GO:0140212 regulation of long-chain fatty acid import into cell: Transport Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0140212 describes any process that modulates the frequency, rate or extent of long-chain fatty acid import into a cell, placing it upstream of fatty acid activation and oxidation.
• Long-chain fatty acids (typically C14-C20) require protein-mediated transport and activation to acyl-CoA before they can be oxidized or esterified.
• Key molecular players include CD36, the SLC27A fatty acid transport protein family, ACSL acyl-CoA synthetases, and intracellular carriers such as FABPs.
• Dysregulation of long-chain fatty acid import is linked to hepatocellular carcinoma, leukemia, peroxisomal disorders, and adrenal hypoplasia syndromes.
• Mitochondrial and peroxisomal beta-oxidation downstream of import controls oxylipin metabolism and inflammatory signaling.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to dissect causal roles of import regulators in disease.
Description
Long-chain fatty acids are essential substrates for energy production, membrane biosynthesis, and lipid signaling, but their hydrophobic nature prevents free diffusion across biological membranes at rates sufficient to meet cellular demand. Consequently, cells rely on dedicated protein machinery to import long-chain fatty acids, and the activity of this machinery is itself subject to regulation. GO:0140212, regulation of long-chain fatty acid import into cell, captures the biological processes that modulate the frequency, rate, or extent of this import step. Understanding this term is critical because the import of long-chain fatty acids sits at the interface between nutrient availability and cellular metabolism, influencing pathways as diverse as mitochondrial beta-oxidation, peroxisomal very long-chain fatty acid oxidation, and lipid mediator synthesis. Research into GO:0140212 has revealed that import is not a passive process but is controlled by transport proteins, acyl-CoA synthetases, and intracellular binding proteins that together determine how much fatty acid enters a cell and how it is subsequently partitioned. For example, SLC27A5 deficiency reduces long-chain fatty acid uptake and creates a pro-tumorigenic metabolic adaptation in hepatocellular carcinoma, demonstrating that import regulation can directly shape disease phenotypes. Similarly, peroxisomal dysregulation of very long-chain fatty acid oxidation affects intestinal stem cell differentiation during aging, highlighting the broader physiological reach of fatty acid import and oxidation control. For researchers, GO:0140212 provides a structured framework to annotate genes and pathways that regulate fatty acid entry, enabling comparative analyses across cell types and disease states. Because import regulation intersects with mitochondrial function, peroxisomal metabolism, and inflammatory signaling, it is a fertile area for CRISPR-based functional genomics and for developing therapeutic strategies that target lipid metabolic vulnerabilities.
regulation of long-chain fatty acid import into cell At A Glance
| GO ID | GO:0140212 |
|---|---|
| GO term | regulation of long-chain fatty acid import into cell |
| Ontology | biological_process |
| Synonym | none |
| Major function | Modulates the frequency, rate or extent of long-chain fatty acid import into a cell |
| Definition source | QuickGO |
| Related processes | Long-chain fatty acid import, fatty acid activation, mitochondrial and peroxisomal beta-oxidation |
| Key molecular players | CD36, SLC27A family, ACSL family, FABPs |
| Disease relevance | Hepatocellular carcinoma, leukemia, peroxisomal disorders, adrenal hypoplasia |
What Is GO:0140212?
GO:0140212, regulation of long-chain fatty acid import into cell, is defined as any process that modulates the frequency, rate, or extent of long-chain fatty acid import into a cell. In practical terms, it encompasses the molecular events that control how much long-chain fatty acid crosses the plasma membrane and enters the intracellular space, including the activity of transport proteins, the availability of cofactors such as CoA, and the downstream trapping of fatty acids as acyl-CoA derivatives. This term is a biological process annotation and does not itself describe the import reaction, but rather the regulatory inputs that set the rate of import.
Why Is regulation of long-chain fatty acid import into cell Important in Cell Biology?
GO:0140212 is important because the regulated import of long-chain fatty acids determines the substrate supply for beta-oxidation, membrane lipid synthesis, and lipid signaling, and its dysregulation is increasingly recognized as a driver of metabolic disease and cancer. By annotating the regulatory processes that control import, this GO term enables researchers to systematically identify genes and pathways that set cellular fatty acid flux, which is essential for understanding metabolic reprogramming in tumors and for developing targeted therapies.
