Lipid phenotyping – also known as a lipid profile – is a way to dig deeper into your cholesterol and triglyceride levels.  A phenotypgn approach can help determine your heart disease risk and provide insight into what treatments will work best for you.

Lipids are fatty compounds, such as cholesterol or triglycerides, that conduct numerous functions in the body. Phenotyping refers to the process of assessing the physical composition of the lipids found in a person’s blood in order to determine patterns and identify appropriate treatment.  For example, many people have heard of total cholesterol, LDLs and HDLs.  But did you know that treatment options may vary depending on the specific constellation of lipids in your blood?

Lipid phenotyping is a cutting-edge approach to understanding the roles lipids play in various biological processes and diseases. By exploring the intricate patterns and interactions of lipids within cells, you can gain valuable insights into cellular functions, metabolism, and the effects of various health conditions on lipid profiles.

As you dive deeper into lipid phenotyping, you’ll discover how this innovative testing approach can shed light on critical aspects of cellular function, disease mechanisms, and potential therapeutic targets. You’ll appreciate the complexity and significance of lipid profiles, opening new doors for treatment and understanding of the role lipids play in health and disease.

Fundamentals of 7 Lipids

Lipids are a diverse group of organic compounds that play crucial roles in your body. They serve as an energy source, provide insulation for your organs, and serve as building blocks for various cellular structures. Key lipids include the following:

• Cholesterol – an essential component of cell membranes, providing both stability and fluidity.
• Sterol lipids – Used for the production of vital hormones and bile acids.
• Phosphatidylethanolamines and phosphatidylcholines – the primary phospholipids found in cell membranes. These lipids contain a hydrophilic head group (dissolves in water) and hydrophobic fatty acid tails (do not dissolve in water), which allows them to create the lipid bilayer that surrounds your cells.
• Sphingomyelins – Another integral class of lipids in cell membranes, especially in nerve cells. They contribute to the structural integrity and signaling functions of the cell.
• Diacylglycerols – (or DAGs) play a fundamental role in cellular signaling.
• Triacylglycerols – (or TAGs) serve as your body’s primary energy storage molecules. TAGs are typically stored in adipocytes (fat cells) and can be broken down into fatty acids if needed for energy production.
• Cholesteryl esters – formed when cholesterol molecules combine with fatty acids. They play a critical role in transporting cholesterol throughout your body, aiding in the synthesis of steroid hormones and bile salts.

In addition to the above, you may have heard of polyunsaturated fatty acids (PUFAs).  They’re a type of lipid crucial for various physiological processes, including the regulation of inflammation. PUFAs include omega-3 and omega-6 fatty acids, which are considered “essential” fatty acids because your body cannot produce them on its own. A proper balance of these fatty acids is critical for maintaining optimal health.

Understanding your lipid profile, including the levels of various lipids discussed above, is essential for maintaining proper heart health and overall well-being. Research into lipid phenotyping aims to explore the insights provided by these various lipids and how they can contribute to the larger picture of health, disease, and personalized medicine.

Lipid Phenotyping and Its Importance

Lipid phenotyping involves the use of advanced technologies such as high-resolution mass spectrometry (HRMS) to accurately profile and measure hundreds of lipids, making it suitable for large-scale studies¹ to easily gain large amounts of health data.  It allows doctors to rapidly and precisely acquire information on different classes, furthering our understanding of lipids and their significance in health and disease.

As mentioned above, lipids play crucial roles in numerous cellular processes, including membrane components and cell signaling. They’re associated with several chronic diseases, including coronary heart disease (CHD) and atherosclerosis – a condition linked to lipid accumulation and aggregation, particularly cholesterol and its derivatives². By obtaining comprehensive lipid profiles through lipid phenotyping, you can understand lipid-related mechanisms and biomarkers of various health disorders. Additionally, it facilitates the identification of potential therapeutic intervention for treatment and prevention. Next, let’s look at the components of a lipid profile, including lipoproteins and common lipid profile patterns.

Footnotes

1. An Unbiased Lipid Phenotyping Approach To Study the Genetic … – PubMed ↩
2. An Unbiased Lipid Phenotyping Approach To Study the Genetic … ↩

Components of a Lipid Profile

A lipid profile or lipid analysis is a simple blood test that provides quantification of the lipids (fats) present in the blood.  Typically, a technique known as tandem mass spectrometry is used for lipoprotein phenotyping. Common lipid markers will be discussed below and include various lipoproteins. 

