GO:0055096 low-density lipoprotein particle mediated signaling: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0055096 describes the molecular signaling events triggered when cells detect low-density lipoprotein (LDL) particles, a process central to vascular and metabolic biology.
• The canonical LDL receptor (LDLR) mediates uptake and initiates signaling that controls cholesterol homeostasis and can influence endothelial and macrophage behavior.
• Oxidized LDL (oxLDL) activates scavenger receptors and downstream pathways such as NLRP3 inflammasome/GSDMD, Nrf2, and PI3K/AKT, linking LDL signaling to inflammation and atherosclerosis.
• LDL can be transcytosed across arterial endothelium, a process that contributes to plaque formation and is a therapeutic target.
• Non-coding RNAs and receptor complexes, including miR-369-3p, LOXL1-AS1, and AT1-LOX1, modulate LDL-mediated signaling in diabetes-associated atherosclerosis and angiotensin II responses.
• Experimental models for studying this term include LDLR knockout, scavenger receptor knockouts, and CRISPR knock-in of signaling reporters to dissect causal mechanisms.
Description
Low-density lipoprotein particle mediated signaling (GO:0055096) is the series of molecular signals initiated by the detection of LDL particles by cellular receptors. This process is fundamental to lipid metabolism and vascular biology, as it couples lipoprotein recognition to intracellular signaling cascades that regulate cholesterol uptake, inflammation, and endothelial function. Dysregulation of LDL signaling is a hallmark of atherosclerosis and related cardiovascular diseases, making it a key area of biomedical research. Understanding the precise molecular players and signaling nodes is essential for developing targeted therapies. This article synthesizes current knowledge from authoritative QuickGO annotation and verified PubMed literature to provide a research-grade overview of GO:0055096, including its mechanisms, key genes, disease relevance, and experimental approaches.
low-density lipoprotein particle mediated signaling At A Glance
| GO ID | GO:0055096 |
|---|---|
| GO term | low-density lipoprotein particle mediated signaling |
| Ontology | biological_process |
| Synonym | low-density lipoprotein mediated signalling; low-density lipoprotein particle-mediated signaling; low-density lipoprotein particle mediated signal transduction |
| Major function | Detection of LDL particles and initiation of intracellular signaling cascades |
| Related receptors | LDLR, scavenger receptors (e.g., CD36, SR-A), LOX-1 |
| Key downstream pathways | NLRP3 inflammasome, Nrf2, PI3K/AKT, MAPK |
| Disease relevance | Atherosclerosis, cardiovascular disease, diabetes-associated vascular complications |
What Is GO:0055096?
GO:0055096, low-density lipoprotein particle mediated signaling, is defined as the series of molecular signals mediated by the detection of low-density lipoprotein particle. In other words, it encompasses the cellular events that occur after a cell senses an LDL particle, leading to signal transduction and downstream responses. This term is a biological process and includes synonyms such as low-density lipoprotein mediated signalling and low-density lipoprotein particle-mediated signaling.
Why Is low-density lipoprotein particle mediated signaling Important in Cell Biology?
LDL particle mediated signaling is critically important because it links lipid metabolism to cellular responses that drive atherosclerosis, the leading cause of cardiovascular disease. The signaling events triggered by LDL and its oxidized forms influence endothelial activation, macrophage foam cell formation, and smooth muscle cell proliferation, all of which contribute to plaque development. Moreover, this process is implicated in diabetes-associated vascular complications and is modulated by non-coding RNAs and receptor complexes, offering multiple entry points for therapeutic intervention. Studying GO:0055096 helps researchers understand how cells interpret lipoprotein cues and how to target these pathways in disease.
• Central to cholesterol homeostasis and feedback regulation of LDLR expression.
• Drives endothelial dysfunction and inflammation in atherosclerosis.
• Mediates oxLDL-induced pyroptosis via NLRP3/GSDMD in endothelial cells.
• Regulates lipophagy and lipid degradation through PARP1/PI3K/AKT signaling.
• Involved in angiogenesis and VEGF signaling in response to oxLDL.
• Modulated by microRNAs such as miR-369-3p and miR-590-5p.
• Interacts with angiotensin II signaling via AT1-LOX1 receptor complex.
• Provides targets for therapeutic intervention in cardiovascular disease.
• Relevant to diabetes-associated atherosclerosis and metabolic syndrome.
