ACOX1

The ACOX1 gene, located on chromosome 17, encodes the peroxisomal acyl-CoA oxidase 1 enzyme, crucial for peroxisomal fatty acid beta-oxidation.  This enzyme, the first and rate-limiting step in the pathway, converts acyl-CoAs to 2-trans-enoyl-CoAs while generating hydrogen peroxide (H₂O₂). 

ACOX1 is essential for shortening very long-chain fatty acids (VLCFAs) into acetyl-CoA, which is further metabolized by the cell.  Inducible by peroxisome proliferators, ACOX1 is involved in lipid metabolism and can be influenced by diet and fasting. 

Elevated ACOX1 levels, linked to oxidative stress and hepatocarcinogenesis, underscore its significance in metabolic regulation and inflammation resolution.

The ACOX1 Gene and Enzyme  [7.]

The ACOX1 gene, positioned on chromosome 17, is responsible for encoding the peroxisomal acyl-CoA oxidase 1 enzyme, which plays a leading role in peroxisomal fatty acid beta-oxidation.  [3.] 

ACOX1 is the first and rate-limiting enzyme in this pathway, catalyzing the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs while generating hydrogen peroxide (H₂O₂). 

The enzyme plays a key role in shortening VLCFAs by two carbon atoms at a time until they are converted to acetyl-CoA, which can then be transported out of the peroxisomes for further metabolism by the cell. 

ACOX1 plays a crucial role in lipid metabolism and is highly inducible by peroxisome proliferators, substances that can cause peroxisome proliferation and hepatomegaly in the liver. Such proliferators include certain drugs and environmental chemicals.

A high-fat diet and fasting can also increase ACOX1 levels.  [4.] 

Elevated levels of ACOX1, resulting from exposure to these compounds, are linked to oxidative stress and hepatocarcinogenesis due to the increased production of H₂O₂.

The structure of the ACOX1 gene allows for the production of several isoforms of the enzyme, which may differ slightly in their activity and function, depending on the tissue distribution and cellular needs.  [8.] 

ACOX1’s Anti-Inflammatory and Anti-Aging Role  [6.] 

Interestingly, the upregulation of ACOX1 by exposure to certain drugs and environmental toxins may also promote anti-inflammatory and anti-aging actions.  

One study examined the effects of argan oil on hepatic inflammation, and found that argan oil has been shown to protect the liver from LPS-induced inflammation and toxicity by preserving the activity of ACOX1.  

ACOX1 is involved in the production of specialized pro-resolving mediators (SPM), which are crucial for resolving inflammation. This protective effect of argan oil extends to aging-related disorders, where reduced ACOX1 activity and SPM levels are common. 

Strategies to increase ACOX1 and SPM levels can potentially improve conditions like metabolic syndrome, diabetes, neurodegenerative diseases, and cardiovascular disorders.  

The findings of this study suggest that ACOX1 is an emerging anti-aging protein due to its role in metabolic regulation and inflammation resolution. 

Diseases Associated with ACOX1

Over 20 mutations in the ACOX1 gene have been identified in individuals with peroxisomal acyl-CoA oxidase deficiency, which disrupt the enzyme's ability to efficiently break down very long-chain fatty acids (VLCFAs), leading to their accumulation in the body. 

Leukodystrophy, or the loss of myelin-containing white matter in the nervous system, is a common feature and is believed to play a significant role in the development of the neurological abnormalities associated with peroxisomal acyl-CoA oxidase deficiency.

Although the precise mechanism by which VLCFA accumulation results in the clinical features of this deficiency remains unclear, researchers hypothesize that the buildup of VLCFAs triggers inflammation within the nervous system which ultimately degrades myelin.  [1.]

Pseudoneonatal Adrenoleukodystrophy  [2.] 

Pseudoneonatal adrenoleukodystrophy (P-NALD) is a rare neurodegenerative disorder characterized by ACOX1 (acyl-CoA oxidase 1) deficiency, leading to the accumulation of very-long-chain fatty acids (VLCFA) and inflammatory demyelination, particularly affecting white matter. 

Clinical manifestations of P-NALD include craniofacial dysmorphia, generalized hypotonia, hepatomegaly, infantile seizures, loss of motor skills, and white matter demyelination.

ACOX1 deficiency in P-NALD leads to significant inflammatory responses mediated primarily by the IL-1 pathway.

ACOX1 is essential for the β-oxidation of VLCFA in peroxisomes and its deficiency triggers the IL-1 inflammatory pathway, resulting in elevated secretion of IL-6 and IL-8 cytokines.  Studies have shown that VLCFA accumulation in patient fibroblasts induces mRNA expression of IL-1α and IL-1β cytokines. 

