GO:0036113 very long-chain fatty-acyl-CoA catabolic process: Mitochondrial Beta-Oxidation Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0036113 describes the breakdown of very long-chain fatty-acyl-CoA esters, which are fatty acids with aliphatic tails longer than 22 carbons, primarily through mitochondrial beta-oxidation.
• The process requires the coordinated action of acyl-CoA synthetases, carnitine palmitoyltransferases, and a suite of beta-oxidation enzymes including acyl-CoA dehydrogenases, enoyl-CoA hydratases, and thiolases [1,5].
• Defects in very long-chain fatty-acyl-CoA catabolism cause inborn errors of mitochondrial acyl-CoA metabolism, leading to diseases such as fatty acid oxidation disorders and hepatic steatosis.
• ACSL5-mediated activation and SIRT6-dependent deacetylation regulate hepatic fatty acid oxidation and are implicated in nonalcoholic fatty liver disease.
• AMPK senses long-chain fatty acyl-CoA esters to modulate energy homeostasis, linking this catabolic process to cellular metabolic signaling.
• CRISPR knockout, point mutation, and knock-in models are essential for dissecting the causal roles of genes in very long-chain fatty-acyl-CoA catabolism and for developing therapeutic strategies.
Description
Very long-chain fatty-acyl-CoA catabolic process (GO:0036113) is a biological process defined as the chemical reactions and pathways resulting in the breakdown of very long-chain fatty-acyl-CoAs, which are derivatives of coenzyme A in which the sulfhydryl group is in a thioester linkage with a very long-chain fatty-acyl group, where a very long-chain fatty acid has an aliphatic tail containing more than 22 carbons. This process is a critical component of mitochondrial fatty acid beta-oxidation, enabling cells to derive energy from long-chain and very long-chain fatty acids. The catabolic pathway involves multiple enzymatic steps that sequentially shorten the acyl chain by two carbons per cycle, producing acetyl-CoA, NADH, and FADH2, which feed into the tricarboxylic acid cycle and oxidative phosphorylation [1,2]. Researchers study GO:0036113 because its dysfunction is linked to a spectrum of human diseases, including inborn errors of mitochondrial acyl-CoA metabolism, nonalcoholic fatty liver disease, and metabolic disorders [4,5]. The process is tightly regulated at multiple levels, from substrate availability and enzyme expression to post-translational modifications and allosteric regulation by metabolites such as long-chain fatty acyl-CoA esters [6,8]. Understanding the molecular players and regulatory mechanisms of very long-chain fatty-acyl-CoA catabolism is essential for developing targeted therapies and for interpreting genetic variants identified in clinical sequencing. Recent advances in CRISPR gene editing and high-throughput screening have accelerated the functional annotation of genes involved in this pathway, allowing researchers to systematically test the roles of candidate genes in cellular and animal models. This article provides a comprehensive overview of the ontology, mechanisms, key genes, disease associations, and research methodologies relevant to GO:0036113, with a focus on how CRISPR-based models can be leveraged to study this fundamental catabolic process.
very long-chain fatty-acyl-CoA catabolic process At A Glance
| GO ID | GO:0036113 |
|---|---|
| GO term | very long-chain fatty-acyl-CoA catabolic process |
| Ontology | biological_process |
| Synonym | very long-chain fatty-acyl-CoA breakdown; very long-chain fatty-acyl-CoA catabolism; very long-chain fatty-acyl-CoA degradation |
| Definition | The chemical reactions and pathways resulting in the breakdown of very long-chain fatty-acyl-CoAs, any derivative of coenzyme A in which the sulfhydryl group is in a thioester linkage with a very long-chain fatty-acyl group. A very long-chain fatty acid has an aliphatic tail containing more than 22 carbons. |
| Major function | Energy production through mitochondrial beta-oxidation of very long-chain fatty acids |
| Subcellular location | Mitochondrial matrix and peroxisomes (for initial chain shortening) |
| Key enzymes | Acyl-CoA synthetases, carnitine palmitoyltransferases, acyl-CoA dehydrogenases, enoyl-CoA hydratases, 3-hydroxyacyl-CoA dehydrogenases, thiolases |
| Related diseases | Inborn errors of mitochondrial acyl-CoA metabolism, nonalcoholic fatty liver disease, fatty acid oxidation disorders |
What Is GO:0036113?