• Requires sophisticated models like CRISPR knockouts to dissect causal roles.
What Happens During low-density lipoprotein particle mediated signaling?
LDL Particle Recognition and Receptor Binding
In simple terms: First, the cell spots an LDL particle and grabs it with a receptor.
The process begins when LDL particles are detected by cell surface receptors, most notably the LDL receptor (LDLR). LDLR binds apolipoprotein B-100 on LDL, leading to internalization and initiation of signaling. Scavenger receptors such as CD36 and SR-A also recognize modified LDL, particularly oxidized LDL (oxLDL), and contribute to signaling in macrophages and endothelial cells. This recognition step is the trigger for downstream cascades.
Receptor Activation and Intracellular Signal Transduction
In simple terms: Once the receptor binds LDL, it sends a signal inside the cell.
Ligand binding induces receptor clustering and activation of intracellular signaling pathways. For example, oxLDL binding to scavenger receptors can activate NLRP3 inflammasome and GSDMD-mediated pyroptosis in endothelial cells, a process dependent on Nrf2 signaling. Additionally, LDL signaling can modulate PI3K/AKT pathways, as shown by geniposide restoring lipophagy via suppression of PARP1/PI3K/AKT. The AT1-LOX1 receptor complex potentiates angiotensin II-induced Gq activation, linking LDL to G-protein signaling.
Downstream Cellular Responses
In simple terms: The signal leads to changes in cell behavior, like inflammation or lipid processing.
Downstream responses include activation of transcription factors such as NF-kB and Nrf2, production of inflammatory cytokines, and modulation of autophagy/lysosomal pathways. In endothelial cells, oxLDL can induce angiogenesis via miR-590-5p-mediated KLF6/VEGF signaling. Macrophage succinate-GPR91 signaling is regulated by miR-369-3p, affecting diabetes-associated atherosclerosis. These responses collectively influence cell survival, proliferation, and function.
Transcytosis and Tissue-Level Effects
In simple terms: LDL can also be carried across cells, affecting the artery wall.
LDL transcytosis across arterial endothelium is a key process in atherogenesis, delivering LDL particles into the subendothelial space where they can be modified and trigger further signaling. This transcytosis is regulated by receptors such as ALK1 and scavenger receptors, and is considered a therapeutic target. The signaling events initiated by LDL at the endothelial surface can thus have profound effects on vascular wall biology.
Key Genes Involved in GO:0055096 low-density lipoprotein particle mediated signaling
The following genes and proteins are central to low-density lipoprotein particle mediated signaling, based on verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| LDLR | Binds and internalizes LDL, initiates signaling | Mutations cause familial hypercholesterolemia; key target for cholesterol-lowering therapies |
| CD36 | Scavenger receptor for oxLDL, mediates signaling | Involved in macrophage foam cell formation and inflammation |
| MSR1 (SR-A) | Scavenger receptor for modified LDL | Contributes to oxLDL uptake and signaling in macrophages |
| OLR1 (LOX-1) | Receptor for oxLDL, activates signaling | Mediates endothelial dysfunction and atherosclerosis |
| NLRP3 | Inflammasome sensor, activated by oxLDL | Drives pyroptosis and inflammation in endothelial cells |
| GSDMD | Executioner of pyroptosis | Mediates oxLDL-induced endothelial cell death |
| NFE2L2 (Nrf2) | Transcription factor, antioxidant response | Protects against oxLDL-induced pyroptosis |
| PARP1 | DNA repair enzyme, regulates autophagy | Suppresses lipophagy; target of geniposide |
| PIK3CA/PI3K | Kinase in PI3K/AKT pathway | Modulates lipophagy and survival signaling |
| AKT1 | Serine/threonine kinase | Downstream of PI3K, regulates metabolism and survival |
| KLF6 | Transcription factor | Mediates oxLDL-induced angiogenesis via VEGF |
| VEGFA | Angiogenic growth factor | Upregulated by oxLDL signaling in endothelium |
| MIR369-3p | MicroRNA | Regulates macrophage succinate-GPR91 signaling in diabetes-associated atherosclerosis |
| MIR590-5p | MicroRNA | Mediates LOXL1-AS1 effects on KLF6/VEGF signaling |
| LOXL1-AS1 | Long non-coding RNA | Inhibits oxLDL-induced angiogenesis via miR-590-5p |
| AGTR1 (AT1) | Angiotensin II receptor | Forms complex with LOX-1 to potentiate Gq signaling |
| GPR91 (SUCNR1) | Succinate receptor | Mediates macrophage signaling in atherosclerosis |
How Is low-density lipoprotein particle mediated signaling Regulated?
