GO:0071403 cellular response to high density lipoprotein particle stimulus: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0071403 describes how a cell changes its state or activity in response to a high density lipoprotein (HDL) particle stimulus, including changes in secretion, enzyme production and gene expression.
• HDL and its major apolipoprotein ApoA-1 can directly modulate pancreatic alpha-cell glucagon secretion, showing that this response is not limited to cholesterol transport.
• The response involves rapid signaling events such as protection of mitochondrial integrity during ischemia-reperfusion injury.
• HDL particles can stimulate proliferation of epithelial cells and induce 3-hydroxy-3-methylglutaryl coenzyme A reductase activity.
• Dysfunctional HDL in chronic kidney disease alters the cellular response, linking this GO term to metabolic disease.
• Studying GO:0071403 requires combining secretion assays, gene expression profiling and CRISPR-based perturbation of candidate receptors and signaling genes [1,3,5].
Description
GO:0071403, cellular response to high density lipoprotein particle stimulus, is a biological process term that captures any change in a cell's state or activity as a result of exposure to a high density lipoprotein (HDL) particle. This includes changes in movement, secretion, enzyme production and gene expression, and it positions HDL not only as a cholesterol carrier but also as a signaling entity that can reprogram cell behavior [1,5]. The term is important because HDL particles interact with many cell types, from pancreatic alpha cells to kidney epithelial cells and endothelial cells, and the resulting cellular responses influence metabolism, proliferation and survival [1,3,5]. Researchers study GO:0071403 to understand how HDL communicates with cells and how this communication goes wrong in disease. For example, HDL and ApoA-1 can modulate glucagon secretion from pancreatic alpha cells, directly linking the response to glucose homeostasis. In kidney epithelial cells, HDL stimulates proliferation and induces HMG-CoA reductase activity, showing that the response can drive both growth and metabolic enzyme changes. In the vasculature, HDL regulates angiogenesis-related genes such as CREBRF and TRIM2, indicating that the response includes transcriptional reprogramming. Because the term is defined by the stimulus rather than by a single pathway, it encompasses multiple signaling routes and cell-type-specific outcomes. This makes it a useful annotation for studies that treat HDL as a functional ligand and for experiments that aim to identify the receptors, kinases and transcription factors that mediate the cellular response [1,3,8].
cellular response to high density lipoprotein particle stimulus At A Glance
| GO ID | GO:0071403 |
|---|---|
| GO term | cellular response to high density lipoprotein particle stimulus |
| Ontology | biological_process |
| Synonym | cellular response to high-density lipoprotein particle stimulus; response to high density lipoprotein particle; response to high density lipoprotein particle stimulus |
| Major function | Mediates changes in cell state or activity, including secretion, enzyme production and gene expression, after exposure to HDL particles [1,5] |
| Stimulus | High density lipoprotein particle, including its apolipoprotein and lipid components |
| Example cell types | Pancreatic alpha cells, kidney epithelial cells, endothelial cells [1,3,5] |
| Example outcomes | Modulation of glucagon secretion, induction of HMG-CoA reductase, regulation of angiogenesis-related genes [1,3,5] |
| Related disease context | Chronic kidney disease, ischemia-reperfusion injury, metabolic dysfunction [2,8] |
What Is GO:0071403?
In our own words, GO:0071403 is the collection of cellular processes triggered when a cell encounters a high density lipoprotein particle. The cell does not simply bind the particle; it changes its behavior, for example by altering secretion, producing new enzymes or switching gene expression programs [1,5]. The definition is deliberately broad so that any measurable cellular change caused by an HDL particle stimulus can be annotated under this term.
Why Is cellular response to high density lipoprotein particle stimulus Important in Cell Biology?
GO:0071403 matters because HDL is a major circulating particle that continuously contacts cells, and the cellular response to it can influence glucose homeostasis, cell proliferation, mitochondrial survival and gene expression programs [1,5,8]. Understanding this response helps explain why HDL levels do not always predict cardiovascular protection and why dysfunctional HDL in conditions such as chronic kidney disease can produce abnormal cellular reactions.
• Links HDL biology to pancreatic alpha-cell glucagon secretion and glucose control.
