ACAT1

The Acetyl-CoA Acetyltransferase 1 (ACAT1) gene encodes an enzyme crucial for both protein and fat metabolism within the mitochondria of cells. 

ACAT1 plays a pivotal role in breaking down the amino acid isoleucine and fats from our diet into smaller molecules like acetyl-CoA and propionyl-CoA, essential for energy production. 

This enzyme is also key in ketone body metabolism, performing critical reactions in both the synthesis and breakdown of ketones. 

Mutations in the ACAT1 gene can lead to beta-ketothiolase deficiency, a condition characterized by harmful accumulation of organic acids and severe metabolic crises.  This disorder typically manifests in early childhood, leading to episodes of ketoacidosis, which can damage vital organs and affect the nervous system. 

Understanding the function and regulation of ACAT1 is crucial for managing conditions linked to this enzyme and developing therapeutic strategies for related metabolic disorders.

Understanding ACAT1  [1., 2., 3., 10.] 

The Acetyl-CoA Acetyltransferase 1 (ACAT1) gene provides instructions for making an enzyme called acetyl-CoA acetyltransferase 1, also known as mitochondrial acetoacetyl-CoA thiolase (T2).  This enzyme is found in the energy-producing centers (mitochondria) of cells and plays an essential role in breaking down proteins and fats from the diet.

During protein metabolism, ACAT1 is responsible for a step in processing the amino acid isoleucine. It converts a molecule called 2-methyl-acetoacetyl-CoA into two smaller molecules, propionyl-CoA and acetyl-CoA, which can be used to produce energy.  

In fat metabolism, ACAT1 carries out the last step in ketone breakdown (ketolysis).  The enzyme converts a molecule called acetoacetyl-CoA into two molecules of acetyl-CoA, which can also be used for energy production.

In the liver, ACAT1 also performs this chemical reaction in reverse, which is a step in building new ketones (ketogenesis).

By facilitating the breakdown of proteins and fats, ACAT1 ensures that the body has sufficient energy and building blocks for various cellular processes. Disruption of ACAT1 function, as seen in beta-ketothiolase deficiency, leads to the accumulation of toxic organic acids and impaired energy metabolism.

More than 100 mutations in the ACAT1 gene have been identified in people with beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase (T2) deficiency.  [1.]  

This condition usually appears before age 2 and causes episodes of vomiting, dehydration, and other health problems, which can lead to coma.

Some ACAT1 mutations disrupt the normal function of the enzyme, while others prevent cells from producing any functional enzyme.  

A shortage of the ACAT1 enzyme prevents the body from processing proteins and fats properly, leading to the accumulation of toxic organic acids in the blood.  This can cause the blood to become too acidic (ketoacidosis) and damage the body's tissues and organs, particularly the nervous system.

Mutations in ACAT1 can cause beta-ketothiolase deficiency, a rare disorder characterized by episodes of metabolic crisis and organ damage due to impaired enzyme function and accumulation of toxic metabolites.

Cellular Localization  [5., 9., 10.]

ACAT1 exhibits tissue-specific expression patterns with prominent expression observed in tissues with high metabolic activity such as the liver, intestine, and macrophages.  [5.] 

Its expression is subject to regulation by various factors including cellular cholesterol levels, transcriptional regulators, and post-translational modifications.  [5., 9.]

ACAT1 is highly expressed in the liver and intestine, which are central to cholesterol and lipid metabolism.  In macrophages, ACAT1 plays a crucial role in cholesterol esterification and foam cell formation, contributing to the development of atherosclerosis.  

Metabolic and Hormonal Regulation  [12., 13., 14.]

Metabolic and hormonal factors exert tight regulation over ACAT1 expression and activity in response to cellular energy status and physiological demands.  

Insulin, a key regulator of glucose and lipid metabolism, stimulates ACAT1 expression in hepatocytes and adipocytes, promoting cholesterol esterification and lipid storage. 

Conversely, glucagon and catecholamines inhibit ACAT1 activity, promoting lipolysis and fatty acid oxidation. 

Dietary factors such as cholesterol and fatty acids also influence ACAT1 expression and activity, modulating cellular lipid metabolism and cholesterol homeostasis.

