GO:0036111 very long-chain fatty-acyl-CoA metabolic process: Fatty Acid Oxidation Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0036111 describes the chemical reactions and pathways involving very long-chain fatty-acyl-CoAs, which are coenzyme A derivatives with fatty acyl chains longer than 22 carbons.
• Very long-chain fatty-acyl-CoAs are essential intermediates in mitochondrial and peroxisomal fatty acid oxidation, and their metabolism is tightly linked to energy homeostasis.
• Key enzymes include ACSL family ligases, which activate very long-chain fatty acids to their CoA esters, and acyl-CoA dehydrogenases that initiate beta-oxidation.
• Dysregulation of very long-chain fatty-acyl-CoA metabolism contributes to insulin resistance, nonalcoholic fatty liver disease, and metabolic disorders.
• Malonyl-CoA and long-chain acyl-CoAs act as signaling molecules that modulate insulin sensitivity and AMPK activity.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) enable precise dissection of genes involved in very long-chain fatty-acyl-CoA metabolism.
Description
Very long-chain fatty-acyl-CoA metabolic process (GO:0036111) encompasses the biochemical reactions and pathways that convert very long-chain fatty acids (VLCFAs, with aliphatic tails longer than 22 carbons) into their coenzyme A thioester derivatives and subsequently metabolize them. These acyl-CoA species are central to cellular lipid handling, serving as substrates for beta-oxidation, membrane lipid synthesis, and signaling. The process is essential for energy production, particularly in tissues with high metabolic demand such as liver, muscle, and heart. Researchers study GO:0036111 because its dysregulation is increasingly linked to metabolic diseases, including insulin resistance, nonalcoholic fatty liver disease (NAFLD), and mitochondrial dysfunction. The activation of VLCFAs to their CoA esters by acyl-CoA synthetase long-chain family members (ACSLs) is a prerequisite for both catabolic and anabolic fates. Moreover, very long-chain fatty-acyl-CoAs participate in signaling pathways that sense nutrient status and regulate energy balance. Understanding the molecular players and regulatory mechanisms of this process is critical for developing therapeutic strategies targeting lipid metabolism. This article synthesizes authoritative QuickGO annotations and verified PubMed literature to provide a comprehensive overview of GO:0036111, its genes, disease relevance, and experimental approaches.
very long-chain fatty-acyl-CoA metabolic process At A Glance
| GO ID | GO:0036111 |
|---|---|
| GO term | very long-chain fatty-acyl-CoA metabolic process |
| Ontology | biological_process |
| Synonym | very long-chain fatty acyl CoA metabolic process; very long-chain fatty acyl-CoA metabolism |
| Major function | Metabolism of coenzyme A thioesters of fatty acids with aliphatic tails longer than 22 carbons, including their synthesis and oxidation. |
| Key enzymes | ACSL family ligases, acyl-CoA dehydrogenases, and thiolases. |
| Subcellular locations | Mitochondria, peroxisomes, and cytosol. |
| Related pathways | Fatty acid beta-oxidation, lipid biosynthesis, energy homeostasis. |
| Disease relevance | Insulin resistance, NAFLD, metabolic syndrome. |
What Is GO:0036111?
GO:0036111, very long-chain fatty-acyl-CoA metabolic process, is defined as the chemical reactions and pathways involving very long-chain fatty-acyl-CoAs. These molecules are derivatives 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. This process includes the synthesis, modification, and degradation of these acyl-CoA species, which are key intermediates in fatty acid oxidation and lipid biosynthesis.
Why Is very long-chain fatty-acyl-CoA metabolic process Important in Cell Biology?
Very long-chain fatty-acyl-CoA metabolic process is fundamental to cellular energy metabolism and lipid homeostasis. It provides substrates for mitochondrial and peroxisomal beta-oxidation, which generates ATP and acetyl-CoA, and supplies acyl-CoAs for membrane lipid synthesis. Dysregulation of this process leads to accumulation of toxic lipid intermediates, mitochondrial dysfunction, and metabolic diseases such as insulin resistance and NAFLD. Furthermore, very long-chain acyl-CoAs act as signaling molecules that modulate AMPK activity and insulin sensitivity, making this pathway a critical node in nutrient sensing.
• Provides essential substrates for mitochondrial beta-oxidation and energy production.
• Supplies acyl-CoAs for synthesis of complex lipids and membrane components.