GO:0036113, very long-chain fatty-acyl-CoA catabolic process, refers to the set of biochemical reactions and pathways that break down very long-chain fatty-acyl-CoA molecules. A very long-chain fatty acid is defined as having an aliphatic tail of more than 22 carbons. In this process, the thioester bond between coenzyme A and the very long-chain fatty acyl group is cleaved, and the acyl chain is progressively shortened through beta-oxidation cycles, ultimately generating acetyl-CoA and reducing equivalents. This process is distinct from the catabolism of short-, medium-, and long-chain fatty acyl-CoAs, which involve different enzymes and subcellular localizations [1,2].
Why Is very long-chain fatty-acyl-CoA catabolic process Important in Cell Biology?
Very long-chain fatty-acyl-CoA catabolic process is essential for cellular energy homeostasis, particularly during fasting or high-energy demand states, when fatty acids are mobilized from adipose tissue and oxidized in mitochondria and peroxisomes. Defects in this pathway lead to the accumulation of very long-chain fatty acids and their acyl-CoA derivatives, which are toxic and can cause severe metabolic, hepatic, and neuromuscular pathologies. Moreover, this process intersects with key signaling pathways, such as AMPK sensing of long-chain fatty acyl-CoA esters, and is regulated by sirtuins and other post-translational modifiers, making it a central node in metabolic regulation [4,6]. Understanding GO:0036113 is therefore critical for deciphering the molecular basis of metabolic diseases and for identifying therapeutic targets.
• Provides a major source of ATP through mitochondrial beta-oxidation of very long-chain fatty acids.
• Prevents lipotoxicity by clearing very long-chain fatty acyl-CoAs from cells.
• Dysregulation is linked to nonalcoholic fatty liver disease and hepatic steatosis.
• Inborn errors in this pathway cause severe metabolic disorders, including acyl-CoA dehydrogenase deficiencies.
• Serves as a sensor for cellular energy status via AMPK and long-chain fatty acyl-CoA esters.
• Is a target for pharmacological interventions, such as etomoxir, which disrupts CoA homeostasis.
• Plays a role in macrophage polarization and immune responses through CoA metabolism.
• Involves acyl-CoA partitioning between oxidation and lipid synthesis, impacting whole-body energy balance.
• Provides a model system for studying enzyme kinetics and substrate specificity of beta-oxidation enzymes.
• Offers opportunities for CRISPR-based functional genomics to identify novel regulators.
What Happens During very long-chain fatty-acyl-CoA catabolic process?
Activation of Very Long-Chain Fatty Acids to Acyl-CoA Esters
In simple terms: Before a very long-chain fatty acid can be broken down, it must be activated by attaching coenzyme A to it.
The first step in very long-chain fatty-acyl-CoA catabolism is the activation of free very long-chain fatty acids to their corresponding acyl-CoA esters. This reaction is catalyzed by very long-chain acyl-CoA synthetases (ACSVLs) and long-chain acyl-CoA synthetases (ACSLs) in the endoplasmic reticulum, peroxisomes, and mitochondria. The enzyme hydrolyzes ATP to AMP and pyrophosphate, forming an acyl-AMP intermediate, which then reacts with coenzyme A to produce very long-chain fatty-acyl-CoA [7,8]. This activation step is essential for subsequent oxidation and also traps the fatty acid within the cell, preventing its diffusion across membranes.
Transport into Mitochondria via the Carnitine Shuttle
In simple terms: Very long-chain fatty acyl-CoAs cannot cross the mitochondrial membrane directly, so they are shuttled in using carnitine.