Low-density lipoprotein particle mediated signaling is regulated at multiple levels. Receptor availability is controlled by feedback mechanisms, such as sterol-regulated degradation of LDLR. Non-coding RNAs, including miR-369-3p and miR-590-5p, modulate key signaling nodes in macrophages and endothelial cells. The AT1-LOX1 receptor complex enhances angiotensin II-induced Gq activation, illustrating cross-talk with other signaling systems. Additionally, oxidative modifications of LDL generate oxLDL, which activates scavenger receptors and downstream pathways like NLRP3 inflammasome and Nrf2, providing redox-sensitive regulation. Pharmacological agents such as geniposide and pinocembrin can modulate these pathways, highlighting potential therapeutic regulation.
low-density lipoprotein particle mediated signaling and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| LDLR | Familial hypercholesterolemia, atherosclerosis | LDLR knockout mouse, CRISPR KO in HepG2 cells |
| NLRP3 | Atherosclerosis, inflammation | NLRP3 KO mice, endothelial cell KO |
| GSDMD | Pyroptosis in atherosclerosis | GSDMD KO mice, CRISPR KO in HUVECs |
| MIR369-3p | Diabetes-associated atherosclerosis | miR-369-3p mimic/inhibitor in macrophages, ApoE-/- mice |
| LOXL1-AS1 | Angiogenesis in atherosclerosis | LOXL1-AS1 knockdown in endothelial cells, zebrafish |
Atherosclerosis and Cardiovascular Disease
Dysregulated LDL signaling is a primary driver of atherosclerosis. OxLDL activates endothelial cells and macrophages, leading to inflammation, foam cell formation, and plaque development. Transcytosis of LDL across the endothelium delivers particles to the subendothelial space, initiating fatty streak formation. Key signaling pathways such as NLRP3 inflammasome/GSDMD and PI3K/AKT are implicated in plaque progression and instability. Targeting these pathways, for example with pinocembrin or geniposide, shows therapeutic promise in preclinical models.
Diabetes-Associated Vascular Complications
In diabetes, hyperglycemia and dyslipidemia exacerbate LDL signaling, contributing to accelerated atherosclerosis. miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signaling. This microRNA modulates inflammatory responses and lipid handling, suggesting that non-coding RNA-based interventions could be beneficial. Additionally, LOXL1-AS1 and miR-590-5p are involved in oxLDL-induced angiogenesis, a process relevant to diabetic vascular complications.
Hypertension and Angiotensin II Cross-Talk
Oxidized LDL potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex, linking lipid signaling to hypertension and vascular remodeling. This cross-talk amplifies vasoconstriction and inflammatory responses, contributing to cardiovascular pathology. Understanding this interaction may lead to dual-target therapies for patients with both dyslipidemia and hypertension.
From low-density lipoprotein particle mediated signaling-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does LDLR mediate specific signaling independent of uptake? | LDLR point-mutant knock-in mice or cells |
| What is the role of scavenger receptors in oxLDL signaling? | CD36 or MSR1 knockout macrophages |
| How does NLRP3 inflammasome activation by oxLDL affect endothelial function? | NLRP3 knockout endothelial cells, CRISPR KO |
| Can miR-369-3p regulate macrophage signaling in diabetes? | miR-369-3p transgenic or knockout mice |
| Does the AT1-LOX1 complex potentiate angiotensin II signaling? | LOX-1 knockout or AT1 mutant knock-in cells |
| Is PI3K/AKT pathway required for lipophagy restoration? | PI3K or AKT knockout cells, CRISPR KO |
How to Study the low-density lipoprotein particle mediated signaling Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression changes | Identify LDL-responsive genes and pathways |
| Small RNA-seq | MicroRNA expression | Discover miRNAs regulating LDL signaling |
| Phosphoproteomics | Phosphorylation events | Map kinase cascades downstream of LDLR |
| Confocal microscopy | LDL uptake and transcytosis | Visualize LDL trafficking in endothelium |
| CRISPR knockout screen | Gene essentiality for signaling | Identify novel regulators of LDL signaling |
| Western blot | Protein expression and activation | Validate signaling changes (e.g., NLRP3, AKT) |
| ELISA | Cytokine secretion | Measure inflammatory responses to oxLDL |
| Flow cytometry | Cell surface receptor levels | Quantify LDLR or scavenger receptor expression |
Transcriptomic and Non-coding RNA Profiling
RNA-seq and small RNA-seq can identify changes in gene expression and microRNAs following LDL stimulation. For example, miR-369-3p and miR-590-5p were discovered through such approaches in atherosclerosis models. These methods help map the regulatory network of LDL signaling.