The regulation of ACAT1 by insulin has been demonstrated in macrophages, where insulin upregulates ACAT1 expression.  This suggests that insulin may play a similar role in hepatocytes and adipocytes, promoting cholesterol esterification and storage in response to nutrient availability. 

Glucagon and catecholamines, on the other hand, are known to stimulate lipolysis and fatty acid oxidation.  Their inhibitory effect on ACAT1 activity likely contributes to the mobilization of stored lipids during fasting or exercise.

Dietary cholesterol and fatty acids can also modulate ACAT1 expression and activity.  High cholesterol levels induce ACAT1 expression, facilitating the esterification and storage of excess cholesterol.

Fatty acids may influence ACAT1 activity through their effects on cellular energy status and signaling pathways.  These dietary factors play a crucial role in regulating cellular lipid metabolism and maintaining cholesterol homeostasis.

In summary, ACAT1 is subject to tight metabolic and hormonal regulation, allowing the cell to adapt its cholesterol esterification capacity in response to changing energy demands and nutrient availability. This regulation involves key metabolic hormones, such as insulin, glucagon, and catecholamines, as well as dietary factors like cholesterol and fatty acids.

Diseases Associated with ACAT1 Mutations

ACAT1 (acetyl-CoA acetyltransferase 1) mutations are commonly associated with several diseases, including beta-ketothiolase deficiency, alpha-methylacetoacetic aciduria, and prostate cancer. 

Beta-Ketothiolase Deficiency  [1.]

Beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is an inherited disorder of ketone body and isoleucine metabolism.

This condition is characterized by episodic ketoacidosis and the accumulation of specific isoleucine-derived metabolites, which are crucial for diagnosis.  To date, over 100 ACAT1 variants have been identified, with many affecting amino acid residues that are crucial for the proper folding and stability of the enzyme, thereby reducing its activity.  

The condition does not show a direct correlation between genotype and clinical phenotype, indicating that the remaining enzyme activity can influence the severity of the biochemical phenotype. This has important implications for the management of the disease and for newborn screening strategies.

Alpha-Methylacetoacetic Aciduria  [6.]

Alpha-methylacetoacetic aciduria is a rare autosomal recessive disorder caused by ACAT1 deficiency, leading to the accumulation of alpha-methylacetoacetic acid and other metabolites, which can cause neurological symptoms, developmental delays, and metabolic crises. 

Additionally, ACAT1 expression has been associated with prostate cancer, with higher levels observed in aggressive prostate cancer tissue samples compared to benign cells, suggesting a potential role in cancer progression.

ACAT1 in Cardiometabolic Health  [7., 10.]

‍

ACAT1 in Lipid Metabolism and Cholesterol Homeostasis  [7.]

ACAT1 plays a central role in lipid metabolism by catalyzing the esterification of cholesterol—a process essential for the storage and transport of this lipid molecule within cells.  

By converting cholesterol into its esterified form, ACAT1 contributes to the formation of lipid droplets and the packaging of cholesterol into lipoprotein particles, thereby regulating cellular cholesterol levels and maintaining lipid homeostasis. 

Dysregulation of ACAT1 activity can disrupt lipid metabolism, leading to aberrant cholesterol accumulation and impaired cellular function, which has implications for various physiological processes and disease states.

ACAT1 in Atherosclerosis  [7., 9., 10.]

The dysregulation of ACAT1 has been implicated in the pathogenesis of atherosclerosis, a chronic inflammatory condition characterized by the buildup of cholesterol-rich plaques within arterial walls. 

Increased ACAT1 expression and activity in macrophages within atherosclerotic plaques promote the accumulation of cholesterol esters, contributing to foam cell formation—a hallmark of early atherosclerotic lesions.  

Furthermore, ACAT1-mediated cholesterol esterification influences the susceptibility of macrophages to apoptosis and the secretion of pro-inflammatory cytokines, thereby exacerbating inflammation and plaque progression. 

Targeting ACAT1 activity has emerged as a potential therapeutic strategy for mitigating atherosclerosis and its associated cardiovascular complications.

ACAT1 in Metabolic Disorders  [7.]

Beyond its role in atherosclerosis, ACAT1 dysregulation has been implicated in the pathogenesis of metabolic disorders such as obesity, insulin resistance, and non-alcoholic fatty liver disease (NAFLD).