1. “Total Cholesterol” represents the totality of all cholesterol types in your blood.  It includes HDL, LDL, VLDL, etc. A “normal” value for an adult is 180 – 200 mg/dL.  A “regular” lipid panel simply provides the total cholesterol, LDL, HDL, and triglyceride levels.  In order to obtain more specific categorization to assess risk factors and treatment options, lipid phenotyping is performed.
2. Triglycerides are the most common lipid in your blood and are derived from the foods you eat.  “Normal” levels in an adult are considered to be below 150 mg/dL.  Triglycerides can be elevated due to obesity, diabetes, certain medication, hypothyroidism, smoking, alcohol use, and more[1].
3. Lipoproteins transport fats around the body and are classified in terms of their density or their mobility.

Lipoproteins Classified by Density:

• HDL is a “High-Density Lipoprotein.” It’s sometimes called “Good Cholesterol” because it removes cholesterol from your blood and arteries and transports it back to the liver to be eliminated from the body. An adult’s “normal” HDL level is over 59 mg/dL. A general rule of thumb is that you want to “keep your highs, high.” Niacin has been shown to increase the levels of HDL, while statins have been found to have no impact on HDLs[2]. Always make sure to take your niacin with a good B-complex supplement to mitigate homocysteine issues!
• IDL is an “Intermediate Density Lipoprotein” and is created when HDLs and VLDLs degrade.
• LDL is a “Low-Density Lipoprotein.” It’s sometimes called “Bad Cholesterol” because it is responsible for moving fat molecules to cells. Each LDL can carry 3,000 – 6,000 fat molecules! LDLs can be elevated due to a fatty diet, a sedentary lifestyle, certain medications, high stress, age, and more. A “normal” value for LDLs in adults is less than 100 mg/dL. The target range is 70 mg/dL if a person has already had a stroke or cardiovascular issue.  LDLs can be oxidized by free radicals in the body, contributing to cardiovascular disease. A general rule of thumb is that you want to “keep your lows, low.” Niacin (B3) has been shown to lower LDL levels.[3]
• VLDL is “a Very Low-Density Lipoprotein” produced by the liver to shuttle triglycerides to fat and muscle for storage.
• ULDL is an “Ultra Low-Density Lipoprotein” also called a chylomicron. These are made mostly of triglycerides, and transport ingested fats from the intestines to the rest of the body.

Lipoproteins Classified by Mobility

Very simply, lipoproteins with more protein (increased density) move slower than lipoproteins with less protein[4].

• Alpha Lipoproteins: Have the most protein and move the slowest. (HDLs)
• Broad Beta Lipoproteins: IDLs
• Beta Lipoproteins: Have the least protein and move the fastest. (LDLs)
• Pre-Beta Lipoproteins: VLDLs

Now that we have a good understanding of a lipid profile and its components, let’s take a look at why this categorization is important.  If you’re told you have “high cholesterol,” it could be that all of your lipids are high.  It could also be that one lipid is very high while the rest are normal, resulting in a net increase.  Drilling down to see exactly which lipids are high, low, or normal allows us to identify common patterns.  These patterns give us a tremendous amount of information related to cardiac risk, management, and treatment.

Lipid Profile Patterns

Hypolipidemia occurs when a person has low lipid levels in the blood.  This is less common in our society, so we won’t focus on it in this article.  Hypolipidemia can result in hormonal imbalances, fatigue, digestive issues, and more.

Hyperlipidemia is much more common in the United States with the Standard American Diet (SAD is the appropriate acronym).  Hyperlipidemia occurs when a person has high lipid levels in the blood, and can be categorized into one of 6 types identified through phenotyping.

• Type I: Hyperchylomicronemia or Familial Fat-Induced Hyperglyceridemia[5] is often diagnosed before age 10, and is characterized by extremely high triglyceride levels (over 2000 mg/dL), liver and spleen enlargement, recurrent abdominal pain, and/or acute pancreatitis[6].  The total cholesterol is normal to low, and the LDL is normal.
• Type IIa: Hypercholesterolemia with Increased Beta-Lipoproteins[5].  This variant is characterized by having high cholesterol levels and high Beta Lipoproteins.  LDL is increased, total cholesterol is normal, and triglycerides are normal to high. This type is considered “familial,” so dietary changes may not help.  This person can be at high risk for atherosclerosis and early cardiac events, so proper identification is critical. Medications are often needed to mitigate these risks.