Patient-derived fibroblasts exhibit increased secretion of IL-6 and IL-8, a reduction in the number of peroxisomes, and enlarged peroxome sizes.  

Mitchell Syndrome  [5.] 

Mitchell Syndrome (MITCH) is an extremely rare, autosomal dominant hereditary disorder marked by episodic demyelination, sensorimotor polyneuropathy, and hearing loss.  This condition results from a heterozygous mutation in the ACOX1 gene, specifically a heterozygous c.710A>G (p.Asp237Ser) variant in the ACOX1 gene. 

Clinicians should consider MITCH in patients with recurrent rash, gait instability, hearing loss, and autonomic symptoms, and initiate prompt genetic testing and treatment. This case underscores the importance of early diagnosis and intervention in managing MITCH.

Genetic Alterations in the ACOX1 Gene

The gene for the ACOX1 protein may contain alterations or mutations that cause increase or decrease of function of the ACOX1 protein.  

Testing for genetic alterations in the form of SNPs is increasingly available and can shed light on an individual’s potential for health and disease.  

What is a SNP?

A SNP, or single nucleotide polymorphism, refers to a variation at a single position in a gene along its DNA sequence.  A gene encodes a protein, so an alteration in that gene programs the production of an altered protein.  

As a type of protein with great functionality in human health, alterations in genes for enzymes may confer a difference in function of that enzyme.  The function of that enzyme may be increased or decreased, depending on the altered protein produced.  

SNPs are the most common type of genetic variation in humans and can occur throughout the genome, influencing traits, susceptibility to diseases, and response to medications.

The completion of the Human Genome Project has significantly expanded opportunities for genetic testing by providing a comprehensive map of the human genome that facilitates the identification of genetic variations associated with various health conditions, including identifying SNPs that may cause alterations in protein structure and function.  

Genetic testing for SNPs enables the identification of alterations in genes, shedding light on their implications in health and disease susceptibility.

Laboratory Testing for ACOX1

Genetic testing for single nucleotide polymorphisms (SNPs) typically involves obtaining a sample of DNA which can be extracted from blood, saliva, or cheek swabs. 

The sample may be taken in a lab, in the case of a blood sample.  Alternatively, a saliva or cheek swab sample may be taken from the comfort of home. 

Test Preparation

Prior to undergoing genetic testing, it's important to consult with a healthcare provider or genetic counselor to understand the purpose, potential outcomes, and implications of the test.  This consultation may involve discussing medical history, family history, and any specific concerns or questions. 

Additionally, individuals may be advised to refrain from eating, drinking, or chewing gum for a short period before providing a sample to ensure the accuracy of the test results.  Following sample collection, the DNA is processed in a laboratory where it undergoes analysis to identify specific genetic variations or SNPs. 

Once the testing is complete, individuals will typically receive their results along with interpretation and recommendations from a healthcare professional. 

Patient-Centric Approaches

A patient-centered approach to SNP genetic testing emphasizes individualized medicine, tailoring healthcare decisions and interventions based on an individual's unique genetic makeup.

When that is combined with the individual’s health status and health history, preferences, and values, a truly individualized plan for care is possible. 

By integrating SNP testing into clinical practice, healthcare providers can offer personalized risk assessment, disease prevention strategies, and treatment plans that optimize patient outcomes and well-being. 

Genetic testing empowers a deeper understanding of genetic factors contributing to disease susceptibility, drug response variability, and overall health, empowering patients to actively participate in their care decisions. 

Furthermore, individualized medicine recognizes the importance of considering socioeconomic, cultural, and environmental factors alongside genetic information to deliver holistic and culturally sensitive care that aligns with patients' goals and preferences. 

Through collaborative decision-making and shared decision-making processes, patients and providers can make informed choices about SNP testing, treatment options, and lifestyle modifications, promoting patient autonomy, engagement, and satisfaction in their healthcare journey.

Genetic Panels and Combinations

Integrating multiple biomarkers into panels or combinations enhances the predictive power and clinical utility of pharmacogenomic testing.  

Biomarker panels comprising a variety of transporter proteins and enzymes including drug metabolizing enzymes offer comprehensive insights into individual drug response variability and treatment outcomes. 

Combining genetic SNP testing associated with drug transport, metabolism, and pharmacodynamics enables personalized medicine approaches tailored to individual patient characteristics and genetic profiles.

Order Genetic Testing

Click here to compare genetic test panels and order genetic testing for health-related SNPs.