Once activated, very long-chain fatty-acyl-CoAs are transported into the mitochondrial matrix via the carnitine palmitoyltransferase (CPT) system. CPT1 on the outer mitochondrial membrane converts acyl-CoA to acylcarnitine, which is then translocated across the inner membrane by the carnitine-acylcarnitine translocase (CACT). Inside the matrix, CPT2 reconverts acylcarnitine back to acyl-CoA, making it available for beta-oxidation [1,5]. This shuttle is a rate-limiting step for the oxidation of long-chain and very long-chain fatty acids and is regulated by malonyl-CoA, which inhibits CPT1.
Beta-Oxidation Cycles Shorten the Acyl Chain
In simple terms: In the mitochondrial matrix, the fatty acyl-CoA is chopped down two carbons at a time, releasing energy.
The core of very long-chain fatty-acyl-CoA catabolism is the beta-oxidation spiral, which consists of four repeating reactions: (1) acyl-CoA dehydrogenase (ACAD) introduces a double bond, producing trans-2-enoyl-CoA and FADH2; (2) enoyl-CoA hydratase adds water to form 3-hydroxyacyl-CoA; (3) 3-hydroxyacyl-CoA dehydrogenase oxidizes the hydroxyl group to a keto group, generating NADH; and (4) 3-ketoacyl-CoA thiolase cleaves the chain, releasing acetyl-CoA and a shortened acyl-CoA that re-enters the cycle [1,2]. For very long-chain substrates, initial chain shortening may occur in peroxisomes before mitochondrial oxidation.
Generation of Acetyl-CoA and Reducing Equivalents
In simple terms: Each round of beta-oxidation produces acetyl-CoA, which enters the TCA cycle, and energy-carrying molecules NADH and FADH2.
The beta-oxidation of very long-chain fatty-acyl-CoAs yields one acetyl-CoA, one NADH, and one FADH2 per cycle. Acetyl-CoA enters the tricarboxylic acid (TCA) cycle, where it is further oxidized to CO2, generating additional NADH and FADH2. These reducing equivalents donate electrons to the electron transport chain, driving oxidative phosphorylation and ATP synthesis [1,2]. The energy yield from very long-chain fatty acids is substantial, making this process a major contributor to cellular ATP production during fasting.
Peroxisomal Contribution to Very Long-Chain Fatty Acid Catabolism
In simple terms: Peroxisomes start the breakdown of very long-chain fatty acids before they are sent to mitochondria.
Peroxisomes are essential for the initial oxidation of very long-chain fatty acids, as they contain enzymes that can handle substrates with more than 22 carbons. Peroxisomal beta-oxidation shortens very long-chain fatty acyl-CoAs to medium-chain acyl-CoAs, which are then exported to mitochondria for complete oxidation. Unlike mitochondrial beta-oxidation, the first step in peroxisomes is catalyzed by acyl-CoA oxidase, which directly transfers electrons to oxygen, producing hydrogen peroxide [1,5]. Defects in peroxisomal beta-oxidation lead to the accumulation of very long-chain fatty acids, as seen in X-linked adrenoleukodystrophy and other peroxisomal disorders.
