerosis and other inflammatory diseases. The response to LDL involves complex crosstalk between lipid metabolism, innate immunity, and adaptive immunity, as shown by the recognition of oxLDL by plaque T cells and the suppression of neutrophil stimulation by LDL. Dysregulation of this response contributes to foam cell formation, plaque development, and chronic inflammation [1, 8]. Moreover, the term is relevant beyond cardiovascular disease; oxidative stress associated with LDL has been implicated in conditions such as endometriosis. By studying GO:0071404, researchers can identify molecular targets for therapeutic intervention and develop biomarkers for disease progression.
• Central to atherosclerosis: LDL-driven macrophage foam cell formation is a hallmark of plaque development.
• Links lipid metabolism to inflammation: LDL modulates neutrophil and macrophage inflammatory responses [2, 3, 5].
• Involves adaptive immunity: oxLDL-specific T cells are found in human atherosclerotic plaques.
• Key signaling nodes: NF-kappaB and IRAK-1 are inhibited by ozLDL, while EGFR-ERK is activated by GOLM1 [1, 7].
• Relevant to oxidative stress diseases: LDL oxidation is associated with endometriosis.
• Provides a framework for CRISPR screens to identify causal genes in LDL response.
• Enables development of targeted therapies for cardiovascular disease.
• Supports research on lipid-lowering drugs and their cellular effects.
• Facilitates cross-species comparison of LDL response mechanisms.
• Helps interpret genome-wide association study (GWAS) loci related to lipid metabolism.
What Happens During cellular response to low-density lipoprotein particle stimulus?
LDL Recognition and Binding
In simple terms: The cell first detects LDL particles, often through receptors or direct membrane interactions.
The cellular response to LDL begins with recognition of the particle at the cell surface. While classic LDL receptor (LDLR) binding is well known, GO:0071404 also encompasses non-receptor-mediated effects. For instance, apolipoprotein B on LDL mediates the suppression of neutrophil stimulation by particulates, indicating direct interaction with inflammatory cells. Similarly, LDL inhibits the physical interaction of phlogistic crystals with inflammatory cells, suggesting that LDL can interfere with cell-surface events. These early recognition steps set the stage for downstream signaling.
Transcriptional Reprogramming
In simple terms: The cell changes which genes are turned on or off in response to LDL.
Exposure to oxidized LDL alters the transcriptional response of macrophages to inflammatory stimuli, as shown by Mikita et al.. This indicates that LDL particles can prime or modulate gene expression programs, affecting cytokine production and other inflammatory mediators. The transcriptional changes are a core component of the cellular response, enabling long-term adaptation to the lipid environment.
Inflammatory Signaling Modulation
In simple terms: LDL can either promote or suppress inflammatory signals, depending on its form and context.
Ozonized LDL (ozLDL) inhibits NF-kappaB and IRAK-1-associated signaling, demonstrating that modified LDL can actively suppress pro-inflammatory pathways. In contrast, GOLM1 promotes atherogenesis by activating the macrophage EGFR-ERK signaling cascade in response to LDL. These opposing effects highlight the context-dependent nature of the cellular response to LDL and the importance of specific signaling nodes.
Adaptive Immune Activation
In simple terms: T cells can recognize oxidized LDL, linking the response to immune memory.
T lymphocytes from human atherosclerotic plaques recognize oxidized low-density lipoprotein, indicating that the cellular response to LDL includes adaptive immune activation. This recognition can drive T cell proliferation and cytokine secretion, contributing to plaque inflammation and progression. Thus, GO:0071404 extends beyond innate immune cells to include lymphocytes.
Foam Cell Formation and Atherogenesis
In simple terms: Macrophages engorged with LDL become foam cells, a key step in atherosclerosis.
SPA promotes atherosclerosis by mediating macrophage foam cell formation. This process involves the uptake of modified LDL and the accumulation of cholesterol esters, leading to the characteristic foam cell morphology. Foam cells secrete inflammatory mediators and contribute to plaque instability, making this a critical output of the cellular response to LDL.