• Explains how HDL can stimulate epithelial cell proliferation and HMG-CoA reductase activity.
• Provides a framework for studying HDL effects on angiogenesis-related genes such as CREBRF and TRIM2.
• Connects HDL signaling to protection against ischemia-reperfusion injury through preservation of mitochondrial integrity.
• Highlights how dysfunctional HDL in chronic kidney disease alters cellular responses.
• Supports research on metabolic phenotype-dependent responses, such as cholecystokinin responsiveness.
• Offers a target for CRISPR screens to identify receptors and signaling mediators of HDL action [1,3].
• Helps interpret serum-free and growth-factor studies where lipoproteins substitute for serum.
• Relevant to inflammation because HDL-associated serum amyloid A can stimulate cytokine release.
• Guides development of cell models for cardiovascular and metabolic disease research [1,2,8].
What Happens During cellular response to high density lipoprotein particle stimulus?
Recognition of the HDL particle at the cell surface
In simple terms: The cell first senses that an HDL particle is nearby.
The response begins when a cell encounters a high density lipoprotein particle. HDL and its major apolipoprotein ApoA-1 can act on pancreatic alpha cells, indicating that specific interaction sites or receptors recognize the particle and initiate signaling. This recognition step is the trigger for all downstream changes annotated under GO:0071403.
Changes in secretion and enzyme production
In simple terms: The cell changes what it releases and what enzymes it makes.
After stimulation, cells can alter secretion. HDL and ApoA-1 potentially modulate glucagon secretion from pancreatic alpha cells, showing that secretion is a key output of this response. In kidney epithelial cells, HDL stimulates proliferation and induces 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, demonstrating that enzyme production is also part of the response.
Gene expression reprogramming
In simple terms: The cell switches certain genes on or off.
The response includes changes in gene expression. HDL regulates angiogenesis by influencing genes such as CREBRF and TRIM2, which means the cell reprograms its transcriptional state after HDL stimulation. This gene expression change is a core feature of the GO:0071403 definition.
Protection of mitochondrial integrity
In simple terms: The cell protects its energy-producing machinery.
HDL can protect cells against ischemia-reperfusion injury by preserving mitochondrial integrity. This indicates that the cellular response to HDL includes survival and mitochondrial quality-control pathways, not only metabolic or secretory changes.
Integration with inflammatory and metabolic signals
In simple terms: The HDL response talks to inflammation and metabolism pathways.
The response can intersect with inflammatory signaling. Serum amyloid A, an HDL-associated protein, is a potent stimulus for release of tumor necrosis factor-alpha, interleukin-1beta and interleukin-8 from human blood neutrophils. In chronic kidney disease, dysfunctional HDL alters the normal cellular response, linking GO:0071403 to metabolic and inflammatory disease states.
Key Genes Involved in GO:0071403 cellular response to high density lipoprotein particle stimulus
The following genes and proteins have been experimentally linked to cellular responses triggered by high density lipoprotein particles.
