GO:0031999 negative regulation of fatty acid beta-oxidation: Metabolic Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0031999 describes any process that stops, prevents, or reduces the frequency, rate or extent of fatty acid beta-oxidation.
• Fatty acid beta-oxidation is the mitochondrial and peroxisomal pathway that breaks down fatty acids into acetyl-CoA for energy production.
• Negative regulation of this pathway is critical in diseases such as MASLD, NAFLD, NASH, and triple-negative breast cancer.
• Key regulators include PPARα, FABP5, ACSL1, and CD24, which modulate beta-oxidation through transcriptional and metabolic reprogramming.
• Experimental models for studying this process include CRISPR knockout, point mutation, knock-in, and overexpression cell lines.
• Understanding negative regulation of fatty acid beta-oxidation offers therapeutic targets for metabolic and oncological disorders.
Description
Fatty acid beta-oxidation is a central catabolic pathway that converts fatty acids into acetyl-CoA, generating energy and reducing equivalents. The Gene Ontology term GO:0031999, negative regulation of fatty acid beta-oxidation, encompasses any process that stops, prevents, or reduces the frequency, rate or extent of this oxidation. This regulatory mechanism is essential for maintaining metabolic homeostasis and is implicated in a wide range of physiological and pathological states. Researchers study this term to understand how cells adapt to energy demands, how metabolic reprogramming occurs in cancer, and how dysregulation contributes to diseases such as non-alcoholic steatohepatitis (NASH) and metabolic dysfunction-associated steatotic liver disease (MASLD). The importance of negative regulation of fatty acid beta-oxidation extends to immunology, as fatty acid oxidation can influence immune cell function, including double-negative T cells. In cancer, reprogramming of fatty acid oxidation supports proliferation and metastasis, making its negative regulation a potential therapeutic target. This article synthesizes authoritative QuickGO data and verified PubMed literature to provide a comprehensive overview of GO:0031999, covering its definition, mechanisms, key genes, disease relevance, and research methodologies.
negative regulation of fatty acid beta-oxidation At A Glance
| GO ID | GO:0031999 |
|---|---|
| GO term | negative regulation of fatty acid beta-oxidation |
| Ontology | biological_process |
| Synonym | down regulation of fatty acid beta-oxidation, down-regulation of fatty acid beta-oxidation, downregulation of fatty acid beta-oxidation, inhibition of fatty acid beta-oxidation |
| Major function | Reduces the rate of fatty acid beta-oxidation, thereby modulating energy production and lipid metabolism. |
| Related pathways | PPARα signaling, mitochondrial fatty acid transport, and acetyl-CoA production. |
| Disease relevance | MASLD, NAFLD, NASH, triple-negative breast cancer, and metabolic disorders. |
| Key regulators | PPARα, FABP5, ACSL1, CD24, and vitamin B12/folate metabolism. |
What Is GO:0031999?
According to the Gene Ontology, GO:0031999 (negative regulation of fatty acid beta-oxidation) is defined as any process that stops, prevents, or reduces the frequency, rate or extent of fatty acid beta-oxidation. This biological process acts as a brake on the catabolic breakdown of fatty acids, ensuring that energy production and lipid utilization are tightly controlled. It includes mechanisms such as transcriptional repression of beta-oxidation enzymes, inhibition of fatty acid transport into mitochondria, and post-translational modifications that reduce enzyme activity.
Why Is negative regulation of fatty acid beta-oxidation Important in Cell Biology?
Negative regulation of fatty acid beta-oxidation is crucial because it controls the balance between lipid storage and energy expenditure. Dysregulation of this process contributes to the pathogenesis of metabolic diseases such as MASLD and NASH, where excessive fatty acid oxidation can lead to inflammation and fibrosis. In cancer, cancer cells often reprogram their metabolism to favor fatty acid oxidation for energy and biomass, and negative regulation can influence tumor growth and metastasis. Furthermore, this regulatory mechanism impacts immune cell function, as seen in double-negative T cells where fatty acid beta-oxidation enhances immune regulatory function. Understanding how this process is negatively regulated provides insights into potential therapeutic strategies for a range of disorders.
• Maintains metabolic homeostasis by preventing excessive fatty acid breakdown.
• Plays a role in the development of MASLD and NAFLD by modulating lipid accumulation.
• Influences inflammation and fibrosis in NASH through vitamin B12 and folate metabolism.
• Supports cancer cell proliferation and metastasis in triple-negative breast cancer.
• Regulates immune cell function, including double-negative T cells.
• Affects intramuscular fat deposition in cattle via rumen microbiota-host interactions.
• Provides targets for therapeutic intervention in metabolic and oncological diseases.
• Helps researchers understand metabolic flexibility and energy adaptation.
What Happens During negative regulation of fatty acid beta-oxidation?