Key Genes Involved in GO:0071404 cellular response to low-density lipoprotein particle stimulus
The following genes and proteins have been experimentally linked to the cellular response to low-density lipoprotein particle stimulus, based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| GOLM1 | Activates macrophage EGFR-ERK signaling cascade to promote atherogenesis | Potential therapeutic target for atherosclerosis; studied in macrophage foam cell formation |
| EGFR | Receptor tyrosine kinase activated by GOLM1 in response to LDL | Downstream effector of GOLM1; target for signaling inhibitors |
| ERK | Mitogen-activated protein kinase downstream of EGFR | Mediates pro-atherogenic signaling; readout of pathway activation |
| NF-kappaB | Transcription factor inhibited by ozonized LDL | Central regulator of inflammatory gene expression; modulated by LDL |
| IRAK-1 | Kinase associated with IL-1 receptor signaling, inhibited by ozLDL | Links LDL to innate immune signaling suppression |
| APOB | Apolipoprotein B, mediates LDL suppression of neutrophil stimulation | Structural component of LDL; directly involved in cell interaction |
| SPA | Promotes atherosclerosis through macrophage foam cell formation | Potential target to inhibit foam cell formation |
| LDLR | Classic LDL receptor, mediates uptake of LDL particles | Well-known but not directly cited in provided literature; included for context |
| T cell receptor (TCR) | Recognizes oxidized LDL in plaque T cells | Adaptive immune recognition of oxLDL |
| CD36 | Scavenger receptor for oxidized LDL | Commonly studied in foam cell formation; not directly cited in provided literature |
| SR-A | Scavenger receptor for modified LDL | Mediates macrophage uptake of oxLDL; not directly cited in provided literature |
| ABCA1 | Cholesterol efflux transporter | Counteracts foam cell formation; not directly cited in provided literature |
| ABCG1 | Cholesterol efflux transporter | Counteracts foam cell formation; not directly cited in provided literature |
| IL-1beta | Pro-inflammatory cytokine modulated by LDL | Inflammatory mediator in atherosclerosis; not directly cited in provided literature |
| TNF-alpha | Pro-inflammatory cytokine | Modulated by oxLDL in macrophages |
| MMP-9 | Matrix metalloproteinase | Associated with plaque instability; not directly cited in provided literature |
| MCP-1 | Monocyte chemoattractant protein | Recruits monocytes to plaques; not directly cited in provided literature |
| VCAM-1 | Adhesion molecule | Mediates leukocyte adhesion in atherosclerosis; not directly cited in provided literature |
How Is cellular response to low-density lipoprotein particle stimulus Regulated?
The cellular response to LDL is regulated at multiple levels. Ozonized LDL inhibits NF-kappaB and IRAK-1-associated signaling, providing a negative regulatory mechanism that can dampen inflammation. Conversely, GOLM1 activates the EGFR-ERK cascade, a positive regulatory axis that promotes atherogenesis. Transcriptional regulation is also key, as oxidized LDL alters the macrophage transcriptional response to inflammatory stimuli. These regulatory layers ensure that the cellular response to LDL is context-dependent and tightly controlled.
cellular response to low-density lipoprotein particle stimulus and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| GOLM1 | Atherosclerosis | Macrophage-specific knockout or overexpression in ApoE-/- mice |
| SPA | Atherosclerosis, foam cell formation | SPA knockout macrophages treated with oxLDL |
| NF-kappaB / IRAK-1 | Inflammation, atherosclerosis | OzLDL-treated macrophages with NF-kappaB reporter |
| TCR (oxLDL-specific) | Atherosclerosis, adaptive immunity | Human plaque T cell clones |
| APOB | Neutrophil suppression, inflammation | Apolipoprotein B knockout or knockdown in neutrophil assays |
Atherosclerosis and Cardiovascular Disease
Atherosclerosis is the most well-characterized disease linked to GO:0071404. GOLM1 promotes atherogenesis by activating macrophage EGFR-ERK signaling in response to LDL. SPA mediates macrophage foam cell formation, a critical step in plaque development. T cells from human atherosclerotic plaques recognize oxidized LDL, linking adaptive immunity to disease progression. These findings underscore the central role of the cellular response to LDL in cardiovascular pathology.
Inflammatory and Immune Disorders
LDL particles modulate inflammatory cell behavior. Apolipoprotein B mediates the capacity of LDL to suppress neutrophil stimulation by particulates, and LDL inhibits the physical interaction of phlogistic crystals with inflammatory cells. Oxidized LDL exposure alters the transcriptional response of macrophages to inflammatory stimuli. These effects suggest that dysregulated LDL responses may contribute to chronic inflammatory conditions beyond atherosclerosis.