Proteomic and Phosphoproteomic Analysis
Mass spectrometry-based proteomics can quantify phosphorylation events downstream of LDL receptor activation, revealing kinase cascades such as PI3K/AKT. This approach identifies signaling nodes and potential drug targets.
Imaging and Transcytosis Assays
Confocal microscopy and live-cell imaging can track LDL particle uptake and transcytosis across endothelial monolayers. Fluorescently labeled LDL allows visualization of trafficking and signaling events in real time.
CRISPR Screening and Functional Genomics
Genome-wide CRISPR knockout screens can identify genes required for LDL-mediated signaling, such as receptors and downstream effectors. This unbiased approach accelerates target discovery.
How CRISPR Can Be Used to Study GO:0055096 low-density lipoprotein particle mediated signaling
Knockout
CRISPR knockout of LDLR, CD36, NLRP3, or other genes allows researchers to test their requirement in LDL-mediated signaling. For example, NLRP3 knockout endothelial cells show reduced oxLDL-induced pyroptosis. Knockout models are essential for establishing causality.
Point Mutation
Introducing point mutations in signaling domains, such as LDLR internalization motifs or kinase active sites, can dissect specific functions. For instance, mutating the NPXY motif in LDLR abolishes signaling while preserving binding. This precision helps separate uptake from signaling.
Knock-in
Knock-in of fluorescent reporters or epitope tags into endogenous loci (e.g., NLRP3-GFP) enables real-time tracking of protein localization and activation during LDL signaling. Tagged knock-in models are valuable for imaging and proteomics.
Overexpression
Overexpression of wild-type or mutant forms of key genes (e.g., constitutively active AKT) can amplify signaling and reveal downstream effects. This approach is useful for gain-of-function studies and drug screening.
How EDITGENE Supports low-density lipoprotein particle mediated signaling Research
Researchers studying low-density lipoprotein particle mediated signaling-related genes often need to determine whether a candidate gene is causally involved in the pathway or merely correlated. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such functional studies, from knockout to precise point mutations, ensuring rigorous mechanistic insights.
Contact EDITGENE today to design your custom CRISPR model for low-density lipoprotein particle mediated signaling research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| CD36 Knockout HEK293 Cell Line | EDJ-KQ1885 | Human | 948 | Details Get a Quote |
| APP Knockout HEK293 Cell Line | EDC09598 | Human | 351 | Details Get a Quote |
| CDH13 Knockout HEK293 Cell Line | EDJ-KQ4242 | Human | 1012 | Details Get a Quote |
| LPL Knockout HEK293 Cell Line | EDJ-KQ5140 | Human | 4023 | Details Get a Quote |
| LPL Knockout HeLa Cell Line | EDJ-KQ28102 | Human | 4023 | Details Get a Quote |
| APP Knockout A-549 Cell Line | EDJ-KQ25351 | Human | 351 | Details Get a Quote |
| APP Knockout HCT 116 Cell Line | EDJ-KQ25352 | Human | 351 | Details Get a Quote |
| APP Knockout HeLa Cell Line | EDJ-KQ25353 | Human | 351 | Details Get a Quote |
| CDH13 Knockout HeLa Cell Line | EDJ-KQ26713 | Human | 1012 | Details Get a Quote |
| CD36 Knockout HeLa Cell Line | EDJ-KQ52836 | Human | 948 | Details Get a Quote |
| CD36 Knockout A-549 Cell Line | EDJ-KQ61306 | Human | 948 | Details Get a Quote |
| CDH13 Knockout A-549 Cell Line | EDJ-KQ61326 | Human | 1012 | Details Get a Quote |
| LPL Knockout A-549 Cell Line | EDJ-KQ62283 | Human | 4023 | Details Get a Quote |
| CD36 Knockout HCT 116 Cell Line | EDJ-KQ69800 | Human | 948 | Details Get a Quote |
| CDH13 Knockout HCT 116 Cell Line | EDJ-KQ69824 | Human | 1012 | Details Get a Quote |
Frequently Asked Questions About low-density lipoprotein particle mediated signaling
What is low-density lipoprotein particle mediated signaling?