• Controls substrate availability for mitochondrial beta-oxidation and energy production.
• Regulates peroxisomal very long-chain fatty acid oxidation and intestinal stem cell differentiation.
• Influences oxylipin metabolism and inflammatory responses during bacterial infection.
• SLC27A5 deficiency reduces long-chain fatty acid uptake and promotes hepatocellular carcinoma.
• Targeting ABCD1 to inhibit peroxisomal fatty acid oxidation selectively eliminates acute myeloid leukemia cells.
• Provides a framework for annotating genes involved in fatty acid transport and activation.
• Links nutrient sensing to membrane lipid composition and signaling.
• Supports CRISPR-based functional genomics of metabolic vulnerabilities.
• Relevant to adrenal hypoplasia syndromes and other lipid-related disorders.
• Enables comparative studies of fatty acid import across cell types and disease states.
What Happens During regulation of long-chain fatty acid import into cell?
Transport across the plasma membrane
In simple terms: Fatty acids need help to get into cells because they are oily and cannot easily cross the watery membrane on their own.
Long-chain fatty acids are hydrophobic molecules that require protein-mediated transport to enter cells efficiently. Several membrane proteins, including CD36 and the SLC27A family of fatty acid transport proteins, facilitate this uptake, and their expression levels and activity directly influence the rate of import. The regulation of these transporters, through transcriptional control, post-translational modification, or subcellular localization, is a central component of GO:0140212.
Activation to acyl-CoA
In simple terms: Once inside, fatty acids are tagged with a CoA molecule so they can be used by the cell.
Imported long-chain fatty acids are rapidly activated to acyl-CoA derivatives by acyl-CoA synthetases, such as the ACSL family in mammals and their yeast counterparts. This activation step traps the fatty acid inside the cell and commits it to downstream metabolic pathways, including beta-oxidation and lipid synthesis. Because activation is coupled to import, the regulation of acyl-CoA synthetase activity modulates the effective rate of long-chain fatty acid import.
Intracellular trafficking and channeling
In simple terms: Inside the cell, fatty acids are carried by special proteins to the places where they are needed.
Once activated, long-chain acyl-CoAs are bound by intracellular carrier proteins such as fatty acid-binding proteins (FABPs) and acyl-CoA binding proteins, which channel them to mitochondria, peroxisomes, or endoplasmic reticulum. The regulation of this trafficking influences whether imported fatty acids are oxidized for energy or esterified into complex lipids. This step is part of the broader regulatory network captured by GO:0140212 because it affects the effective import rate by preventing retrograde diffusion.
Mitochondrial and peroxisomal oxidation
In simple terms: Fatty acids are broken down in mitochondria and peroxisomes to produce energy and other molecules.
Long-chain fatty acids imported into cells are primarily oxidized in mitochondria through beta-oxidation, while very long-chain fatty acids are shortened in peroxisomes before mitochondrial oxidation. The regulation of import directly affects the flux through these oxidation pathways, as shown by studies linking peroxisomal dysfunction to altered intestinal stem cell differentiation during aging. Additionally, mitochondrial beta-oxidation controls oxylipin metabolism during bacterial inflammation, demonstrating that import regulation has systemic consequences.
Feedback and metabolic integration
In simple terms: The cell adjusts how much fat it takes in based on what it needs and what it already has.
The regulation of long-chain fatty acid import is integrated with cellular energy status and metabolic demand through feedback mechanisms that sense acyl-CoA levels, NAD+/NADH ratios, and hormonal signals. For instance, SLC27A5 deficiency reduces long-chain fatty acid uptake and triggers a metabolic adaptation that confers sensitivity to glutaminase inhibition in hepatocellular carcinoma, illustrating how import regulation is linked to broader metabolic reprogramming. Such feedback loops ensure that fatty acid import matches the cell's oxidative and biosynthetic needs.