• Regulates insulin sensitivity and glucose homeostasis through malonyl-CoA and long-chain acyl-CoA signaling.
• Implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) via ACSL5 and SIRT6.
• Modulates AMPK activity, a master regulator of cellular energy balance.
• Dysfunction contributes to metabolic syndrome, type 2 diabetes, and cardiovascular disease.
• Target for therapeutic intervention in lipid disorders and obesity.
• Essential for peroxisomal metabolism of very long-chain fatty acids, defects in which cause adrenoleukodystrophy.
• Involved in macrophage polarization and inflammatory responses.
• Provides biomarkers for metabolic disease progression and treatment response.
What Happens During very long-chain fatty-acyl-CoA metabolic process?
Activation of Very Long-Chain Fatty Acids to Acyl-CoAs
In simple terms: Fatty acids must be activated by attaching coenzyme A before they can be metabolized.
The first step in very long-chain fatty-acyl-CoA metabolism is the activation of free very long-chain fatty acids to their coenzyme A thioesters, catalyzed by acyl-CoA synthetase long-chain family members (ACSLs). This reaction requires ATP and CoA, forming a thioester bond between the fatty acid carboxyl group and the sulfhydryl group of CoA. ACSL5, for example, is a key isoform that activates long-chain and very long-chain fatty acids in the liver, and its activity is regulated by deacetylation via SIRT6. This activation step is essential for subsequent oxidation or lipid synthesis.
Mitochondrial Beta-Oxidation of Very Long-Chain Acyl-CoAs
In simple terms: Once activated, very long-chain acyl-CoAs are broken down in mitochondria to produce energy.
Very long-chain acyl-CoAs undergo beta-oxidation in mitochondria, a process that removes two-carbon units as acetyl-CoA, generating FADH2 and NADH. The first step is catalyzed by acyl-CoA dehydrogenases, which introduce a double bond between the alpha and beta carbons. This is followed by hydration, dehydrogenation, and thiolytic cleavage by a thiolase. The acetyl-CoA produced enters the TCA cycle for further energy production. Mitochondrial beta-oxidation of very long-chain fatty acids requires the carnitine shuttle for transport into the mitochondrial matrix.
Peroxisomal Oxidation of Very Long-Chain Fatty Acids
In simple terms: Peroxisomes also break down very long-chain fatty acids, especially those that mitochondria cannot handle.
Peroxisomes are the primary site for the initial oxidation of very long-chain fatty acids (VLCFAs) because mitochondrial beta-oxidation is inefficient for chains longer than 22 carbons. Peroxisomal beta-oxidation shortens VLCFAs to medium-chain fatty acids, which are then shuttled to mitochondria for complete oxidation. This process involves acyl-CoA oxidases, which generate hydrogen peroxide, and multifunctional enzymes with hydratase and dehydrogenase activities. Defects in peroxisomal beta-oxidation lead to accumulation of VLCFAs, as seen in X-linked adrenoleukodystrophy.
Regulation by Malonyl-CoA and AMPK Signaling
In simple terms: The levels of very long-chain acyl-CoAs are sensed by cellular energy sensors to adjust metabolism.
Malonyl-CoA, a key intermediate in fatty acid synthesis, inhibits carnitine palmitoyltransferase 1 (CPT1), thereby preventing very long-chain acyl-CoAs from entering mitochondria for oxidation. This regulation ensures that fatty acid oxidation is suppressed when fatty acid synthesis is active. Conversely, AMPK senses increases in long-chain fatty acyl-CoA esters and is activated by them, leading to enhanced fatty acid oxidation and inhibition of lipogenesis. This feedback loop maintains energy homeostasis and insulin sensitivity.
Partitioning of Very Long-Chain Acyl-CoAs Between Oxidation and Lipid Synthesis
In simple terms: Acyl-CoAs can be used either for energy production or for building complex lipids.
Very long-chain acyl-CoAs are partitioned between catabolic pathways (beta-oxidation) and anabolic pathways (synthesis of triglycerides, phospholipids, and sphingolipids) depending on cellular needs. This partitioning is regulated by the availability of substrates, the activity of acyltransferases, and hormonal signals. For example, in the liver, excess acyl-CoAs are esterified into triglycerides for storage, contributing to steatosis when dysregulated. The balance between oxidation and esterification is critical for preventing lipotoxicity.
