ACSL1

ACSL1, or long-chain acyl-CoA synthetase 1, is an enzyme crucial for lipid metabolism. It converts long-chain fatty acids into acyl-CoA esters, a key step in synthesizing various lipids and producing energy via the beta-oxidation pathway. 

ACSL1 has a high affinity for long-chain fatty acids, particularly those with 16 to 20 carbon atoms, and prefers substrates like palmitoleate, oleate, and linoleate. 

It is abundantly expressed in the heart, liver, and adipose tissue, and is the most prevalent acyl-CoA synthetase in these tissues. 

ACSL1's role in triglyceride synthesis impacts heart health, with high triglyceride levels being linked to increased heart disease risk. It is also involved in myelination within the brain's white matter. 

In cancer, ACSL1's behavior varies, affecting cancer growth and spread, with high levels linked to worse outcomes in colorectal and breast cancers but lower levels suppressing tumor growth in lung and liver cancers. 

Genetic variants, or SNPs, in the ACSL1 gene, such as rs7681334, rs4862423, and rs735949, have been associated with fasting glucose levels, diabetes risk, and subclinical atherosclerosis, highlighting its importance in metabolic health.

What is ACSL1?

ACSL1 is an enzyme encoded by the ACSL1 gene, which is involved in lipid metabolism. It catalyzes the conversion of long-chain fatty acids into acyl-CoA esters, a key step in the synthesis of various lipids and energy production via the beta-oxidation pathway. [2.] 

Enzymatic Activity and Substrate Specificity

ACSL1 exhibits a high affinity for long-chain fatty acids, particularly those with 16 to 20 carbon atoms. ACSL1 preferentially uses palmitoleate, oleate, and linoleate as substrates. [2.] 

Normal Functions of ACSL1

ACSL1 favors triglyceride synthesis, while other ACSL isoforms favor phospholipid production. [7.] 

ACSL1 expression and function may impact heart health due to its preference for triglyceride production; high triglycerides are associated with increased risk of heart disease. [3.] 

It also plays a role in myelination within the white matter of the brain. [1.] 

Tissue Distribution and Expression Levels

ACSL1 is abundantly expressed in the heart, along with the liver and adipose tissue. It is the most prevalent acyl-coenzyme A synthetase subtype in these tissues. [3.] 

ACSL1 is also highly expressed in the nervous system, including the hippocampal formation, amygdala, basal ganglia, midbrain, spinal cord, cerebral cortex, cerebellum, and many other organs and tissues throughout the body. [1.]

ACSL1 is also found in the cytoplasm of cells in several tissues including sebaceous glands and kidney. ACSL1 is also found inside neutrophils. [1.] 

ACSL1 and its Relationship with Peroxisome Proliferator-Activated Receptor α (PPAR-Alpha)

PPARα is a transcription factor that regulates genes involved in fatty acid uptake, activation, mitochondrial β-oxidation, peroxisomal fatty acid oxidation (in rodents), ketone body synthesis, fatty acid elongation, desaturation, and apolipoprotein synthesis. [5.] 

PPARα impacts cell cycle regulation and apoptosis by regulating genes involved in fatty acid metabolism. [6.] 

PPARα is activated by fasting and elevated plasma free fatty acids (FFAs). [5.] 

Both PPARα and ACSL1 are highly expressed in the liver, where they affect lipid metabolism.  

PPARα mediates the expression of ACSL1. When PPARα is activated, it can increase the production of ACSL1. [10.] 

ACSL1 is a target gene of PPARα, and both are involved in fatty acid metabolism. PPARα regulates lipid homeostasis, while ACSL1 plays a crucial role in fatty acid activation and metabolism. [10.] 

Deficient or repressed PPARα expression in the liver leads to decreased activity of ACSL1. [10.] 

This reduction in ACSL1 activity, along with changes in other key enzymes involved in fatty acid metabolism, can result in fat deposition and inflammation, potentially promoting liver fibrosis.

ACSL1 in Health and Disease

Cancer [11.] 

The behavior of ACSL1 has been shown to vary among different types of cancer, affecting how the cancer grows and spreads. 

In cancers like colorectal and breast cancer, ACSL1 levels are high, and this is linked to worse outcomes for patients. [11., 12.] On the other hand, in lung and liver cancers, ACSL1 levels are low, and it helps to suppress tumor growth.

