ACSL5

ACSL5, or Acyl-CoA Synthetase Long-Chain Family Member 5, plays a crucial role in lipid metabolism by catalyzing the activation of long-chain fatty acids into acyl-CoA esters, which are essential for various metabolic pathways including lipid synthesis and degradation. 

Recent studies highlight ACSL5's significant role in nonalcoholic fatty liver disease (NAFLD) by facilitating hepatic fatty acid oxidation. 

Dysregulation of ACSL5 is implicated in the pathogenesis of metabolic disorders, and understanding its function could lead to new therapeutic strategies for conditions like NAFLD, obesity, and insulin resistance.

What is ACSL5? [2., 9.] 

ACSL5, or acyl-CoA synthetase long-chain family member 5, is an enzyme essential for lipid metabolism. It is primarily found in the endoplasmic reticulum and mitochondrial outer membrane of cells. 

ACSL5 helps convert long-chain fatty acids (with 16 to 20 carbon atoms) into fatty acyl-CoAs, which are essential for various metabolic processes.

Its activity is regulated by factors like diet, fasting, and specific proteins, making it a key player in maintaining energy homeostasis and impacting conditions like insulin resistance and metabolic disorders.

Normal Functions of ACSL5 

ACSL5 facilitates the formation of fatty acyl-CoAs from long-chain fatty acids, which can then be used for either synthesizing complex lipids or undergoing β-oxidation in mitochondria to produce energy. [9.] 

Where is ACSL5 Normally Expressed? 

This enzyme plays a significant role in different tissues including the liver, small intestine, adipose tissue, and skeletal muscle.  [9.] 

In the liver and small intestine, ACSL5 is involved in both lipid synthesis and fatty acid breakdown. In skeletal muscle, it primarily aids in fatty acid oxidation. [9.] 

ACSL5 is highly expressed in the small intestinal epithelium, contributing about 80% of total ACSL activity. [9.] 

It is also found in the uterus, spleen, and lung.  Finally, ACSL5 is found in trace amounts in normal brain tissue, but shows markedly increased levels in malignant gliomas. [9.] 

ACSL5 in Health and Disease

Fatty Liver Disease

While ACSL5 has been associated as protective against fatty liver, its role is still being determined, and research findings are nuanced.  

The mechanism of action of ACSL5’s protective role against fatty liver involves the following: [5.] 

When SIRT6, a protein that regulates metabolism, binds with saturated fatty acids like palmitic acid, it moves out of the cell's nucleus to the cytoplasm. 

There, it interacts with ACSL5 and removes acetyl groups from it, a process called deacetylation. This deacetylation activates ACSL5, enhancing its ability to oxidize fatty acids, which helps reduce lipid accumulation in the liver. 

Overexpression of ACSL5 in the liver has been shown to mitigate the effects of a high-fat diet, suggesting that targeting the SIRT6-ACSL5 pathway could be a promising strategy for treating or preventing NAFLD. [5.] 

Overexpression of ACSL5 in human liver cells (HepG2) promotes fatty acid oxidation and reduces triglyceride (TG) accumulation, while ACSL5 knockdown results in increased TG content, suggesting ACSL5 helps prevent TG build-up by enhancing fatty acid oxidation. [9.] 

However, there are contradictory findings, as some studies suggest that ACSL5 knockdown can also increase fatty acid oxidation, adding complexity to its role. [5.] 

One article also points out that inhibiting ACSL5 improves insulin resistance, making ACSL5 a potential therapeutic target for metabolic diseases, including fatty liver disease.  [5.] 

Metabolic Disorders

While not a specific disease, ACSL5 has been implicated in glucose and lipid metabolism, suggesting a potential role in various metabolic disorders.

One study reveals that while ACSL5 boosts fatty acid oxidation in muscle cells, it also increases oxidative stress and reduces insulin sensitivity. This dual effect suggests that ACSL5 plays a complex role in energy metabolism and may contribute to metabolic disorders when overexpressed. [8.] 

Overexpression of ACSL5 doubled the cells' ability to completely and incompletely break down fatty acids for energy, increasing cellular efficiency at using fatty acids for fuel. [8.] 

And ACSL5 overexpression led to higher mitochondrial respiration rates, indicating that the mitochondria were more active in burning fatty acids. [8.] 

