ABCG8

ABCG8, often studied in conjunction with its sister gene ABCG5, forms an integral part of the cellular machinery responsible for the regulation of cholesterol and sterol homeostasis. 

It is primarily expressed in the liver and intestines, playing a pivotal role in the excretion of cholesterol into bile and the prevention of excessive dietary sterol absorption. 

This balance is vital for normal bodily functions, and is crucial in preventing the development of diseases such as gallstones, certain types of hypercholesterolemia, and atherosclerosis.

The importance of ABCG8 extends beyond its physiological roles. In the realm of medical diagnostics, understanding the expression and function of ABCG8 can provide significant insights into individual susceptibilities to lipid-related disorders, guide the choice of therapeutic strategies, and help monitor treatment efficacy. 

What is ABCG8?  [1.]

ABCG8, or ATP-binding cassette sub-family G member 8, is a key component in the human body's regulation of cholesterol and sterols. Encoded by the ABCG8 gene, this protein aids in management of dietary sterol absorption and maintenance of cholesterol homeostasis.

The ABCG8 gene codes for a heterodimer protein, meaning that the ABCG8 protein must bind with another protein in order to be functional.  

The ABCG8 protein couples with its partner protein ABCG5, which is encoded by the ABCG5 gene; this coupling is driven by the hormone leptin.  Each protein is only functional when coupled with the other.  [7.]

The ABCG8 protein, structurally similar to other members of the ABC transporter family, consists of transmembrane domains and nucleotide-binding domains. These features enable it to actively transport sterol molecules across the cell membrane, using energy derived from ATP. 

ABCG8 is expressed only in the liver, intestine, and gallbladder.  The ABCG5/ABCG8 unit plays a crucial role in the body's sterol regulatory system, orchestrating the balance between sterol absorption and excretion.

The gene for the ABCG8 protein may contain alterations or mutations that cause increase or decrease of function of the ABCG8 protein.  When loss of function occurs, this can manifest as sterol accumulation and atherosclerosis, and lead to a condition called sitosterolemia.  

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.

Functions of ABCG8 in Health and Disease

ABCG8’s role in human physiology affects essential processes of cholesterol homeostasis and lipid metabolism.  Because of its role in sterol efflux, alterations in function of ABCG8 can have profound implications for human health.

The ABCG5/ABCG8 complex enables the active transport of cholesterol and plant sterols across cell membranes using energy from ATP, therefore regulating the amount of cholesterol and other plant sterols that are absorbed from our diet and excreted by the liver.

In the intestines, the ABCG5/ABCG8 unit limits the absorption of dietary cholesterol by sending cholesterol back into the intestinal lumen for removal.  In the liver, it promotes cholesterol's excretion into the bile. 

Studies involving animal models have demonstrated that knockout of ABCG5/G8 leads to a significant increase in the absorption of dietary cholesterol, while overexpression results in a notable decrease in absorption.  [7.]

This balance is vital for preventing the buildup of sterols in the body, which can contribute to various cardiovascular diseases.

While cholesterol is necessary for various bodily functions, its excessive accumulation can lead to health issues such as atherosclerosis. Similarly, plant sterols, despite being beneficial in small quantities, can be detrimental in large amounts.

ABCG8 Interaction with Liver X Receptor

ABCG8 interacts with the liver X receptor (LXR) pathway to support lipid homeostasis.  Activation of LXR is a major inducer of the expression of ABCG8, thereby enhancing the efflux of sterols and demonstrating a coordinated response to cholesterol levels in the body.  [2.]

LXRs are key regulators of lipid metabolism, as they exert transcriptional control of genes involved in cholesterol homeostasis and the synthesis of bile acids in the liver.  [4.]

ABCG8 Relationships with Apolipoprotein B

The relationship between ABCG8 and apolipoprotein B highlights the necessity of the proper functioning of lipid transport for the maintenance of lipid homeostasis.

For example, increased hepatic expression of the ABCG5/ABCG8 unit reduces ApoB levels and atherosclerosis, although effect only occurred with decreased intestinal absorption of cholesterol.  [3., 5.]

ABCG8 in Sitosterolemia  [8.]

ABCG8 plays a critical role in the pathogenesis of sitosterolemia, an autosomal recessive disorder characterized by the accumulation of phytosterols in plasma and tissues due to impaired excretion. 