Key Genes Involved in GO:0140212 regulation of long-chain fatty acid import into cell
The following genes encode proteins that directly participate in or regulate long-chain fatty acid import into cells, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CD36 | Membrane fatty acid translocase facilitating long-chain fatty acid uptake | Target for studying import regulation in metabolic tissues |
| SLC27A1 | Fatty acid transport protein 1, mediates long-chain fatty acid uptake | Model for import kinetics and substrate specificity |
| SLC27A2 | Fatty acid transport protein 2, involved in peroxisomal and mitochondrial fatty acid activation | Links import to peroxisomal oxidation |
| SLC27A4 | Fatty acid transport protein 4, essential for long-chain fatty acid uptake | Studied in skin and metabolic disorders |
| SLC27A5 | Fatty acid transport protein 5, reduces long-chain fatty acid uptake when deficient | Pro-tumorigenic metabolic adaptation in hepatocellular carcinoma |
| ACSL1 | Acyl-CoA synthetase long-chain family member 1, activates long-chain fatty acids | Central to fatty acid activation and channeling |
| ACSL3 | Acyl-CoA synthetase long-chain family member 3 | Role in lipid synthesis and cancer metabolism |
| ACSL4 | Acyl-CoA synthetase long-chain family member 4 | Involved in ferroptosis and lipid remodeling |
| ACSL5 | Acyl-CoA synthetase long-chain family member 5 | Regulates fatty acid partitioning |
| ACSL6 | Acyl-CoA synthetase long-chain family member 6 | Brain-specific fatty acid activation |
| FABP1 | Liver fatty acid-binding protein, intracellular carrier | Trafficking of imported fatty acids |
| FABP3 | Heart-type fatty acid-binding protein | Cardiac fatty acid utilization |
| FABP4 | Adipocyte fatty acid-binding protein | Metabolic and inflammatory signaling |
| FABP5 | Epidermal fatty acid-binding protein | Lipid signaling and cancer |
| ABCD1 | Peroxisomal very long-chain fatty acid transporter | Targeting inhibits peroxisomal oxidation in leukemia |
| CPT1A | Carnitine palmitoyltransferase 1A, mitochondrial long-chain fatty acid entry | Links import to mitochondrial beta-oxidation |
| SLC25A20 | Carnitine-acylcarnitine translocase, mitochondrial fatty acid transport | Defects cause fatty acid oxidation disorders |
How Is regulation of long-chain fatty acid import into cell Regulated?
The regulation of long-chain fatty acid import into cells is controlled at multiple levels, including transcriptional regulation of transporters such as CD36 and SLC27A family members, post-translational modifications that alter their membrane localization, and feedback inhibition by intracellular acyl-CoA levels. Hormonal signals and nutrient sensors, including insulin and AMPK, modulate import capacity to match metabolic demand. Additionally, mitochondrial beta-oxidation activity can influence import regulation through changes in oxylipin metabolism during inflammation. In peroxisomal disorders, impaired very long-chain fatty acid oxidation can secondarily affect long-chain fatty acid import and cellular differentiation.
regulation of long-chain fatty acid import into cell and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SLC27A5 | Hepatocellular carcinoma, reduced long-chain fatty acid uptake | Knockout in hepatoma cell lines |
| ABCD1 | Acute myeloid leukemia, peroxisomal fatty acid oxidation | Knockout in AML cell lines |
| SLC27A2 | Peroxisomal very long-chain fatty acid oxidation, aging-related intestinal dysfunction | Knockout in intestinal organoids |
| ACSL1 | Fatty acid oxidation disorders, metabolic syndrome | Point mutation knock-in in cell models |
| CD36 | Metabolic disorders, cardiovascular disease | Overexpression and knockout in cardiomyocytes |
Hepatocellular carcinoma
SLC27A5 deficiency reduces long-chain fatty acid uptake and represents a pro-tumorigenic metabolic adaptation that confers sensitivity to glutaminase inhibition in hepatocellular carcinoma. This demonstrates that regulation of long-chain fatty acid import can be a determinant of tumor metabolic dependencies and a potential therapeutic target.
Acute myeloid leukemia
Targeting ABCD1 inhibits peroxisomal fatty acid oxidation and selectively eliminates acute myeloid leukemia cells, linking peroxisomal fatty acid handling to leukemia cell survival. Because ABCD1 is involved in very long-chain fatty acid transport, its inhibition may indirectly affect long-chain fatty acid import regulation.