In clear cell renal cell carcinoma (ccRCC), a common type of kidney cancer, ACSL1 levels are significantly lower in tumor tissues compared to normal tissues. This decrease in ACSL1 is associated with more advanced stages of cancer, worse pathological grades, and poorer patient outcomes. 

Studies show that DNA methylation, a process that can turn off genes, is a key reason for the low levels of ACSL1 in ccRCC. High methylation levels of certain regions in the ACSL1 gene are linked to its reduced expression and poor prognosis.

Additionally in ccRCC, high levels of ACSL1 are associated with increased activity in pathways related to fatty acid metabolism and breakdown, while low levels of ACSL1 are linked to higher immune cell activity and increased expression of immune checkpoints, which are molecules that help regulate the immune response.

One study showed that patients with low ACSL1 levels are more sensitive to drugs that target the PI3K-Akt-mTOR pathway, while those with high ACSL1 levels respond better to tyrosine kinase inhibitors like sunitinib and pazopanib. [11.]

Heart Disease 

The ACSL1 enzyme significantly affects heart health by influencing triglyceride levels. High levels of ACSL1 in the white blood cells of patients with acute myocardial infarction (AMI) have been used as a marker to help diagnose heart attacks. [3.] 

These patients usually have higher levels of triglycerides in their blood compared to healthy individuals.

Overexpression of ACSL1 in mouse hearts has been shown to increase triglyceride accumulation in heart cells by 12-fold. This suggests that ACSL1 levels can significantly impact cardiac lipid content. [3.] 

Additional research using cultured human liver cells shows that when ACSL1 is overexpressed, it leads to increased triglyceride content. [3.] 

Alternatively, inhibition of ACSL1 has been found to promote cardiomyocyte proliferation and protect cardiac function after myocardial infarction. This suggests a potential therapeutic role for ACSL1 inhibition in cardiac regeneration. [3.] 

Furthermore, increasing ACSL1 in human liver cells significantly reduces the activity of genes involved in fatty acid synthesis, such as SREBP1, ACC, FAS, and SCD1. This suggests that ACSL1 mainly affects triglyceride levels through the process of breaking down fatty acids rather than making new fatty acids. [3.] 

Metabolic Disorders

ACSL1 is essential in fatty acid metabolism, and its dysfunction can lead to various metabolic issues. Alterations in ACSL1 function have been linked to lipid metabolism disorders, which can contribute to conditions like obesity, fatty liver disease and insulin resistance. [9., 10.] 

Liver Diseases

ACSL1 deficiency in the liver has been associated with reduced bile acid synthesis and altered lipid profiles, particularly rising levels of total and LDL cholesterol. [8.] This can potentially contribute to liver disorders such as fatty liver disease. [8., 10.]

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Genetic Alterations in the ACSL1 Gene

The gene for the ACSL1 protein may contain alterations or mutations that cause increase or decrease of function of the ACSL1 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 ACSL1 Function

rs7681334

One study identifies SNP rs7681334 as linked to higher fasting glucose levels in nondiabetic individuals. [4.] 

Specifically, the A allele of rs7681334 is associated with increased fasting glucose levels. This connection was confirmed in the Penn-T2D Meta cohort, highlighting the SNP's importance in glucose metabolism. [4.] 

rs4862423

SNP rs4862423 is connected to both fasting glucose and early signs of atherosclerosis. [4.] 

The MAGIC BMI-adjusted GWAS showed that the T allele of rs4862423 is linked to higher fasting glucose levels. [4.] 

Additionally, this SNP is significantly related to lower CAC (coronary artery calcification) scores, especially in African Americans, as seen in the meta-analysis of CAC among African Americans. [4.] 

The presence of rs4862423 in a DNase I hypersensitive site in various tissues, including the fetal heart and pancreas, suggests it has a regulatory role. It also overlaps with a binding site for the transcription factor RREB1, indicating it might affect gene expression.

rs735949

SNP rs735949 is significantly linked to diabetes status. [4.] 

The T allele of rs735949 increases the risk of diabetes. [4.] 

Laboratory Testing for ACSL1

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.