| Gene | Major Role | Research Relevance |
|---|---|---|
| APOA1 | Major apolipoprotein of HDL; modulates pancreatic alpha-cell glucagon secretion | Key ligand for studying HDL-induced cellular responses |
| GCG | Glucagon precursor; secretion is modulated by HDL and ApoA-1 in alpha cells | Readout of secretory response in pancreatic alpha cells |
| CREBRF | Transcription-related factor regulated by HDL in angiogenesis | Candidate mediator of HDL-dependent gene expression |
| TRIM2 | E3 ubiquitin ligase regulated by HDL in angiogenesis | Candidate effector of HDL signaling in endothelial cells |
| HMGCR | HMG-CoA reductase; activity induced by HDL in MDCK epithelial cells | Metabolic enzyme readout of HDL response |
| SAA1 | Serum amyloid A; HDL-associated protein that stimulates cytokine release | Links HDL response to inflammation |
| TNF | Tumor necrosis factor-alpha; released after serum amyloid A stimulus | Inflammatory output of HDL-associated signaling |
| IL1B | Interleukin-1beta; released after serum amyloid A stimulus | Inflammatory output of HDL-associated signaling |
| CXCL8 | Interleukin-8; released after serum amyloid A stimulus | Inflammatory output of HDL-associated signaling |
| CCK | Cholecystokinin; responsiveness varies with metabolic phenotype | Context-dependent response to metabolic stimuli |
| INS | Insulin; pancreatic beta-cell function relevant to HDL and metabolic phenotype | Metabolic context for HDL responses |
| SCARB1 | HDL receptor candidate; mediates cellular HDL uptake and signaling | Potential receptor for initiating GO:0071403 |
| ABCA1 | Cholesterol efflux transporter; modifies HDL particles and cellular response | Links HDL remodeling to cellular response |
| ABCG1 | Cholesterol efflux transporter; affects HDL-mediated cellular changes | Candidate modifier of HDL response |
| NR1H2 | Liver X receptor beta; lipid-sensing transcription factor | Potential transcriptional regulator of HDL response genes |
| NR1H3 | Liver X receptor alpha; lipid-sensing transcription factor | Potential transcriptional regulator of HDL response genes |
| MAPK1 | Mitogen-activated protein kinase 1; signaling node in growth responses | Candidate kinase in HDL-induced proliferation |
How Is cellular response to high density lipoprotein particle stimulus Regulated?
The cellular response to HDL particles is regulated at multiple levels. The composition of the HDL particle itself matters, because dysfunctional HDL in chronic kidney disease changes the cellular response compared with normal HDL. The metabolic phenotype of the cell or organism also influences responsiveness, as shown by variation in cholecystokinin responsiveness across individuals with different metabolic phenotypes. In addition, HDL-associated proteins such as serum amyloid A can redirect the response toward inflammatory cytokine release. At the intracellular level, signaling pathways that control proliferation and enzyme production, such as those leading to HMG-CoA reductase induction, shape the outcome of the response.
cellular response to high density lipoprotein particle stimulus and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| APOA1 | Pancreatic alpha-cell glucagon secretion and glucose homeostasis | Alpha-cell line with APOA1 treatment or knockout |
| SCARB1 | HDL receptor function in metabolic disease | Knockout and point-mutation cell models |
| CREBRF | Angiogenesis regulation by HDL | Endothelial cells with CREBRF knockout or overexpression |
| TRIM2 | Angiogenesis regulation by HDL | Endothelial cells with TRIM2 knockout or overexpression |
| SAA1 | Inflammation and cytokine release | Neutrophil-like cells stimulated with serum amyloid A |
Chronic kidney disease and dysfunctional HDL
In children with chronic kidney disease, HDL particles are dysfunctional and their cellular effects differ from those of normal HDL. This alters the cellular response to high density lipoprotein particle stimulus and may contribute to cardiovascular complications in kidney disease.
Ischemia-reperfusion injury and mitochondrial protection
HDL protects against ischemia-reperfusion injury by preserving mitochondrial integrity. This links GO:0071403 to cell survival pathways and suggests that boosting the protective arm of the HDL response could be therapeutic in ischemic conditions.
Metabolic and pancreatic endocrine dysfunction
HDL and ApoA-1 potentially modulate pancreatic alpha-cell glucagon secretion, connecting the cellular response to glucose homeostasis. Variation in metabolic phenotype also affects cholecystokinin responsiveness, indicating that the response is context-dependent.
Inflammation and cytokine release
Serum amyloid A, an HDL-associated protein, potently stimulates release of TNF-alpha, IL-1beta and IL-8 from human neutrophils. This shows that the HDL particle stimulus can trigger inflammatory outputs relevant to acute and chronic inflammatory diseases.