Oxidative Stress-Related Conditions
Endometriosis has been described as a disease of oxidative stress, and LDL oxidation is a source of oxidative stress. While direct evidence linking GO:0071404 to endometriosis is limited, the broader context of oxidative stress and lipid peroxidation suggests a potential connection that warrants further investigation.
From cellular response to low-density lipoprotein particle stimulus-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does GOLM1 mediate LDL-induced EGFR-ERK activation? | GOLM1 knockout macrophages + LDL treatment |
| Does SPA promote foam cell formation? | SPA knockout macrophages + oxLDL |
| How does ozLDL inhibit NF-kappaB? | IRAK-1 knockout or point-mutant cells + ozLDL |
| Do T cells recognize oxLDL? | TCR knock-in or transgenic mice with oxLDL immunization |
| Does APOB mediate neutrophil suppression? | APOB knockout neutrophils + particulate stimulation |
| What transcriptional changes occur with oxLDL? | RNA-seq of macrophages treated with oxLDL |
How to Study the cellular response to low-density lipoprotein particle stimulus Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global transcriptional changes | Identify LDL-responsive genes |
| Western blot | Protein phosphorylation and expression | Measure EGFR-ERK or NF-kappaB activation [1, 7] |
| Oil Red O staining | Lipid accumulation in cells | Quantify foam cell formation |
| Neutrophil stimulation assay | Neutrophil activation by particulates | Test LDL-mediated suppression |
| T cell proliferation assay | Antigen-specific T cell response | Assess oxLDL recognition |
| Cholesterol efflux assay | Cholesterol removal from cells | Evaluate reverse cholesterol transport |
| ELISA | Cytokine secretion | Measure inflammatory mediators |
| Flow cytometry | Cell surface marker expression | Characterize immune cell phenotypes |
Transcriptomic Profiling
RNA-seq or microarray analysis of cells treated with LDL or oxidized LDL can reveal global transcriptional changes, as demonstrated by Mikita et al.. This method identifies genes and pathways that are differentially expressed in response to LDL, providing a comprehensive view of the cellular response.
Signaling Pathway Analysis
Western blotting and phospho-specific antibodies can measure activation of key nodes such as EGFR, ERK, NF-kappaB, and IRAK-1 [1, 7]. These methods are essential to confirm which signaling cascades are engaged by LDL in specific cell types.
Foam Cell Formation Assays
Oil Red O staining and cholesterol quantification can assess macrophage foam cell formation after oxLDL treatment. This phenotypic assay is a direct readout of a key output of GO:0071404.
Immune Cell Functional Assays
Neutrophil stimulation assays and T cell proliferation assays can measure the functional consequences of LDL exposure [3, 6]. These methods link the cellular response to immune cell behavior.
How CRISPR Can Be Used to Study GO:0071404 cellular response to low-density lipoprotein particle stimulus
Knockout
CRISPR knockout of candidate genes such as GOLM1, SPA, or APOB can determine their necessity in the cellular response to LDL. For example, GOLM1 knockout macrophages would test whether GOLM1 is required for EGFR-ERK activation and atherogenesis. SPA knockout can assess its role in foam cell formation.
Point Mutation
Introducing point mutations in signaling domains, such as the kinase domain of EGFR or the IRAK-1 kinase domain, can dissect specific phosphorylation events required for LDL response [1, 7]. This approach is useful to separate scaffolding functions from catalytic activity.
Knock-in
Knock-in of tagged versions of proteins (e.g., GFP-GOLM1) allows live-cell imaging and proteomic analysis of LDL-induced trafficking and interactions. Knock-in of disease-associated variants can model human genetic risk.
Overexpression
Overexpression of GOLM1 or SPA in macrophages or other cell types can test sufficiency for promoting foam cell formation or atherogenesis [1, 8]. This is particularly useful when endogenous expression is low.
How EDITGENE Supports cellular response to low-density lipoprotein particle stimulus Research
Researchers studying cellular response to low-density lipoprotein particle stimulus-related genes often need to determine whether a candidate gene is causally involved in LDL sensing, signaling, or downstream phenotypes such as foam cell formation. EDITGENE provides a comprehensive suite of CRISPR services to enable these investigations, from knockout to knock-in and library screening.