Key Genes Involved in GO:0036111 very long-chain fatty-acyl-CoA metabolic process
The following genes and proteins are central to very long-chain fatty-acyl-CoA metabolic process, based on verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| ACSL1 | Activates long-chain and very long-chain fatty acids to acyl-CoAs | Key isoform in liver and adipose tissue; target for metabolic studies |
| ACSL5 | Activates very long-chain fatty acids in liver; regulated by SIRT6 deacetylation | Implicated in NAFLD; potential therapeutic target |
| ACSL6 | Activates very long-chain fatty acids in brain and muscle | Role in neuronal lipid metabolism |
| CPT1A | Transports long-chain acyl-CoAs into mitochondria for beta-oxidation | Regulated by malonyl-CoA; key node in fatty acid oxidation |
| ACADVL | Very long-chain acyl-CoA dehydrogenase; first step of mitochondrial beta-oxidation | Deficiency causes VLCAD deficiency |
| ACADM | Medium-chain acyl-CoA dehydrogenase | Model for beta-oxidation studies |
| HADHA | Trifunctional protein subunit; catalyzes hydration and dehydrogenation in beta-oxidation | Mutations cause mitochondrial trifunctional protein deficiency |
| HADHB | Trifunctional protein subunit; thiolase activity | Deficiency leads to neuropathy and cardiomyopathy |
| SIRT6 | Deacetylates ACSL5 to promote fatty acid oxidation | Suppresses NAFLD progression |
| AMPK | Senses long-chain acyl-CoAs; regulates energy homeostasis | Target for metabolic syndrome |
| ACOX1 | Peroxisomal acyl-CoA oxidase; initiates VLCFA beta-oxidation | Deficiency causes peroxisomal disorders |
| SLC25A17 | Peroxisomal CoA transporter | Required for peroxisomal beta-oxidation |
| ETFA | Electron transfer flavoprotein subunit; accepts electrons from acyl-CoA dehydrogenases | Deficiency causes glutaric acidemia type II |
| ETFB | Electron transfer flavoprotein subunit | Part of mitochondrial beta-oxidation electron transfer |
| ETFDH | Electron transfer flavoprotein dehydrogenase | Links beta-oxidation to respiratory chain |
| ACAA1 | Peroxisomal thiolase | Involved in peroxisomal beta-oxidation |
| SCP2 | Sterol carrier protein 2; involved in lipid transfer and peroxisomal beta-oxidation | Role in VLCFA metabolism |
| CROT | Carnitine O-octanoyltransferase; peroxisomal acyltransferase | Participates in peroxisomal fatty acid oxidation |
How Is very long-chain fatty-acyl-CoA metabolic process Regulated?
Very long-chain fatty-acyl-CoA metabolic process is regulated at multiple levels. Malonyl-CoA, a key intermediate in fatty acid synthesis, inhibits CPT1, thereby preventing very long-chain acyl-CoAs from entering mitochondria for beta-oxidation. AMPK senses increases in long-chain fatty acyl-CoA esters and is activated by them, leading to enhanced fatty acid oxidation and inhibition of lipogenesis. Additionally, SIRT6 deacetylates ACSL5, promoting its activity and facilitating hepatic fatty acid oxidation, which impedes NAFLD progression. Hormonal signals such as insulin and glucagon also modulate the expression and activity of enzymes involved in this pathway.
very long-chain fatty-acyl-CoA metabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| ACSL5 | Nonalcoholic fatty liver disease | Liver-specific knockout or overexpression in mice |
| SIRT6 | NAFLD, metabolic syndrome | SIRT6 knockout or deacetylation-deficient knock-in |
| ACADVL | VLCAD deficiency | Patient-derived fibroblasts or knock-in mouse models |
| HADHA | Mitochondrial trifunctional protein deficiency | Knockout cell lines and mouse models |
| ACOX1 | Peroxisomal disorders | Knockout mice and patient cells |
Nonalcoholic Fatty Liver Disease (NAFLD)
Dysregulation of very long-chain fatty-acyl-CoA metabolism contributes to NAFLD. Cytoplasmic SIRT6-mediated deacetylation of ACSL5 promotes hepatic fatty acid oxidation and impedes NAFLD progression. Reduced ACSL5 activity leads to accumulation of triglycerides and lipotoxicity in hepatocytes. Therefore, targeting ACSL5 or SIRT6 may offer therapeutic strategies for NAFLD.