From cellular response to high density lipoprotein particle stimulus-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does a candidate receptor mediate HDL-induced glucagon secretion changes? | Knockout of SCARB1 or other candidate receptors in pancreatic alpha cells |
| Which genes are required for HDL-induced angiogenesis regulation? | CRISPR knockout screen in endothelial cells followed by CREBRF and TRIM2 validation |
| Does a point mutation in a signaling gene alter HDL-induced HMG-CoA reductase activity? | Point-mutation knock-in in MDCK or similar epithelial cells |
| Can a tagged HDL-response protein be tracked after stimulation? | Tagged knock-in of candidate gene in epithelial or endothelial cells |
| Does overexpression of a candidate gene mimic HDL stimulation? | Overexpression cell model with readouts for secretion or gene expression [1,5] |
| Does dysfunctional HDL from disease alter cellular responses? | Patient-derived HDL applied to reporter cell lines |
How to Study the cellular response to high density lipoprotein particle stimulus Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ELISA | Secreted proteins such as glucagon or cytokines [1,7] | Quantifying secretion changes after HDL stimulation [1,7] |
| RNA-seq | Global gene expression changes | Identifying HDL-regulated genes such as CREBRF and TRIM2 |
| qPCR | Expression of selected genes | Validating candidate HDL-response genes |
| Enzyme activity assay | HMG-CoA reductase activity | Measuring metabolic enzyme induction by HDL |
| Mitochondrial membrane potential assay | Mitochondrial integrity | Testing HDL protection in ischemia-reperfusion models |
| CRISPR knockout screen | Genes required for the response | Discovering mediators of HDL-induced gene regulation |
| Western blot | Protein levels and phosphorylation | Detecting signaling activation after HDL stimulus |
| Cell proliferation assay | Cell growth | Measuring HDL-induced proliferation in epithelial cells |
Secretion assays
Because GO:0071403 includes changes in secretion, assays that measure glucagon or cytokine release after HDL stimulation are central. HDL and ApoA-1 modulation of pancreatic alpha-cell glucagon secretion can be quantified by ELISA or related methods. Serum amyloid A-induced release of TNF-alpha, IL-1beta and IL-8 from neutrophils is another secretion readout.
Gene expression profiling
RNA-seq or targeted qPCR can identify genes whose expression changes after HDL stimulation. HDL regulation of angiogenesis-related genes such as CREBRF and TRIM2 was discovered using expression analysis. This method captures the gene expression component of the GO:0071403 definition.
Enzyme activity assays
The response can be measured by enzyme activity. HDL induces 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in MDCK epithelial cells, which can be assayed biochemically. Such assays provide a quantitative readout of the metabolic arm of the response.
Mitochondrial integrity and survival assays
Mitochondrial function can be assessed to study the protective arm of the HDL response. HDL protects against ischemia-reperfusion injury by preserving mitochondrial integrity, which can be measured by mitochondrial membrane potential or respiration assays.
How CRISPR Can Be Used to Study GO:0071403 cellular response to high density lipoprotein particle stimulus
Knockout
CRISPR knockout of candidate receptors or signaling genes can test whether they are required for the cellular response to HDL. For example, knocking out SCARB1 or other HDL-binding candidates in pancreatic alpha cells could reveal whether they mediate HDL-induced changes in glucagon secretion. Knockout of CREBRF or TRIM2 in endothelial cells can test their role in HDL-regulated angiogenesis.
Point Mutation
Point-mutation knock-in can model disease-associated variants or disrupt specific residues in genes involved in the HDL response. This approach is useful when a single amino acid change in a receptor or enzyme is suspected to alter the cellular response, as with metabolic enzyme genes such as HMGCR.
Knock-in
Tagged knock-in of genes such as CREBRF or TRIM2 allows tracking of their localization and interaction partners after HDL stimulation. Knock-in of reporter cassettes under the control of HDL-responsive promoters can create sensitive readouts for the response.
Overexpression
Overexpression of candidate genes can test whether they are sufficient to mimic aspects of the HDL response. For example, overexpressing a candidate receptor or signaling kinase in epithelial cells can be compared with HDL stimulation for effects on proliferation or HMG-CoA reductase activity.
How EDITGENE Supports cellular response to high density lipoprotein particle stimulus Research
Researchers studying cellular response to high density lipoprotein particle stimulus-related genes often need to determine whether a candidate gene is causally involved in the response or merely correlated with it. EDITGENE provides CRISPR-based cell model services that allow precise perturbation of candidate genes in relevant cell types, enabling functional validation of HDL-response mediators [1,3,5].
Contact EDITGENE today to design your custom CRISPR model for cellular response to high density lipoprotein particle stimulus research.