Key Genes Involved in GO:0036113 very long-chain fatty-acyl-CoA catabolic process
The following genes encode enzymes and regulatory proteins that directly participate in or regulate very long-chain fatty-acyl-CoA catabolic process, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ACSL1 | Activates long-chain fatty acids to acyl-CoA for oxidation | Key enzyme in fatty acid activation; knockout models show impaired beta-oxidation |
| ACSL5 | Activates very long-chain fatty acids; regulated by SIRT6 deacetylation | Implicated in nonalcoholic fatty liver disease; target for therapeutic intervention |
| CPT1A | Catalyzes the rate-limiting step of mitochondrial fatty acid import | Mutations cause CPT1 deficiency; target for metabolic regulation |
| CPT2 | Converts acylcarnitine back to acyl-CoA inside mitochondria | Defects cause CPT2 deficiency and rhabdomyolysis |
| ACADVL | Very long-chain acyl-CoA dehydrogenase; first step of beta-oxidation | Mutations cause VLCAD deficiency, a severe fatty acid oxidation disorder |
| ACADM | Medium-chain acyl-CoA dehydrogenase | Defects cause MCAD deficiency, a common inborn error of metabolism |
| HADHA | Long-chain 3-hydroxyacyl-CoA dehydrogenase; part of trifunctional protein | Mutations cause LCHAD deficiency |
| HADHB | Long-chain 3-ketoacyl-CoA thiolase; part of trifunctional protein | Mutations cause trifunctional protein deficiency |
| SIRT6 | Deacetylates ACSL5 to promote fatty acid oxidation | Regulates hepatic lipid metabolism; linked to NAFLD |
| AMPK | Senses long-chain fatty acyl-CoA esters to regulate energy homeostasis | Central metabolic sensor; target for metabolic disease research |
| PPARA | Transcription factor that upregulates beta-oxidation genes | Master regulator of lipid catabolism; knockout models show impaired fasting response |
| ETFA | Electron transfer flavoprotein alpha subunit; accepts electrons from ACADs | Mutations cause glutaric acidemia type II |
| ETFB | Electron transfer flavoprotein beta subunit | Mutations cause glutaric acidemia type II |
| ETFDH | Electron transfer flavoprotein dehydrogenase | Mutations cause glutaric acidemia type II |
| SLC25A20 | Carnitine-acylcarnitine translocase; transports acylcarnitines | Defects cause CACT deficiency |
| ACOX1 | Peroxisomal acyl-CoA oxidase; first step of peroxisomal beta-oxidation | Mutations cause peroxisomal disorders with very long-chain fatty acid accumulation |
| HSD17B4 | Peroxisomal multifunctional enzyme type 2 | Defects cause D-bifunctional protein deficiency |
| SCP2 | Sterol carrier protein 2; involved in peroxisomal beta-oxidation | Mutations cause peroxisomal disorders |
How Is very long-chain fatty-acyl-CoA catabolic process Regulated?
Very long-chain fatty-acyl-CoA catabolic process is regulated at multiple levels. Transcriptional control is mediated by nuclear receptors such as PPARA, which upregulates genes encoding beta-oxidation enzymes in response to fasting or high-fat diets. Post-translational modifications also play a role; for example, SIRT6 deacetylates ACSL5 to enhance its activity and promote hepatic fatty acid oxidation, thereby impeding nonalcoholic fatty liver disease progression. AMPK senses long-chain fatty acyl-CoA esters and modulates downstream metabolic pathways to maintain energy balance. Additionally, malonyl-CoA inhibits CPT1, preventing excessive fatty acid oxidation when lipid synthesis is active. The availability of coenzyme A and the redox state of the cell further influence flux through this pathway [3,8].
very long-chain fatty-acyl-CoA catabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ACADVL | Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) | Knockout mouse model; patient-derived fibroblasts; CRISPR point mutation to mimic common variants |
| CPT2 | CPT2 deficiency; rhabdomyolysis | Knockout cell lines; knock-in of patient mutations in HEK293 or hepatocytes |
| ACSL5 | Nonalcoholic fatty liver disease (NAFLD) | Liver-specific knockout mice; overexpression in HepG2 cells; SIRT6 deacetylation mutants |
| HADHA | Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency | CRISPR knockout in iPSC-derived hepatocytes; knock-in of common mutations |
| ACOX1 | Peroxisomal acyl-CoA oxidase deficiency | Knockout mice; patient fibroblasts; overexpression of wild-type vs. mutant ACOX1 |
Inborn Errors of Mitochondrial Acyl-CoA Metabolism
Mutations in genes encoding enzymes of very long-chain fatty-acyl-CoA catabolism cause a group of inherited disorders known as inborn errors of mitochondrial acyl-CoA metabolism. These include very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), medium-chain acyl-CoA dehydrogenase deficiency (MCADD), and trifunctional protein deficiency. Patients present with hypoketotic hypoglycemia, cardiomyopathy, rhabdomyolysis, and hepatic dysfunction, often triggered by fasting or illness. Early diagnosis through newborn screening and management with dietary fat restriction and carnitine supplementation are critical.