• Type IIb: Hypercholesterolemia with Increased Triglycerides[5]. This variant is often referred to as “overindulgent.”  Beta and pre-Beta lipoproteins are elevated. This type is characterized by having high total cholesterol (300-600 mg/dL) and moderately high (less than 400 mg/dL) triglycerides. LDL, VLDL, and HDL can all be elevated.
• Type III: Hypercholesterolemia with hypertriglyceridemia[5]. This variant is uncommon.  It’s characterized by high cholesterol (300 – 600 mg/dL) and high triglycerides (200 – 1000 mg/dL). Dietary changes for a person with Type III hyperlipidemia can be highly effective at normalizing lipid levels.
• Type IV: Hypertriglyceridemia[5] is carb-induced.    The VLDL is elevated, the total cholesterol is normal to elevated, and the triglycerides are 500 – 1500 mg/dL.  Dietary changes and supplementation with niacin may be more helpful than a statin.
• Type V: Hyperlipidemia with Chylomicronemia[5] (Essentially a combination of I and IV). This variant is characterized by elevated lipids with chylomicrons / ULDLs.  The VLDLs and LDLs are elevated, total cholesterol is elevated, and the triglycerides are extremely elevated at more than 10,000 mg/dL. Dietary changes, especially decreasing alcohol intake can help improve lipid profiles for this category.

Remember, these lipid patterns are only identified with phenotyping – not a standard “lipid panel.”  As you can see from the above explanation, some types respond to diet alone…some respond to treatment with niacin…and some require the use of prescription medications.  Do you see how knowing your classification would guide treatment?  Awesome!  For those that are interested in more of the science, as well as some natural treatment options, keep reading!   We’re going to shift gears, and discuss “lipidomics,” the role of lipids in cellular functioning, cholesterol (the molecule), and epidemiology as well as treatment options.  There are also a few FAQs at the end of the article!

Footnotes

[1] https://www.health.harvard.edu/heart-health/should-you-worry-about-high-triglycerides

[2] Meyers CD, Kamanna VS, Kashyap ML (December 2004). “Niacin therapy in atherosclerosis“. Current Opinion in Lipidology. 15 (6): 659–65. doi:10.1097/00041433-200412000-00006. PMID 15529025.

[3] Meyers CD, Kamanna VS, Kashyap ML (December 2004). “Niacin therapy in atherosclerosis“. Current Opinion in Lipidology. 15 (6): 659–65. doi:10.1097/00041433-200412000-00006. PMID 15529025.

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893739/

[5] https://www.labcorp.com/tests/235036/lipoprotein-phenotyping-profile 

[6] Julve, Josep; Martín-Campos, Jesús M.; Escolà-Gil, Joan Carles; Blanco-Vaca, Francisco (2016). “Chylomicrons: Advances in biology, pathology, laboratory testing, and therapeutics”. Clinica Chimica Acta. 455: 134–148. doi:10.1016/j.cca.2016.02.004. PMID 26868089.

Lipidomics in Disease States

Lipidomics is the comprehensive study of lipid molecules in a biological system — in this case, humans! It’s primarily concerned with understanding the role and impact of lipids in cellular metabolism and signaling pathways. Lipidomics involves the identification (the “what,” for example, cholesterol, triglyceride, etc.), quantification (how many), and characterization of lipid molecules within a biological sample. This is done using mass spectrometry-based techniques, which can provide detailed information about lipid classes, species, and individual molecules. This is the basis of lipid phenotyping as we discussed, above.

Lipidomics plays a crucial role in understanding the pathophysiology of various disease states. By analyzing the lipid profiles in your body, doctors can unravel the complex relationships between lipids and several health conditions, such as atherosclerosis, coronary heart disease, cardiovascular disorders, obesity, diabetes, stroke, and hypertension.

In the context of atherosclerosis, lipidomics can help identify specific lipid species and their roles in plaque formation. This knowledge can provide insights into the progression of coronary heart disease, enabling researchers to develop targeted therapies for its prevention and management.

Cardiovascular disorders are often associated with alterations in lipid metabolism. Through lipid phenotyping, you can gain a better understanding of the underlying molecular mechanisms involved in these disorders. This information can facilitate the development of lipid-based biomarkers for early detection and targeted interventions.

Obesity and diabetes, two closely related metabolic diseases, are known to be associated with significant changes in lipid profiles. Lipid phenotyping in these cases can highlight the specific lipid species involved in the development and progression of these conditions. This knowledge can guide the development of novel therapeutic strategies and help monitor their effectiveness.