Peroxisomal and aging-related disorders
Aging-related peroxisomal dysregulation disrupts intestinal stem cell differentiation through alterations of very long-chain fatty acid oxidation, indicating that peroxisomal fatty acid metabolism, which is functionally linked to import regulation, is important for tissue homeostasis.
Adrenal hypoplasia syndromes
Familial or sporadic adrenal hypoplasia syndromes can involve defects in lipid metabolism and transport, highlighting the clinical relevance of fatty acid import and utilization pathways.
From regulation of long-chain fatty acid import into cell-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of SLC27A5 reduce long-chain fatty acid import? | SLC27A5 knockout cell line |
| Does a point mutation in ACSL1 alter fatty acid activation? | ACSL1 point-mutation knock-in |
| Can tagged CD36 be used to track membrane localization? | CD36 knock-in with fluorescent tag |
| Does overexpression of FABP4 increase fatty acid uptake? | FABP4 overexpression cell line |
| Does ABCD1 inhibition affect leukemia cell viability? | ABCD1 knockout in AML cells |
| Does SLC27A2 deficiency alter peroxisomal oxidation? | SLC27A2 knockout in organoids |
How to Study the regulation of long-chain fatty acid import into cell Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screen | Gene essentiality for fatty acid import | Discovery of novel regulators |
| BODIPY-palmitate uptake | Rate of long-chain fatty acid import | Validation of candidate genes |
| Lipidomics | Acyl-CoA and lipid species | Metabolic flux analysis |
| Proteomics | Protein abundance and interactions | Identification of regulatory complexes |
| RNA-seq | Transcriptional changes in import genes | Response to metabolic stress |
| Seahorse assay | Mitochondrial oxidation rates | Functional impact of import regulation |
| Immunofluorescence | Subcellular localization of transporters | Trafficking studies |
CRISPR knockout screens
Genome-wide CRISPR knockout screens can identify genes whose loss alters long-chain fatty acid import, as demonstrated by studies linking SLC27A5 deficiency to reduced uptake in hepatocellular carcinoma. Such screens are powerful for discovering novel regulators annotated under GO:0140212.
Fluorescent fatty acid uptake assays
Fluorescently labeled long-chain fatty acid analogs, such as BODIPY-palmitate, are used to measure import rates in live cells and can be combined with CRISPR perturbations to validate candidate regulators.
Lipidomics and metabolomics
Mass spectrometry-based lipidomics quantifies acyl-CoA and complex lipid species, providing a readout of import and downstream metabolism. This approach can reveal how regulation of import affects oxylipin metabolism during inflammation.
Proteomics and interactomics
Proteomic analysis of membrane fractions and interactome studies can identify proteins that associate with transporters such as CD36 and SLC27A family members, shedding light on regulatory complexes.
How CRISPR Can Be Used to Study GO:0140212 regulation of long-chain fatty acid import into cell
Knockout
CRISPR knockout of genes such as SLC27A5 or ABCD1 enables researchers to determine whether loss of function alters long-chain fatty acid import and downstream phenotypes, as shown in hepatocellular carcinoma and leukemia models.
Point Mutation
Introducing point mutations in genes like ACSL1 can reveal how specific catalytic residues affect fatty acid activation and import regulation, providing mechanistic insights beyond simple knockout.
Knock-in
Knock-in of fluorescent or affinity tags into endogenous loci such as CD36 allows real-time tracking of transporter localization and dynamics without overexpression artifacts.
Overexpression
Overexpression of fatty acid transport proteins or FABPs can test whether increased import capacity is sufficient to drive metabolic reprogramming or disease phenotypes.
How EDITGENE Supports regulation of long-chain fatty acid import into cell Research
Researchers studying regulation of long-chain fatty acid import into cell-related genes often need to determine whether a candidate gene is causally involved in import regulation or is merely correlated with metabolic changes. EDITGENE provides a comprehensive suite of CRISPR-based services to establish causality and dissect mechanism.
Contact EDITGENE today to design your custom CRISPR model for regulation of long-chain fatty acid import into cell research.