However, despite the increased fatty acid oxidation, overexpression of ACSL5 also caused a 30% rise in the production of mitochondrial superoxide, a type of reactive oxygen species (ROS). [8.] High levels of ROS are damaging to cells and contribute to various diseases. 

ACSL5 overexpression also resulted in decreased insulin signaling. [8.] Specifically, it reduced the activity of important proteins in the insulin signaling pathway, such as Akt and AS160, which are crucial for glucose uptake. 

This suggests that higher ACSL5 levels might impair the muscle cells' ability to respond to insulin, potentially leading to insulin resistance.

Celiac Disease [4.] 

Impaired expression of ACSL5 has been associated with coeliac disease.

In celiac disease, there is a reduction in ACSL5 expression in enterocytes. This diminished expression of ACSL5 in celiac disease correlates with a decrease in apoptosis at the villus tips, suggesting a potential mechanism for the observed enterocyte pathology in celiac disease.

The reduced apoptosis might contribute to the malabsorption and villous atrophy characteristic of celiac disease.

Intestinal Complaints

A genetic study identified a homozygous mutation in ACSL5 (c.1358C > A p. T453K) in a family with six affected members who experienced recurrent vomiting and diarrhea. [2., 3., 9.] 

This mutation resulted in significantly reduced ACSL5 activity compared to the normal protein, suggesting that ACSL5 dysfunction can lead to chronic gastrointestinal symptoms.

Malignant Gliomas

Markedly increased levels of ACSL5 have been observed in malignant gliomas compared to normal brain tissue. [A1.] 

Amyotrophic Lateral Sclerosis (ALS) 

The ACSL5 gene is believed to be involved in the pathogenesis of ALS through its role in lipid metabolism and its potential neurotoxic effects. [10.] 

ACSL5 is identified as a gene related to neurotoxic A1 astrocytes. These astrocytes are abundant in various neurodegenerative diseases, including ALS. [10.] They are known to induce the death of neurons in the central nervous system. 

The increased expression of ACSL5 may lead to the formation of these harmful astrocytes, causing motor neuron death and contributing to ALS development. [10.] 

The higher expression of ACSL5 seen with certain genetic variants may disrupt normal lipid metabolism, which has been linked to ALS. [10.] 

However, ALS is recognized as a multifactorial disease, meaning it results from multiple genetic and environmental factors. 

Cancer [9., 11., 12.]

Dysregulation of ACSL5 has been observed in various cancers, including glioma and colon cancer. 

Specifically, in acute myeloid leukemia (AML), ACSL5 expression is higher in the bone marrow cells of patients compared to healthy individuals. Elevated ACSL5 levels can predict poorer overall survival in AML patients. [11.] 

Knock-down of ACSL5 in AML cells inhibits their growth both in lab conditions and in living organisms. 

Additionally, triacsin C, an inhibitor affecting the ACS family, combined with ABT-199 (an FDA-approved BCL-2 inhibitor for AML), induces cell apoptosis and hinders cell growth. 

These findings suggest that ACSL5 could be an important marker for AML prognosis and a potential target for its treatment.

Furthermore, ACSL5 is implicated in hepatocellular carcinoma (HCC) through the PPARGC1A/BAMBI/ACSL5 pathway. [12.] 

PPARGC1A, typically low in HCC and linked to poor prognosis, inhibits the WNT/β-catenin signaling pathway, thereby repressing BAMBI and regulating ACSL5 via TGF-β/SMAD signaling. This regulation impacts ROS production and ferroptosis-related cell death. 

Genetic Alterations in the ACSL5 Gene

The gene for the ACSL5 protein may contain alterations or mutations that cause increase or decrease of function of the ACSL5 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.

Specific SNPs Associated with Alterations in ACSL5 Function

c.1358C-A, THR453LYS [3., 9.] 

In five children from a large Arab family with severe growth issues, vomiting, and diarrhea in infancy, researchers found a specific genetic mutation in the ACSL5 gene. 

This mutation, called c.1358C-A, causes a change in the protein made by the gene, swapping a threonine (Thr) for a lysine (Lys) at position 453. This change occurs in a crucial part of the protein. 

The mutation was present in all affected family members and was not found in public genetic databases.

When scientists tested this mutated protein in cells, they found it had no enzyme activity, unlike the normal version, which had more than three times the usual activity. 