Insulin Resistance and Type 2 Diabetes
Elevated levels of long-chain fatty acyl-CoAs in skeletal muscle are associated with insulin resistance. Malonyl-CoA and long-chain acyl-CoAs inhibit insulin-stimulated glucose uptake and glycogen synthesis. This link between lipid metabolism and insulin signaling highlights the importance of very long-chain fatty-acyl-CoA metabolic process in metabolic diseases.
Mitochondrial Fatty Acid Oxidation Disorders
Defects in mitochondrial beta-oxidation of very long-chain fatty acids cause diseases such as very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and mitochondrial trifunctional protein deficiency. These disorders present with hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis. Understanding the metabolic process is essential for diagnosis and management.
Peroxisomal Disorders
Impaired peroxisomal oxidation of very long-chain fatty acids leads to their accumulation, as seen in X-linked adrenoleukodystrophy. This disease affects the nervous system and adrenal glands, underscoring the importance of peroxisomal very long-chain fatty-acyl-CoA metabolism.
From very long-chain fatty-acyl-CoA metabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of ACSL5 impair hepatic fatty acid oxidation? | ACSL5 knockout hepatocytes or liver-specific KO mice |
| Does SIRT6 deacetylation of ACSL5 regulate NAFLD? | SIRT6 knockout or deacetylation-deficient knock-in mice |
| How does AMPK sense long-chain acyl-CoAs? | AMPK knockout or point-mutant cell lines |
| What is the role of ACADVL in very long-chain fatty acid oxidation? | ACADVL knockout cell lines and patient fibroblasts |
| Can overexpression of ACSL5 protect against steatosis? | Adenoviral overexpression in mouse liver |
| Does malonyl-CoA inhibition of CPT1 affect insulin sensitivity? | CPT1 knock-in mice with altered malonyl-CoA sensitivity |
How to Study the very long-chain fatty-acyl-CoA metabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| LC-MS/MS | Quantification of acyl-CoA species | Profiling very long-chain fatty-acyl-CoAs in tissues |
| Radioactive ACSL assay | Acyl-CoA synthetase activity | Enzyme kinetics and inhibitor testing |
| Seahorse XF | Mitochondrial respiration and fatty acid oxidation | Assessing metabolic phenotypes |
| CRISPR knockout screen | Gene essentiality and pathway interactions | Identifying novel regulators of acyl-CoA metabolism |
| Western blot | Protein expression of ACSL, CPT1, etc. | Validating knockout or overexpression |
| qRT-PCR | mRNA levels of metabolic genes | Gene expression analysis |
| Immunofluorescence | Subcellular localization of enzymes | Visualizing peroxisomal and mitochondrial proteins |
| CoA homeostasis assay | Total CoA and acetyl-CoA levels | Evaluating CoA pool size |
Measuring Acyl-CoA Levels by LC-MS/MS
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is the gold standard for quantifying very long-chain fatty-acyl-CoA species in cells and tissues. This method allows simultaneous measurement of multiple acyl-CoA esters, providing insights into pathway flux and substrate availability. Sample preparation involves extraction of acyl-CoAs under acidic conditions to prevent hydrolysis.
Enzymatic Assays for ACSL Activity
Acyl-CoA synthetase activity can be measured using radioactive or fluorescent substrates. The assay typically monitors the formation of acyl-CoA from fatty acid, ATP, and CoA. This method is useful for determining the kinetic properties of ACSL isoforms and the effects of mutations.
Seahorse Extracellular Flux Analysis
Seahorse XF analyzers measure oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) to assess mitochondrial function and fatty acid oxidation in live cells. This technique can be used to evaluate the impact of very long-chain fatty-acyl-CoA metabolism on cellular bioenergetics.
CRISPR Screens for Metabolic Genes
Genome-wide CRISPR knockout screens can identify genes required for very long-chain fatty-acyl-CoA metabolism and its crosstalk with other pathways. Such screens have revealed roles for CoA homeostasis in macrophage polarization. Bioinformatics analysis of screen data helps prioritize candidate genes for follow-up.
How CRISPR Can Be Used to Study GO:0036111 very long-chain fatty-acyl-CoA metabolic process
Knockout
CRISPR knockout of genes such as ACSL5 or SIRT6 enables researchers to study their loss-of-function phenotypes in very long-chain fatty-acyl-CoA metabolism. Knockout cell lines and mouse models have demonstrated the importance of these genes in hepatic fatty acid oxidation and NAFLD progression. Knockout of ACADVL recapitulates features of VLCAD deficiency.