Mutations in the ABCG8 gene disrupt the normal function of the ABCG5/ABCG8 heterodimeric transporter, leading to reduced efflux of plant sterols from enterocytes into the intestinal lumen and from hepatocytes into bile. 

This impairment results in the elevated absorption of dietary plant sterols and cholesterol and decreased biliary excretion, contributing to the accumulation of phytosterols in various tissues. 

The clinical manifestations of sitosterolemia include premature atherosclerosis, tendon and tuberous xanthomas, and hematologic abnormalities. 

Treatment strategies focus on reducing sterol absorption through dietary modification, bile acid sequestrants, and, in severe cases, liver transplantation.

ABCG8 in Atherosclerosis  [9.]

ABCG8 plays a significant role in the pathogenesis of atherosclerosis, a chronic inflammatory condition characterized by the accumulation of cholesterol-rich plaques in the arterial walls. 

Dysfunctional ABCG5/ABCG8 transporters, caused by mutations in the ABCG8 gene, disrupt the efflux of cholesterol and plant sterols from hepatocytes into bile and from enterocytes into the intestinal lumen. As a result, there is increased absorption of dietary cholesterol and plant sterols, leading to their systemic accumulation. 

Elevated levels of cholesterol and plant sterols contribute to the formation of atherosclerotic plaques by promoting lipid deposition within arterial walls. Moreover, these sterols may induce endothelial dysfunction, inflammation, and oxidative stress, further exacerbating the development of atherosclerosis. 

Therapeutic strategies targeting ABCG5/ABCG8 function may offer promising approaches for mitigating the progression of atherosclerosis and reducing cardiovascular risk.

ABCG8 and Gallstones  [6.]

ABCG8 upregulation is associated with the formation of gallstones, particularly cholesterol gallstones, by regulating the hepatic secretion of cholesterol into bile. 

Increased function of the ABCG5/ABCG8 transporter, caused by genetic variations or mutations, increases the efflux of cholesterol and plant sterols from the liver into bile. 

Consequently, there is an accumulation of cholesterol in bile, leading to supersaturation and precipitation of cholesterol crystals, which are the primary constituents of gallstones. 

Furthermore, alterations in the expression or function of ABCG8 may influence the composition of bile and the balance between cholesterol and bile salts, further predisposing individuals to gallstone formation. 

Understanding the role of ABCG8 in cholesterol homeostasis and bile formation is essential for developing therapeutic interventions aimed at preventing or treating gallstone disease.

ABCG8 directly influences the pathogenesis of certain metabolic disorders. Its critical role in regulating cholesterol and plant sterol levels means that any dysfunction can lead to abnormal lipid accumulations. 

Pharmaceutical interventions that enhance the action of ABCG8 could help in reducing the intestinal absorption of cholesterol, thereby lowering blood cholesterol levels.  Additionally, appropriate diet and lifestyle practices including regular exercise are essential.  

Laboratory Testing for ABCG8

Laboratory testing for ABCG8 involves a range of techniques aimed at assessing its expression, function, and genetic variations. These tests play a crucial role in diagnosing lipid metabolism disorders, predicting cardiovascular disease risk, and guiding personalized treatment strategies.

Genetic Testing

Genetic testing is a fundamental approach to assessing ABCG8-related disorders. Next-generation sequencing techniques allow for comprehensive analysis of the entire gene, enabling the detection of both common and rare variants. Genetic testing helps clinicians establish a definitive diagnosis, assess disease risk, and inform treatment decisions.

Lab Testing for ABCG8

Genetic testing involves sequencing the gene in question to identify mutations or genetic variations associated with health or disease conditions. 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 and Genes Related to ABCG8

ABCG8 is one piece of the much larger puzzle of lipid metabolism.  A full assessment may include testing for other genes such as ABCG5, APOE, and others.   

Other related biomarkers to consider include those involved in cholesterol metabolism and transport such as sdLDL, apolipoprotein B (apoB), Lipoprotein a [Lp(a)], and others. These biomarkers can provide additional insights into lipid metabolism disorders and cardiovascular risk.

Biochemical markers included in a standard lipid panel like total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides are also relevant. These markers offer a direct measure of lipid levels in the blood, helping to assess the functional impact of ABCG8 activity in lipid metabolism.

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