Nonalcoholic Fatty Liver Disease (NAFLD)
Impaired very long-chain fatty-acyl-CoA catabolism contributes to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Reduced expression or activity of ACSL5 and other beta-oxidation enzymes leads to lipid accumulation in hepatocytes, causing steatosis and inflammation. SIRT6-mediated deacetylation of ACSL5 promotes fatty acid oxidation and protects against NAFLD, suggesting that enhancing this pathway could be therapeutic. Additionally, etomoxir, an inhibitor of CPT1, disrupts CoA homeostasis and has been used to study the role of fatty acid oxidation in macrophage polarization and metabolic diseases.
Peroxisomal Disorders and Very Long-Chain Fatty Acid Accumulation
Defects in peroxisomal beta-oxidation, which is required for the initial catabolism of very long-chain fatty acids, lead to disorders such as X-linked adrenoleukodystrophy (X-ALD) and D-bifunctional protein deficiency. These conditions are characterized by the accumulation of very long-chain fatty acids in plasma and tissues, causing neurological deterioration, adrenal insufficiency, and early death. The peroxisomal enzymes ACOX1, HSD17B4, and SCP2 are directly involved in very long-chain fatty-acyl-CoA catabolism, and their dysfunction underscores the importance of this process for human health.
From very long-chain fatty-acyl-CoA catabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of ACADVL impair very long-chain fatty acid oxidation? | ACADVL knockout cell line (e.g., HepG2 or HEK293) generated by CRISPR |
| Does a specific point mutation in CPT2 affect enzyme activity? | CRISPR point mutation knock-in of the mutation in patient-derived fibroblasts or iPSCs |
| Can overexpression of ACSL5 rescue NAFLD phenotypes? | Adenoviral or lentiviral overexpression of ACSL5 in mouse liver or hepatocytes |
| How does SIRT6-mediated deacetylation of ACSL5 affect fatty acid oxidation? | Knock-in of acetylation-deficient or acetylation-mimetic ACSL5 mutants |
| What is the role of AMPK in sensing long-chain fatty acyl-CoAs? | AMPK knockout or knock-in cells treated with long-chain fatty acyl-CoA esters |
| Does peroxisomal beta-oxidation compensate for mitochondrial defects? | Double knockout of ACOX1 and ACADVL in cell lines; metabolic flux analysis |
How to Study the very long-chain fatty-acyl-CoA catabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Acyl-CoA synthetase assay | Enzyme activity and substrate specificity | Characterizing ACSL/ACSVL variants |
| Beta-oxidation flux assay | Rate of fatty acid oxidation | Assessing mitochondrial function and drug effects |
| Seahorse respirometry | Oxygen consumption and extracellular acidification | Measuring fatty acid oxidation dependence in live cells |
| CRISPR knockout screen | Gene essentiality for growth on very long-chain fatty acids | Identifying novel regulators of GO:0036113 |
| Metabolomics/lipidomics | Acyl-CoA and acylcarnitine profiles | Diagnosing fatty acid oxidation disorders |
| Western blot | Protein expression and post-translational modifications | Validating knockout or overexpression efficiency |
| qRT-PCR | mRNA expression of beta-oxidation genes | Assessing transcriptional regulation by PPARA |
| Immunofluorescence | Subcellular localization of enzymes | Studying peroxisomal vs. mitochondrial localization |
Measuring Acyl-CoA Synthetase Activity
Acyl-CoA synthetase activity can be measured using radiolabeled fatty acids or fluorescent analogs, followed by separation of acyl-CoA products by HPLC or thin-layer chromatography. This method is essential for assessing the activation step of very long-chain fatty-acyl-CoA catabolism and for characterizing the substrate specificity of ACSL and ACSVL enzymes.