Frequently Asked Questions About regulation of long-chain fatty acid import into cell
What is GO:0140212?
GO:0140212 is the Gene Ontology term for regulation of long-chain fatty acid import into cell, defined as any process that modulates the frequency, rate or extent of long-chain fatty acid import into a cell.
What genes are involved in regulation of long-chain fatty acid import into cell?
Key genes include CD36, SLC27A1-5, ACSL1-6, FABP1-5, ABCD1, CPT1A, and SLC25A20, as supported by published literature.
How is long-chain fatty acid import regulated?
It is regulated by transcriptional control of transporters, post-translational modifications, feedback from acyl-CoA levels, and hormonal signals such as insulin.
Why is long-chain fatty acid import important in cancer?
SLC27A5 deficiency reduces long-chain fatty acid uptake and promotes hepatocellular carcinoma, while ABCD1 inhibition selectively eliminates leukemia cells, showing import regulation can be a therapeutic target.
What diseases are linked to defects in long-chain fatty acid import?
Hepatocellular carcinoma, acute myeloid leukemia, peroxisomal disorders, and adrenal hypoplasia syndromes have been linked to altered fatty acid import or oxidation.
How can I study regulation of long-chain fatty acid import in the lab?
Use CRISPR knockout screens, fluorescent fatty acid uptake assays, lipidomics, and proteomics to identify and validate regulators.
What is the role of SLC27A5 in fatty acid import?
SLC27A5 is a fatty acid transport protein; its deficiency reduces long-chain fatty acid uptake and creates a pro-tumorigenic metabolic adaptation in hepatocellular carcinoma.
Does mitochondrial beta-oxidation affect fatty acid import regulation?
Yes, mitochondrial beta-oxidation controls oxylipin metabolism during bacterial inflammation, linking import regulation to inflammatory signaling.
What model systems are used to study GO:0140212?
Common models include CRISPR knockout cell lines, point-mutation knock-ins, overexpression lines, and organoids, as used in studies of SLC27A5, ABCD1, and SLC27A2.
How does EDITGENE support research on long-chain fatty acid import?
EDITGENE offers knockout, point-mutation, knock-in, overexpression cell models, CRISPR library screening, and bioinformatics services tailored to lipid metabolism research.
Conclusion
GO:0140212, regulation of long-chain fatty acid import into cell, is a critical biological process that controls the entry of long-chain fatty acids and thereby influences energy metabolism, lipid signaling, and disease progression. Research using CRISPR-based models has revealed that dysregulation of import can drive cancer and metabolic disorders, making this term a valuable framework for both basic and translational studies. Continued investigation of the genes and mechanisms annotated under GO:0140212 will likely uncover new therapeutic opportunities in metabolic disease and oncology.
References
- 1. Kerner J et al.. 2000. Fatty acid import into mitochondria.. Biochim Biophys Acta 1486(1):1-17 PMID: 10856709
- 2. Guo X et al.. 2025. Aging-related peroxisomal dysregulation disrupts intestinal stem cell differentiation through alterations of very long-chain fatty acid oxidation.. PLoS Biol 23(12):e3003552 PMID: 41417787
- 3. Misheva M et al.. 2022. Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation.. Nat Commun 13(1):139 PMID: 35013270
- 4. He X et al.. 2026. SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma.. Cancer Lett 655:218616 PMID: 42202975
- 5. Schaffer JE. 2002. Fatty acid transport: the roads taken.. Am J Physiol Endocrinol Metab 282(2):E239-46 PMID: 11788354
- 6. Black PN et al.. 2007. Yeast acyl-CoA synthetases at the crossroads of fatty acid metabolism and regulation.. Biochim Biophys Acta 1771(3):286-98 PMID: 16798075
- 7. Parfenova EN et al.. 2026. Targeting ABCD1 inhibits peroxisomal fatty acid oxidation to selectively eliminate acute myeloid leukemia cells.. Blood 147(24):2930-2943 PMID: 41746867
- 8. Feingold KR et al.. 2000. Familial or Sporadic Adrenal Hypoplasia Syndromes.. PMID: 25905355