Transcriptional repression of beta-oxidation genes
In simple terms: The cell reduces the production of enzymes needed to break down fats.
Negative regulation of fatty acid beta-oxidation often occurs at the transcriptional level, where factors such as PPARα and other nuclear receptors modulate the expression of genes involved in fatty acid transport and oxidation. For example, asprosin interacts with FABP5 to modulate mitochondrial fatty acid oxidation through PPARα, contributing to MASLD development. Similarly, CD24 negativity reprograms mitochondrial metabolism to PPARα and NF-κB-driven fatty acid beta-oxidation in triple-negative breast cancer.
Inhibition of fatty acid uptake and transport
In simple terms: The cell limits how much fat gets into the mitochondria to be burned.
Reducing fatty acid uptake or transport into mitochondria can negatively regulate beta-oxidation. Vitamin D improves hepatic steatosis in NAFLD via regulation of fatty acid uptake and beta-oxidation, indicating that modulation of uptake affects oxidation rates. Additionally, ACSL1-mediated fatty acid beta-oxidation enhances metastasis and proliferation in endometrial cancer, suggesting that ACSL1 activity is a point of regulation.
Post-translational modifications of beta-oxidation enzymes
In simple terms: Chemical changes to enzymes can slow down fat burning.
Post-translational modifications, such as homocysteinylation, can impair enzyme function. Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation, which may affect beta-oxidation. This highlights how nutritional status can influence the negative regulation of fatty acid beta-oxidation.
Metabolic reprogramming in cancer
In simple terms: Cancer cells change their metabolism, sometimes turning down fat burning to grow.
In triple-negative breast cancer, a metabolic switch regulates lineage plasticity and induces synthetic lethality, involving changes in fatty acid beta-oxidation. CD24 negativity reprograms mitochondrial metabolism to PPARα and NF-κB-driven fatty acid beta-oxidation, demonstrating that negative regulation can be part of oncogenic reprogramming.
Microbiota-host interactions
In simple terms: Gut bacteria can influence how the host breaks down fats.
Rumen microbiota-host interactions regulate intramuscular fat deposition in cattle via the alpha-linolenic acid-fatty acid beta-oxidation/L-carnitine-MPO axis, showing that negative regulation of beta-oxidation can be modulated by microbial metabolites.
Key Genes Involved in GO:0031999 negative regulation of fatty acid beta-oxidation
The following genes and proteins are key players in the negative regulation of fatty acid beta-oxidation, as supported by recent literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PPARα | Transcriptional regulator of fatty acid oxidation genes | Modulates beta-oxidation in MASLD and cancer |
| FABP5 | Fatty acid binding protein, interacts with asprosin | Regulates mitochondrial fatty acid oxidation in MASLD |
| ACSL1 | Activates long-chain fatty acids for beta-oxidation | Enhances metastasis and proliferation in endometrial cancer |
| CD24 | Cell surface marker, affects mitochondrial metabolism | Reprograms metabolism to PPARα and NF-κB-driven beta-oxidation in TNBC |
| Syntaxin 17 | Autophagosomal SNARE, affected by homocysteinylation | Vitamin B12/folate prevent homocysteinylation in NASH |
| MPO | Myeloperoxidase, involved in oxidative stress | Part of microbiota-host axis regulating intramuscular fat |
| STAT4 | Signal transducer and activator of transcription | pSTAT4-OX40 signaling enhances immune regulatory function via beta-oxidation |
| OX40 | Costimulatory receptor | Part of pSTAT4-OX40 pathway in double-negative T cells |
| NF-κB | Transcription factor, inflammatory and metabolic regulator | Drives fatty acid beta-oxidation in TNBC |
| L-carnitine | Carrier for fatty acid transport into mitochondria | Involved in microbiota-host axis for fat deposition |
| Alpha-linolenic acid | Polyunsaturated fatty acid | Substrate for beta-oxidation in cattle intramuscular fat |
| Vitamin D receptor | Nuclear receptor, regulates fatty acid uptake | Improves hepatic steatosis in NAFLD |
| Vitamin B12 | Cofactor for methionine synthase | Prevents homocysteinylation and decreases NASH inflammation |
| Folate | Cofactor in one-carbon metabolism | Works with vitamin B12 in NASH |
| Asprosin | Adipokine, interacts with FABP5 | Modulates PPARα and beta-oxidation in MASLD |
| CD24 (negative) | Loss of CD24 expression | Reprograms metabolism in TNBC |
How Is negative regulation of fatty acid beta-oxidation Regulated?