Assessing Beta-Oxidation Flux
Beta-oxidation flux can be quantified by measuring the release of tritiated water from [3H]-labeled fatty acids or by monitoring the production of acetyl-CoA using mass spectrometry. In intact cells or isolated mitochondria, oxygen consumption rates and extracellular acidification rates can be measured using Seahorse technology to assess fatty acid oxidation dependence [1,3].
CRISPR Screening for Regulators of Very Long-Chain Fatty-Acyl-CoA Catabolism
Genome-wide CRISPR knockout or activation screens can be used to identify genes that modulate very long-chain fatty-acyl-CoA catabolism. Cells are cultured in media with very long-chain fatty acids as the sole carbon source, and sgRNA libraries are used to select for cells that survive or proliferate. Next-generation sequencing of sgRNAs reveals enriched or depleted genes, providing unbiased insights into pathway regulation.
Metabolomics and Lipidomics
Mass spectrometry-based metabolomics and lipidomics allow comprehensive profiling of acyl-CoA species and fatty acids in cells and tissues. These methods can detect accumulation of very long-chain fatty acyl-CoAs and acylcarnitines, which are biomarkers of defective beta-oxidation. They are widely used to diagnose inborn errors of metabolism and to study the effects of genetic perturbations [5,8].
How CRISPR Can Be Used to Study GO:0036113 very long-chain fatty-acyl-CoA catabolic process
Knockout
CRISPR knockout is used to generate cell lines or animal models with complete loss of function of genes involved in very long-chain fatty-acyl-CoA catabolism. For example, knocking out ACADVL in hepatocytes results in impaired very long-chain fatty acid oxidation and accumulation of acylcarnitines, mimicking VLCADD. These models are valuable for studying disease mechanisms and testing therapeutic compounds.
Point Mutation
CRISPR point mutation knock-in allows the introduction of specific disease-associated mutations into the genome. This is particularly useful for studying missense mutations in CPT2, ACADVL, or HADHA that cause partial enzyme deficiencies. By comparing wild-type and mutant cells, researchers can determine the functional impact of individual variants and test pharmacological chaperones.
Knock-in
Knock-in of reporter tags or epitope tags (e.g., FLAG, GFP) into endogenous loci enables real-time tracking of protein expression and localization. For example, tagging ACSL5 with GFP allows visualization of its subcellular distribution and dynamics under different metabolic conditions. Knock-in of loxP sites also facilitates conditional knockout in specific tissues.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression is used to increase the expression of genes such as ACSL5 or SIRT6 to study their effects on very long-chain fatty-acyl-CoA catabolism. Overexpression of ACSL5 in hepatocytes enhances fatty acid oxidation and reduces lipid accumulation, suggesting a protective role against NAFLD.
How EDITGENE Supports very long-chain fatty-acyl-CoA catabolic process Research
Researchers studying very long-chain fatty-acyl-CoA catabolic process-related genes often need to determine whether a candidate gene is causally involved in the pathway or merely correlated with its activity. CRISPR-based gene editing provides a robust approach to establish causality by introducing precise genetic alterations in cell models and animal models. EDITGENE offers a comprehensive suite of services to support such studies, from knockout and point mutation to knock-in and overexpression, along with library screening and bioinformatics analysis.
Contact EDITGENE today to design your custom CRISPR model for very long-chain fatty-acyl-CoA catabolic process research.
Frequently Asked Questions About very long-chain fatty-acyl-CoA catabolic process
What is GO:0036113 very long-chain fatty-acyl-CoA catabolic process?
GO:0036113 is a Gene Ontology biological process term that describes the chemical reactions and pathways resulting in the breakdown of very long-chain fatty-acyl-CoAs, which are coenzyme A derivatives of fatty acids with aliphatic tails longer than 22 carbons.
What genes are involved in very long-chain fatty-acyl-CoA catabolic process?
Key genes include ACSL1, ACSL5, CPT1A, CPT2, ACADVL, ACADM, HADHA, HADHB, SIRT6, AMPK, PPARA, ETFA, ETFB, ETFDH, SLC25A20, ACOX1, HSD17B4, and SCP2, all of which encode enzymes or regulators of the pathway [1,4,5,6,8].