Biomarkers Related to ACSL1 

Fasting Insulin

Fasting insulin levels should be considered alongside ACSL1 genetic testing due to the intricate relationship between lipid metabolism and insulin sensitivity. 

ACSL1 plays a crucial role in fatty acid activation and metabolism, which can significantly impact insulin signaling and glucose uptake in tissues. Variations in ACSL1 function, as indicated by genetic testing, may influence insulin sensitivity and secretion. 

Therefore, measuring fasting insulin provides valuable information about how ACSL1 genetic variants might affect an individual's insulin response and overall metabolic health.

Fasting Glucose and Hemoglobin A1c

Fasting glucose and hemoglobin A1c should be considered in conjunction with ACSL1 genetic testing because they offer insights into glucose homeostasis, which is indirectly influenced by ACSL1's role in lipid metabolism. 

SNPs in the ACSL1 gene have been associated with alterations in fasting glucose levels and diabetes risk. [4.] 

Fasting glucose provides a snapshot of current glucose regulation, while hemoglobin A1c reflects average blood glucose levels over the past 2-3 months. 

These markers can help elucidate how specific ACSL1 variants might impact long-term glucose control and diabetes risk.

Lipid Panel

A lipid panel is particularly relevant when conducting ACSL1 genetic testing due to ACSL1's direct involvement in fatty acid metabolism. 

This panel typically includes measurements of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. Since ACSL1 is responsible for the activation of long-chain fatty acids and is known to increase triglyceride levels, variations in its function can significantly affect lipid profiles. 

By analyzing the lipid panel alongside ACSL1 genetic variants, clinicians and researchers can gain insights into how these genetic differences might influence an individual's lipid metabolism, potentially affecting their risk for conditions such as cardiovascular disease and metabolic syndrome.

FAQ: Understanding ACSL1 Biomarker

ACSL1 is a biomarker associated with lipid metabolism and various metabolic disorders. Understanding ACSL1, its function, and its role in health and disease can provide valuable insights for both clinical and research applications. 

What is ACSL1?

ACSL1 stands for Acyl-CoA Synthetase Long-Chain Family Member 1. 

It is an enzyme encoded by the ACSL1 gene, which is important in lipid metabolism by converting free long-chain fatty acids into fatty acyl-CoA esters.

What is the Function of ACSL1?

The primary function of ACSL1 is to catalyze the activation of long-chain fatty acids by converting them into acyl-CoA derivatives. 

This process is essential for various cellular processes including lipid biosynthesis, fatty acid degradation, and energy production.

What is the ACSL1 Gene?

The ACSL1 gene is the genetic blueprint for the ACSL1 enzyme. It is located on chromosome 4 in humans and is part of the larger acyl-CoA synthetase gene family. 

Mutations or variations in the ACSL1 gene can impact lipid metabolism and have been associated with metabolic disorders.

What are ACSL1 Antibodies?

ACSL1 antibodies are valuable tools for detecting and quantifying ACSL1 protein levels in various experimental settings. This could help researchers study ACSL1 expression patterns, localization, and function in different cell types and tissues.

How is ACSL1 Related to Metabolic Health?

ACSL1 is critical in regulating lipid metabolism, and its dysregulation can contribute to metabolic disorders such as obesity, diabetes, and cardiovascular disease. 

Changes in ACSL1 activity or expression can affect how the body processes and stores fats, influencing overall metabolic health.

How is ACSL1 Measured?

ACSL1 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 the Clinical Implications of Altered ACSL1 Expression?

Altered ACSL1 expression can be indicative of metabolic imbalances and may be associated with conditions such as insulin resistance, fatty liver disease, and cardiovascular disease. 

Monitoring ACSL1 levels can provide insights into the metabolic state of an individual and help guide therapeutic interventions.

How Can ACSL1 Research Benefit Metabolic Disease Treatment?

Research on ACSL1 can lead to a better understanding of lipid metabolism and its role in metabolic diseases. 

This knowledge can contribute to the development of targeted therapies aimed at modulating ACSL1 activity to treat conditions like diabetes, obesity, and cardiovascular disease.

When Should I Consult a Healthcare Provider About ACSL1-Related Concerns?

If you have a family history of metabolic disorders or are experiencing 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 ACSL1 involvement, and recommend appropriate tests and treatments.

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