Additionally, the mutated protein formed clumps, which were 20 times more abundant than the normal protein. This suggests that the mutation causes the protein to malfunction and clump together, leading to the severe diarrhea seen in these children.

rs3736947

The risk allele of the SNP rs3736947 in ACSL5 is associated with higher expression of the gene. 

In a study involving 1,173 sporadic ALS cases and 8,925 controls in a Japanese population looking at amyotrophic lateral sclerosis (ALS), a specific genetic variant of the ACSL5 gene was found to be strongly associated with ALS. [10.] 

This SNP is located within a non-coding region of the gene, and the risk allele (C) is linked to higher ACSL5 expression. Increased ACSL5 expression might lead to the production of neurotoxic cells that could cause motor neuron death, contributing to ALS. [10.] 

Rs11195948 [6.] 

The SNP rs11195948 within the ACSL5 gene has also been associated with ALS. rs11195948 can affect gene expression and regulation. 

This SNP was identified as significantly linked to ALS in a Japanese cohort and was validated in a replication study with a Chinese population and an independent Japanese population. 

In the Japanese study, this SNP had a strong association with ALS. When combined with a large ALS study from Europe, rs11195948 showed an even stronger association. 

This association was confirmed in a meta-analysis that included data from Japanese and European datasets, as well as the Chinese replication cohort. 

The rs11195948 SNP was found to significantly influence ACSL5 gene expression, suggesting its potential role in the genetic predisposition to ALS. 

Overall, rs11195948 is becoming known as a crucial genetic marker associated with ALS, highlighting its importance in understanding the disease's genetic factors.

Laboratory Testing for ACSL5

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. 

It's crucial to approach genetic testing with proper understanding and consideration of its implications for one's health and well-being.

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.

FAQ: Understanding ACSL5 Biomarker

ACSL5 is a biomarker associated with lipid metabolism, playing a vital role in various metabolic processes. This FAQ section addresses common questions about ACSL5, its gene, function, and the relevance of ACSL5 antibodies in research and clinical settings.

What is ACSL5?

ACSL5 stands for Acyl-CoA Synthetase Long-Chain Family Member 5. It is an enzyme that catalyzes the activation of long-chain fatty acids by converting them into acyl-CoA derivatives, which are crucial for lipid metabolism and energy production.

What is the Function of ACSL5?

The primary function of ACSL5 is to activate long-chain fatty acids, facilitating their incorporation into metabolic pathways. This process is essential for the synthesis of complex lipids, energy storage, and the regulation of lipid signaling molecules.

What is the ACSL5 Gene?

The ACSL5 gene provides the instructions for producing the ACSL5 enzyme. Located on chromosome 10 in humans, this gene is part of the acyl-CoA synthetase gene family. Variations or mutations in the ACSL5 gene can influence lipid metabolism and may be linked to metabolic disorders.

How Does ACSL5 Impact Metabolic Health?

ACSL5 plays a critical role in lipid metabolism, and its dysregulation can contribute to metabolic conditions such as obesity, diabetes, and fatty liver disease. Proper functioning of ACSL5 ensures efficient fatty acid utilization and energy balance within the body.

How is ACSL5 Measured?

ACSL5 is generally assessed as a genetic test to determine whether specific genetic alterations are present that might affect lipid metabolism.  

Metabolic markers such as fasting insulin, glucose and hemoglobin A1c, and cholesterol levels should be considered in patients with concern for metabolic health.

What are ACSL5 Antibodies?

ACSL5 antibodies are valuable tools for detecting and quantifying ACSL5 protein levels in various experimental settings. This could help researchers study ACSL5 expression patterns, localization, and function in different cell types and tissues.

What are the Clinical Implications of Altered ACSL5 Expression?

Altered ACSL5 expression can indicate metabolic imbalances and may be associated with conditions such as insulin resistance, obesity, and non-alcoholic fatty liver disease.  

It is also associated with some gastrointestinal symptoms and conditions as well as glioma and ALS.  

When Should I Consult a Healthcare Provider About ACSL5-Related Concerns?

If you have a family history of metabolic disorders or experience symptoms related to lipid metabolism imbalances, such as unexplained weight gain, fatigue, or abnormal blood lipid levels, consult a healthcare provider. 

They can evaluate your condition, including potential ACSL5 involvement, and recommend appropriate tests and treatments.

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