It is the series of molecular signals triggered when cells detect LDL particles, as defined by GO:0055096. This process involves receptor binding and downstream cascades that regulate lipid metabolism and inflammation.
What genes are involved in low-density lipoprotein particle mediated signaling?
Key genes include LDLR, CD36, MSR1, OLR1, NLRP3, GSDMD, NFE2L2, PARP1, PIK3CA, AKT1, KLF6, VEGFA, MIR369-3p, MIR590-5p, LOXL1-AS1, AGTR1, and GPR91.
How does oxidized LDL affect endothelial cells?
Oxidized LDL activates scavenger receptors and can trigger NLRP3 inflammasome/GSDMD-mediated pyroptosis, as well as Nrf2-dependent antioxidant responses.
What is the role of LDLR in signaling?
LDLR binds and internalizes LDL, initiating signaling that controls cholesterol homeostasis. Mutations in LDLR cause familial hypercholesterolemia.
Can CRISPR be used to study LDL signaling?
Yes, CRISPR knockout, knock-in, and point mutation models are powerful tools to dissect gene function in LDL signaling pathways.
What diseases are associated with dysregulated LDL signaling?
Atherosclerosis, cardiovascular disease, diabetes-associated vascular complications, and hypertension are linked to aberrant LDL signaling.
How is LDL transcytosis related to atherosclerosis?
LDL transcytosis across arterial endothelium delivers LDL to the subendothelial space, where it can be modified and initiate plaque formation.
What microRNAs regulate LDL signaling?
miR-369-3p and miR-590-5p are examples that modulate macrophage and endothelial signaling in atherosclerosis.
What experimental models are used to study LDL signaling?
Common models include LDLR knockout mice, scavenger receptor knockouts, and CRISPR-engineered cell lines.
How can EDITGENE help with LDL signaling research?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression, library screening, and bioinformatics services to study genes involved in LDL signaling.
Conclusion
Low-density lipoprotein particle mediated signaling (GO:0055096) is a critical biological process that links lipid detection to cellular responses underlying cardiovascular disease. The pathway involves a complex network of receptors, kinases, and non-coding RNAs, with significant implications for atherosclerosis, diabetes, and hypertension. Continued research using advanced CRISPR models and multi-omics approaches will further elucidate its mechanisms and identify new therapeutic targets.
References
- 1. Goldstein JL et al.. 2009. The LDL receptor.. Arterioscler Thromb Vasc Biol 29(4):431-8 PMID: 19299327
- 2. Bolanle IO et al.. 2025. Transcytosis of LDL Across Arterial Endothelium: Mechanisms and Therapeutic Targets.. Arterioscler Thromb Vasc Biol 45(4):468-480 PMID: 40013359
- 3. Rawal S et al.. 2024. miR-369-3p ameliorates diabetes-associated atherosclerosis by regulating macrophage succinate-GPR91 signalling.. Cardiovasc Res 120(14):1693-1712 PMID: 38703377
- 4. Wang T et al.. 2022. Pinocembrin suppresses oxidized low-density lipoprotein-triggered NLRP3 inflammasome/GSDMD-mediated endothelial cell pyroptosis through an Nrf2-dependent signaling pathway.. Sci Rep 12(1):13885 PMID: 35974041
- 5. Lin J et al.. 2024. Geniposide ameliorates atherosclerosis by restoring lipophagy via suppressing PARP1/PI3K/AKT signaling pathway.. Phytomedicine 129:155617 PMID: 38614041
- 6. Adachi H et al.. 2006. Endothelial scavenger receptors.. Prog Lipid Res 45(5):379-404 PMID: 16712941
- 7. Cheng X et al.. 2021. Inhibition of LOXL1-AS1 alleviates oxidative low-density lipoprotein induced angiogenesis via downregulation of miR-590-5p mediated KLF6/VEGF signaling pathway.. Cell Cycle 20(17):1663-1680 PMID: 34334119
- 8. Ihara J et al.. 2025. Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex.. Elife 13 PMID: 40131218