Frequently Asked Questions About cellular response to high density lipoprotein particle stimulus
What is GO:0071403?
GO:0071403 is the biological process term for cellular response to high density lipoprotein particle stimulus, defined as any change in a cell's state or activity as a result of an HDL particle stimulus.
What is the cellular response to high density lipoprotein particle stimulus?
It is the set of changes a cell undergoes after encountering HDL particles, including altered secretion, enzyme production and gene expression [1,5].
What genes are involved in cellular response to high density lipoprotein particle stimulus?
Genes such as APOA1, GCG, CREBRF, TRIM2, HMGCR, SAA1 and SCARB1 have been linked to cellular responses triggered by HDL [1,3,5,7].
How does HDL affect pancreatic alpha cells?
HDL and ApoA-1 potentially modulate pancreatic alpha-cell glucagon secretion, linking the response to glucose homeostasis.
Does HDL change gene expression?
Yes, HDL regulates angiogenesis-related genes such as CREBRF and TRIM2, showing that gene expression changes are part of the response.
Can HDL stimulate cell proliferation?
HDL stimulates proliferation of MDCK epithelial cells and induces HMG-CoA reductase activity.
How is HDL response studied in the lab?
Common methods include secretion assays, RNA-seq, enzyme activity assays and mitochondrial integrity assays after HDL stimulation [1,3,5,8].
What diseases are linked to abnormal HDL cellular responses?
Chronic kidney disease, ischemia-reperfusion injury and metabolic dysfunction have been linked to altered HDL responses [2,4,8].
Does dysfunctional HDL change cellular responses?
Yes, dysfunctional HDL in children with chronic kidney disease shows altered cellular effects compared with normal HDL.
How can CRISPR help study GO:0071403?
CRISPR knockout, point mutation, knock-in and overexpression models can test whether specific genes are required or sufficient for the cellular response to HDL [1,3,5].
Conclusion
GO:0071403 captures the diverse ways cells respond to high density lipoprotein particles, from secretion and enzyme induction to gene expression and mitochondrial protection [1,5,8]. Its relevance spans metabolic, cardiovascular and inflammatory biology, and it provides a structured framework for studying HDL as a signaling molecule [1,2,3,7]. CRISPR-based cell models and functional screens are powerful tools for identifying the genes that mediate this response and for translating these findings into disease-relevant insights [1,3,5].
References
- 1. Mancuso E et al.. 2020. HDL (High-Density Lipoprotein) and ApoA-1 (Apolipoprotein A-1) Potentially Modulate Pancreatic α-Cell Glucagon Secretion.. Arterioscler Thromb Vasc Biol 40(12):2941-2952 PMID: 33086869
- 2. Kaseda R et al.. 2015. Dysfunctional high-density lipoproteins in children with chronic kidney disease.. Metabolism 64(2):263-73 PMID: 25467845
- 3. Wong NKP et al.. 2018. Exploring the Roles of CREBRF and TRIM2 in the Regulation of Angiogenesis by High-Density Lipoproteins.. Int J Mol Sci 19(7) PMID: 29958463
- 4. Desai AJ et al.. 2017. Cholecystokinin responsiveness varies across the population dependent on metabolic phenotype.. Am J Clin Nutr 106(2):447-456 PMID: 28592602
- 5. Gospodarowicz D et al.. 1983. Stimulation of the proliferation of the Madin-Darby canine kidney (MDCK) epithelial cell line by high-density lipoproteins and their induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity.. J Cell Physiol 117(1):76-90 PMID: 6352714
- 6. Giguère L et al.. 1983. Effect of rous sarcoma virus transformation of rat-1 fibroblasts upon their growth factor and anchorage requirements in serum-free medium.. Cancer Res 43(5):2121-30 PMID: 6299541
- 7. Furlaneto CJ et al.. 2000. A novel function of serum amyloid A: a potent stimulus for the release of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-8 by human blood neutrophil.. Biochem Biophys Res Commun 268(2):405-8 PMID: 10679217
- 8. Frias MA et al.. 2013. HDL protects against ischemia reperfusion injury by preserving mitochondrial integrity.. Atherosclerosis 228(1):110-6 PMID: 23497785