The negative regulation of fatty acid beta-oxidation is controlled at multiple levels. Transcriptional regulation involves nuclear receptors such as PPARα, which can be modulated by factors like asprosin-FABP5 interaction. In cancer, CD24 negativity leads to PPARα and NF-κB-driven beta-oxidation, indicating crosstalk between inflammatory and metabolic pathways. Post-translational modifications, such as homocysteinylation of syntaxin 17, can impair beta-oxidation, and this is prevented by vitamin B12 and folate. Additionally, metabolic switches regulate lineage plasticity and synthetic lethality in triple-negative breast cancer, highlighting the interplay between beta-oxidation and cell fate. Microbiota-host interactions also regulate beta-oxidation through metabolites like alpha-linolenic acid and L-carnitine. These diverse mechanisms ensure that fatty acid beta-oxidation is tightly controlled according to cellular needs.
negative regulation of fatty acid beta-oxidation and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FABP5 | MASLD | Knockout or overexpression in hepatocytes |
| CD24 | Triple-negative breast cancer | Knockout in TNBC cell lines |
| ACSL1 | Endometrial cancer | Knockdown or overexpression in endometrial cancer cells |
| Syntaxin 17 | NASH | Point mutation to prevent homocysteinylation |
| PPARα | NAFLD and MASLD | Knockout or knock-in in liver cells |
Metabolic dysfunction-associated steatotic liver disease (MASLD) and non-alcoholic steatohepatitis (NASH)
Negative regulation of fatty acid beta-oxidation is implicated in the pathogenesis of MASLD and NASH. Asprosin-FABP5 interaction modulates mitochondrial fatty acid oxidation through PPARα, contributing to MASLD development. Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation, which may affect beta-oxidation. Vitamin D improves hepatic steatosis in NAFLD via regulation of fatty acid uptake and beta-oxidation. These findings suggest that targeting negative regulation of beta-oxidation could be therapeutic for liver diseases.
Triple-negative breast cancer (TNBC)
In triple-negative breast cancer, CD24 negativity reprograms mitochondrial metabolism to PPARα and NF-κB-driven fatty acid beta-oxidation, supporting tumor growth. A metabolic switch regulates lineage plasticity and induces synthetic lethality in TNBC, involving changes in beta-oxidation. These studies indicate that negative regulation of fatty acid beta-oxidation plays a role in cancer metabolism and could be exploited for therapy.
Endometrial cancer
ACSL1-mediated fatty acid beta-oxidation enhances metastasis and proliferation in endometrial cancer, suggesting that negative regulation of this process could reduce tumor progression.
Immune regulation and other conditions
Fatty acid beta-oxidation enhances immune regulatory function of double-negative T cells through pSTAT4-OX40 signaling pathway, indicating that negative regulation may affect immune responses. In cattle, rumen microbiota-host interactions regulate intramuscular fat deposition via the alpha-linolenic acid-fatty acid beta-oxidation/L-carnitine-MPO axis, which has implications for meat quality and metabolic research.
From negative regulation of fatty acid beta-oxidation-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate fatty acid beta-oxidation? | CRISPR knockout cell line |
| Does a specific mutation affect beta-oxidation? | Point mutation knock-in cell line |
| Does overexpression of gene Y reduce beta-oxidation? | Overexpression cell line |
| How does a tag affect protein localization during beta-oxidation? | Tagged knock-in cell line |
| What is the role of gene Z in cancer metabolism? | Knockout in cancer cell lines |
| Can a drug modulate beta-oxidation? | Pharmacological treatment in wild-type cells |
How to Study the negative regulation of fatty acid beta-oxidation Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout screening | Gene essentiality and regulators | Identify negative regulators of beta-oxidation |
| Seahorse assay | Oxygen consumption rate | Measure beta-oxidation activity |
| RNA-seq | Transcriptional changes | Assess expression of beta-oxidation genes |
| Proteomics | Protein abundance and modifications | Detect post-translational modifications |
| Western blot | Protein levels | Validate knockout or overexpression |
| Immunofluorescence | Protein localization | Study mitochondrial import |
| Metabolomics | Metabolite levels | Measure acetyl-CoA and intermediates |
| qPCR | mRNA levels | Quantify gene expression changes |
CRISPR screening and functional genomics
CRISPR library screening can identify genes that negatively regulate fatty acid beta-oxidation. By using genome-wide knockout libraries, researchers can uncover novel regulators and pathways.
Metabolic assays
Seahorse extracellular flux analysis and fatty acid oxidation assays measure the rate of beta-oxidation in live cells. These methods are used to quantify the effects of genetic perturbations.
Transcriptomics and proteomics
RNA-seq and proteomics can reveal changes in expression of beta-oxidation enzymes and regulators. For example, PPARα target genes can be assessed upon negative regulation.
Imaging and localization
Fluorescence microscopy with tagged proteins can visualize mitochondrial morphology and localization of beta-oxidation enzymes. This helps understand spatial regulation.
How CRISPR Can Be Used to Study GO:0031999 negative regulation of fatty acid beta-oxidation
Knockout
CRISPR knockout of candidate genes can determine if they are necessary for negative regulation of fatty acid beta-oxidation. For example, knocking out FABP5 or CD24 can increase beta-oxidation rates, confirming their inhibitory roles.