Elevated ACAT1 expression and activity in adipose tissue and hepatocytes contribute to lipid accumulation and insulin resistance—a key feature of metabolic syndrome. 

Additionally, ACAT1-mediated cholesterol esterification in the liver promotes hepatic steatosis and the progression of NAFLD, highlighting the broader implications of ACAT1 in metabolic health and disease.

Genetic Alterations in the ACAT1 Gene

The gene for the ACAT1 protein may contain alterations or mutations that cause alterations of function of the ACAT1 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 Function of the ACAT1 Protein

Two specific SNPs that are associated with alterations in ACAT1 include:

ACAT1 rs1044925 SNP  [8.]

The C allele of this SNP is very common in populations of central and southern Europe (35.4% allele frequency).  In hypercholesterolemic subjects, the rs1044925 SNP showed a sex-specific association with serum HDL-C and ApoAI levels in males.  

The effect of this SNP on ACAT1 activity is unknown, but it may influence ACAT1 protein levels or function, and subsequently, cholesterol levels and cardiometabolic health.  

ACAT1 -77G>A mutation  [11.]

This mutation has been shown to relate to plasma HDL concentration in hyperlipidemic subjects.  The -77G>A mutation may reduce ACAT1 protein levels, leading to increased free cholesterol and HDL-C efflux.  

However, the pathways of ABCA1-mediated cholesterol efflux may be sufficient to protect macrophages from free cholesterol toxicity in physiological conditions.  

While these SNPs have been associated with alterations in ACAT1 function and lipid metabolism, the exact mechanisms are not fully elucidated. More research is needed to determine how specific ACAT1 variants impact enzyme activity, protein levels, and their downstream effects on cellular and systemic cholesterol homeostasis.

Laboratory Testing for ACAT1

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. 

Related Biomarkers to Test

In addition to Acetyl-CoA Acetyltransferase 1 (ACAT1), several other biomarkers associated with lipid metabolism and cholesterol homeostasis play crucial roles in assessing metabolic health and disease risk.

LDL-C: Low-Density Lipoprotein Cholesterol  [4., 11.]

Low-Density Lipoprotein Cholesterol (LDL-C) is a fundamental biomarker in lipid metabolism, reflecting the concentration of cholesterol carried by LDL particles in the bloodstream. 

Elevated LDL-C levels are associated with an increased risk of atherosclerosis and cardiovascular events, making it a primary target for cholesterol-lowering interventions. 

Measuring LDL-C levels alongside ACAT1 testing provides important information on cholesterol transport and metabolism, aiding in risk assessment and treatment decisions for cardiovascular disease prevention.

HDL-C: High-Density Lipoprotein Cholesterol  [4., 11.]

High-Density Lipoprotein Cholesterol (HDL-C) is another important biomarker in lipid metabolism; HDL is considered to play a protective role against cardiovascular disease by promoting reverse cholesterol transport and exerting anti-inflammatory and antioxidant effects. 

Higher HDL-C levels are associated with a reduced risk of atherosclerosis and cardiovascular events, highlighting its significance in cardiometabolic health. 

Assessment of HDL-C levels in conjunction with LDL-C levels and ACAT1 testing offers insights into lipid transport and cholesterol efflux mechanisms to broaden the clinician’s awareness of an individual’s cardiovascular risk and metabolic health.

Triglycerides  [4., 15.]

Triglycerides represent a major component of circulating lipids, serving as a storage form of fatty acids and energy substrate for cellular metabolism.  Elevated triglyceride levels are associated with insulin resistance, metabolic syndrome, and cardiovascular risk.  

Measurement of triglyceride levels alongside ACAT1 testing provides additional information on lipid metabolism and cardiovascular risk, guiding therapeutic interventions and lifestyle modifications aimed at improving metabolic health.

Apolipoprotein B (ApoB)  [4., 11., 15.]

Apolipoprotein B (ApoB) is a structural protein present on LDL particles and reflects the number of atherogenic lipoproteins circulating in the bloodstream.  Elevated ApoB levels are associated with an increased risk of atherosclerosis and cardiovascular events, independent of LDL-C levels. 

Order Genetic Testing

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