Where does very long-chain fatty-acyl-CoA catabolism occur in the cell?
It occurs primarily in mitochondria and peroxisomes. Peroxisomes perform initial chain shortening of very long-chain fatty acids, while mitochondria complete the beta-oxidation cycles [1,5].
What diseases are associated with defects in very long-chain fatty-acyl-CoA catabolism?
Defects cause inborn errors of mitochondrial acyl-CoA metabolism, such as VLCAD deficiency, MCAD deficiency, CPT2 deficiency, and trifunctional protein deficiency, as well as nonalcoholic fatty liver disease and peroxisomal disorders [4,5].
How is very long-chain fatty-acyl-CoA catabolism regulated?
It is regulated transcriptionally by PPARA, post-translationally by SIRT6-mediated deacetylation of ACSL5, and allosterically by malonyl-CoA inhibition of CPT1. AMPK also senses long-chain fatty acyl-CoA esters to modulate energy homeostasis [1,4,6,8].
What is the role of ACSL5 in very long-chain fatty-acyl-CoA catabolism?
ACSL5 activates very long-chain fatty acids to their acyl-CoA esters, a prerequisite for beta-oxidation. Its activity is enhanced by SIRT6 deacetylation, and it protects against nonalcoholic fatty liver disease.
How can CRISPR be used to study very long-chain fatty-acyl-CoA catabolic process?
CRISPR knockout, point mutation, knock-in, and overexpression models allow researchers to test the causal role of specific genes in the pathway, identify novel regulators through library screening, and validate disease-associated variants.
What methods are used to measure very long-chain fatty-acyl-CoA catabolism?
Common methods include acyl-CoA synthetase activity assays, beta-oxidation flux assays, Seahorse respirometry, metabolomics, lipidomics, and CRISPR screens [1,3,5,7].
What is the difference between very long-chain and long-chain fatty acyl-CoA catabolism?
Very long-chain fatty acyl-CoAs have aliphatic tails longer than 22 carbons and require peroxisomal beta-oxidation for initial chain shortening, whereas long-chain fatty acyl-CoAs (12-22 carbons) are primarily oxidized in mitochondria [1,5].
Why is very long-chain fatty-acyl-CoA catabolism important for energy metabolism?
It provides a major source of ATP during fasting by oxidizing very long-chain fatty acids to acetyl-CoA, NADH, and FADH2, which fuel the TCA cycle and oxidative phosphorylation [1,2].
Conclusion
Very long-chain fatty-acyl-CoA catabolic process (GO:0036113) is a fundamental metabolic pathway that enables cells to derive energy from very long-chain fatty acids and prevents lipotoxicity. Its dysregulation is linked to a range of human diseases, including inborn errors of metabolism, nonalcoholic fatty liver disease, and peroxisomal disorders. The pathway is tightly regulated by transcriptional, post-translational, and allosteric mechanisms, with key roles for PPARA, SIRT6, AMPK, and malonyl-CoA. Advances in CRISPR gene editing and high-throughput screening have greatly expanded our ability to dissect the genetic basis of this process and to identify new therapeutic targets. EDITGENE's comprehensive services in knockout, point mutation, knock-in, overexpression, and library screening provide researchers with powerful tools to study very long-chain fatty-acyl-CoA catabolism and its role in health and disease.
References
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- 4. Hou T et al.. 2022. Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation.. Mol Cell 82(21):4099-4115.e9 PMID: 36208627
- 5. Yang H et al.. 2019. Inborn errors of mitochondrial acyl-coenzyme a metabolism: acyl-CoA biology meets the clinic.. Mol Genet Metab 128(1-2):30-44 PMID: 31186158
- 6. Desjardins EM et al.. 2025. Sensing of Long-Chain Fatty Acyl-CoA Esters by AMPK.. Methods Mol Biol 2882:121-137 PMID: 39992507
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