Point Mutation
Point mutations can mimic disease-associated variants or prevent post-translational modifications. For instance, mutating syntaxin 17 at homocysteinylation sites can reveal its role in NASH.
Knock-in
Knock-in of tagged or reporter genes allows tracking of protein localization and dynamics. Tagging PPARα can help visualize its nuclear translocation during beta-oxidation regulation.
Overexpression
Overexpression of genes like ACSL1 can enhance beta-oxidation and promote cancer metastasis, demonstrating gain-of-function effects.
How EDITGENE Supports negative regulation of fatty acid beta-oxidation Research
Researchers studying negative regulation of fatty acid beta-oxidation-related genes often need to determine whether a candidate gene is causally involved in the process, and CRISPR-based models provide a robust way to establish causality. EDITGENE offers a comprehensive suite of services to support such investigations.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of fatty acid beta-oxidation research.
Frequently Asked Questions About negative regulation of fatty acid beta-oxidation
What is GO:0031999?
GO:0031999 is the Gene Ontology term for negative regulation of fatty acid beta-oxidation, describing any process that reduces the rate of fatty acid breakdown.
What genes are involved in negative regulation of fatty acid beta-oxidation?
Key genes include PPARα, FABP5, ACSL1, CD24, and syntaxin 17, among others.
How is fatty acid beta-oxidation negatively regulated?
It can be regulated transcriptionally, post-translationally, or via metabolic reprogramming, often involving PPARα and NF-κB.
What diseases are associated with negative regulation of fatty acid beta-oxidation?
Diseases include MASLD, NAFLD, NASH, triple-negative breast cancer, and endometrial cancer.
How can I study negative regulation of fatty acid beta-oxidation?
Use CRISPR knockout, point mutation, knock-in, overexpression models, and metabolic assays like Seahorse.
What is the role of PPARα in this process?
PPARα is a transcription factor that regulates genes involved in fatty acid oxidation and can be modulated by asprosin-FABP5 interaction.
Does vitamin B12 affect fatty acid beta-oxidation?
Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation, which may impact beta-oxidation.
What is the connection between CD24 and fatty acid beta-oxidation?
CD24 negativity reprograms mitochondrial metabolism to PPARα and NF-κB-driven fatty acid beta-oxidation in triple-negative breast cancer.
Can CRISPR be used to study negative regulation of fatty acid beta-oxidation?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression are powerful tools to dissect this process.
What services does EDITGENE offer for this research?
EDITGENE provides knockout, point mutation, knock-in, overexpression cell models, CRISPR library screening, and bioinformatics services.
Conclusion
Negative regulation of fatty acid beta-oxidation (GO:0031999) is a critical biological process that controls energy metabolism and lipid homeostasis. Its dysregulation is linked to major diseases including MASLD, NASH, and various cancers. Understanding the molecular players and regulatory mechanisms offers opportunities for therapeutic intervention. EDITGENE's CRISPR services empower researchers to investigate this process with precision and efficiency.
References
- 1. Wang Z et al.. 2025. Fatty acid β-oxidation enhances immune regulatory function of double-negative T cells through pSTAT4-OX40 signaling pathway.. Hepatol Commun 9(9) PMID: 40879484
- 2. Yu YY et al.. 2025. Asprosin-FABP5 Interaction Modulates Mitochondrial Fatty Acid Oxidation through PPARα Contributing to MASLD Development.. Adv Sci (Weinh) 12(21):e2415846 PMID: 40231957
- 3. Zhang WT et al.. 2025. Rumen microbiota-host interactions regulate intramuscular fat deposition in cattle via the alpha-linolenic acid-fatty acid β-oxidation/L-carnitine-MPO axis.. Microbiome 14(1):49 PMID: 41372768
- 4. Murthy D et al.. 2024. CD24 negativity reprograms mitochondrial metabolism to PPARα and NF-κB-driven fatty acid β-oxidation in triple-negative breast cancer.. Cancer Lett 587:216724 PMID: 38373689
- 5. Zhang Y et al.. 2024. Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer.. Cell Metab 36(1):193-208.e8 PMID: 38171333
- 6. Tripathi M et al.. 2022. Vitamin B(12) and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation.. J Hepatol 77(5):1246-1255 PMID: 35820507
- 7. Du T et al.. 2023. Vitamin D improves hepatic steatosis in NAFLD via regulation of fatty acid uptake and β-oxidation.. Front Endocrinol (Lausanne) 14:1138078 PMID: 37033263
- 8. Zhou Y et al.. 2024. ACSL1-Mediated Fatty Acid β-Oxidation Enhances Metastasis and Proliferation in Endometrial Cancer.. Front Biosci (Landmark Ed) 29(2):66 PMID: 38420815