Point Mutation
Point mutations can be introduced to mimic disease-associated variants or to dissect catalytic residues. For example, point mutations in ACSL5 can test the importance of specific acetylation sites targeted by SIRT6. Similarly, mutations in CPT1A can alter malonyl-CoA sensitivity, providing insights into regulation of fatty acid oxidation.
Knock-in
Knock-in models allow expression of tagged or mutant proteins at endogenous loci. A tagged ACSL5 knock-in can facilitate studies of protein interactions and localization. Knock-in of disease-causing mutations in ACADVL or HADHA provides accurate models for mitochondrial beta-oxidation disorders.
Overexpression
Overexpression of ACSL5 or SIRT6 can protect against lipid accumulation and improve fatty acid oxidation. Overexpression models are useful for gain-of-function studies and for testing therapeutic hypotheses. Inducible overexpression systems allow temporal control of gene expression.
How EDITGENE Supports very long-chain fatty-acyl-CoA metabolic process Research
Researchers studying very long-chain fatty-acyl-CoA metabolic process-related genes often need to determine whether a candidate gene is causally involved in lipid metabolism, disease progression, or therapeutic response. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this research, from gene knockout to precise point mutations and library screening.
Contact EDITGENE today to design your custom CRISPR model for very long-chain fatty-acyl-CoA metabolic process research.
Frequently Asked Questions About very long-chain fatty-acyl-CoA metabolic process
What is very long-chain fatty-acyl-CoA metabolic process?
It is the set of biochemical reactions involving coenzyme A thioesters of fatty acids with aliphatic tails longer than 22 carbons, including their synthesis and oxidation.
What genes are involved in very long-chain fatty-acyl-CoA metabolic process?
Key genes include ACSL1, ACSL5, ACSL6, CPT1A, ACADVL, HADHA, HADHB, SIRT6, AMPK, and ACOX1.
What is the GO ID for very long-chain fatty-acyl-CoA metabolic process?
The GO ID is GO:0036111.
How is very long-chain fatty-acyl-CoA metabolism regulated?
It is regulated by malonyl-CoA inhibition of CPT1, AMPK sensing of acyl-CoAs, and SIRT6-mediated deacetylation of ACSL5.
What diseases are associated with very long-chain fatty-acyl-CoA metabolic process?
Diseases include nonalcoholic fatty liver disease, insulin resistance, type 2 diabetes, VLCAD deficiency, and peroxisomal disorders.
What methods are used to study very long-chain fatty-acyl-CoA metabolism?
Common methods include LC-MS/MS for acyl-CoA quantification, enzymatic assays for ACSL activity, Seahorse flux analysis, and CRISPR screens.
How can CRISPR be used to study very long-chain fatty-acyl-CoA metabolic process?
CRISPR knockout, point mutation, knock-in, and overexpression models allow precise manipulation of genes like ACSL5 and SIRT6 to study their roles in lipid metabolism.
What is the role of ACSL5 in very long-chain fatty-acyl-CoA metabolism?
ACSL5 activates very long-chain fatty acids to their CoA esters, and its deacetylation by SIRT6 promotes hepatic fatty acid oxidation and impedes NAFLD.
How does AMPK sense long-chain acyl-CoAs?
AMPK is activated by long-chain fatty acyl-CoA esters, leading to enhanced fatty acid oxidation and inhibition of lipogenesis.
What is the significance of very long-chain fatty-acyl-CoA metabolic process in energy homeostasis?
It provides substrates for mitochondrial and peroxisomal beta-oxidation, generating ATP and acetyl-CoA, and regulates insulin sensitivity through signaling metabolites.
Conclusion
Very long-chain fatty-acyl-CoA metabolic process (GO:0036111) is a central pathway in lipid metabolism, linking fatty acid activation to energy production and lipid synthesis. Its dysregulation contributes to prevalent metabolic diseases, including NAFLD and insulin resistance. The genes and enzymes involved, such as ACSL5, SIRT6, and AMPK, are promising therapeutic targets. Advances in CRISPR-based models and analytical methods continue to unravel the complexities of this pathway, offering new opportunities for intervention.
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
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