Contact EDITGENE today to design your custom CRISPR model for cellular response to low-density lipoprotein particle stimulus research.
Frequently Asked Questions About cellular response to low-density lipoprotein particle stimulus
What is GO:0071404?
GO:0071404 is the Gene Ontology term for cellular response to low-density lipoprotein particle stimulus, describing any cellular change in state or activity resulting from exposure to LDL particles.
What genes are involved in cellular response to low-density lipoprotein particle stimulus?
Key genes include GOLM1, EGFR, ERK, NF-kappaB, IRAK-1, APOB, SPA, and T cell receptors that recognize oxidized LDL [1, 3, 6, 7, 8].
How does LDL affect macrophages?
LDL, especially oxidized LDL, alters macrophage transcriptional programs and can promote foam cell formation, a hallmark of atherosclerosis [2, 8].
What is the role of GOLM1 in atherosclerosis?
GOLM1 promotes atherogenesis by activating the macrophage EGFR-ERK signaling cascade in response to LDL.
Does LDL suppress neutrophil function?
Yes, apolipoprotein B on LDL mediates suppression of neutrophil stimulation by particulates.
How is NF-kappaB involved in LDL response?
Ozonized LDL inhibits NF-kappaB and IRAK-1-associated signaling, suggesting a suppressive regulatory mechanism.
Can T cells recognize oxidized LDL?
Yes, T lymphocytes from human atherosclerotic plaques recognize oxidized LDL, linking adaptive immunity to the response.
What experimental models are used to study GO:0071404?
Common models include macrophage and neutrophil cell lines, primary cells, and mouse models with CRISPR knockouts or knock-ins of genes like GOLM1, SPA, and APOB [1, 3, 8].
What is the link between LDL and endometriosis?
Endometriosis has been described as a disease of oxidative stress, and LDL oxidation contributes to oxidative stress, suggesting a potential connection.
How can CRISPR help study the cellular response to LDL?
CRISPR knockout, knock-in, and overexpression models allow researchers to test the causal role of specific genes in LDL sensing, signaling, and downstream phenotypes like foam cell formation [1, 8].
Conclusion
GO:0071404, cellular response to low-density lipoprotein particle stimulus, is a critical biological process that connects lipid metabolism to inflammation, immunity, and cardiovascular disease. The verified literature highlights key signaling nodes such as GOLM1-EGFR-ERK, NF-kappaB, and IRAK-1, as well as the importance of foam cell formation and adaptive immune recognition of oxidized LDL. Understanding this process offers opportunities for therapeutic intervention in atherosclerosis and related disorders. EDITGENE provides the CRISPR tools and services needed to dissect the genetic basis of this response and accelerate discovery.
References
- 1. Gai X et al.. 2025. GOLM1 Promotes Atherogenesis by Activating Macrophage EGFR-ERK Signaling Cascade.. Circ Res 136(8):848-861 PMID: 40026146
- 2. Mikita T et al.. 2001. Oxidized low density lipoprotein exposure alters the transcriptional response of macrophages to inflammatory stimulus.. J Biol Chem 276(49):45729-39 PMID: 11577090
- 3. Terkeltaub R et al.. 1986. Apolipoprotein B mediates the capacity of low density lipoprotein to suppress neutrophil stimulation by particulates.. J Biol Chem 261(33):15662-7 PMID: 3096995
- 4. Murphy AA et al.. 1998. Endometriosis: a disease of oxidative stress?. Semin Reprod Endocrinol 16(4):263-73 PMID: 10101808
- 5. Terkeltaub R et al.. 1986. Low density lipoprotein inhibits the physical interaction of phlogistic crystals and inflammatory cells.. Arthritis Rheum 29(3):363-70 PMID: 3964313
- 6. Stemme S et al.. 1995. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein.. Proc Natl Acad Sci U S A 92(9):3893-7 PMID: 7732003
- 7. Cappello C et al.. 2007. Ozonized low density lipoprotein (ozLDL) inhibits NF-kappaB and IRAK-1-associated signaling.. Arterioscler Thromb Vasc Biol 27(1):226-32 PMID: 17053167
- 8. King SD et al.. 2024. SPA Promotes Atherosclerosis Through Mediating Macrophage Foam Cell Formation-Brief Report.. Arterioscler Thromb Vasc Biol 44(11):e277-e287 PMID: 39360411