Similarly, lipidomics can be employed in the investigation of stroke and hypertension. By identifying specific lipid signatures/profiles in patients with these conditions, researchers can gain valuable insights into the molecular mechanisms at play. This information can contribute to the development of new diagnostic tools and treatments designed to reduce the impact of these serious health issues.

In summary, the application of lipidomics in the study of disease states holds significant promise for advancing our understanding of various health conditions. By exploring the complex relationships between lipids and a range of disorders, you can benefit from the development of more targeted and effective diagnostic techniques, treatments, and preventive measures.

Role of Lipids in Cellular Functioning

Lipids play a significant role in your cellular functioning. They’re essential components of cell membranes and help maintain the structural integrity and fluidity of these membranes. The composition of lipids within a cell can influence various cellular processes, such as receptor signaling and signal transduction. Receptor signaling is the communication that occurs between receptors on cells. (Think of the communication that can occur between radio antennae, except these “antennae” are on the surfaces of all of your cells.) Signal transduction refers to the ability of a signal to be moved along. For example, when a molecule binds to a receptor on the surface of a cell like a lock and key, it can trigger a change in the shape of the receptor and cause a response in the cell.

In addition, lipids are also crucial for moving proteins within the cell. They aid in the formation of vesicles (think of a microsopic Amazon delivery vehicle!) that transport proteins between different cellular compartments. 

In summary, lipids contribute significantly to various aspects of cellular functioning:

• Maintaining the structural integrity and fluidity of cell membranes
• Modulating receptor signaling and signal transduction
• Facilitating protein trafficking within cells by aiding in vesicle formation

Being aware of the crucial role lipids play in cellular functioning allows you to better understand the importance of maintaining a balanced lipid composition in your cells, which ultimately affects your overall health and well-being.

Cholesterol Homeostasis and Trafficking

Cholesterol homeostasis is essential for maintaining the overall functionality and integrity of your cells. It involves a delicate balance between the synthesis, uptake, utilization, and export of cholesterol within your cells. Misregulation of cholesterol homeostasis could lead to various diseases, such as atherosclerosis and neurodegenerative disorders.

Intracellular cholesterol trafficking plays a crucial role in preserving this balance. As you learned above when we reviewed the types of lipoproteins, our cells have a complex system to transport cholesterol to different cellular compartments or parts of the body. This process employs various transport proteins and pathways to ensure seamless cholesterol movement within the cell.

Visualization of cholesterol trafficking and homeostasis in live cells has significantly advanced our understanding of these processes. Using advanced imaging techniques, such as fluorescence and luminescence microscopy, we can track cholesterol movement in real-time! One of these visualization methods employs genetically encoded sensors, which help identify the subcellular localization and dynamics of cholesterol molecules. These sensors, combined with high-resolution imaging, highlight the critical players and molecular mechanisms involved in intracellular cholesterol homeostasis and trafficking. Wow!!  Science is amazing!

In summary, maintaining cholesterol homeostasis and efficient cholesterol trafficking is vital for the optimal function of your cells.  Advanced visualization techniques, like fluorescence microscopy, reveal the dynamics of cholesterol trafficking, greatly improving our knowledge of these critical cellular processes.

Epidemiological Studies and Lipids

Epidemiological and genetic studies play a significant role in identifying risk factors and associations for various health conditions, including coronary heart disease (CHD). A key aspect of these studies is the examination of lipids, which can provide valuable insights into disease progression and potential treatments.

One notable locus in lipid research is the apoa5–apoc3 locus. This genetic region has been associated with CHD risk factors, as it contains genes that regulate lipid levels in your body. These genes influence essential lipoprotein management, and any alterations in their functions could result in abnormal lipid profiles, increasing the risk of CHD.

Epidemiological and genetic studies can reveal patterns of lipid profiles across various demographic and geographic populations, offering a wealth of information to help guide medical research and public health policies. For example, such studies can identify novel genes or environmental factors that influence lipid metabolism, shedding light on disease mechanisms and potential therapeutic targets.

In summary, epidemiological studies play a crucial role in understanding the relationships between lipids and CHD risk factors. A deep understanding of the various genetic and environmental factors involved can help steer future research and public health efforts. Now that we’ve reviewed the science of lipidomics, let’s talk about treatment!

Footnotes

1. An Unbiased Lipid Phenotyping Approach To Study the Genetic … – PubMed ↩
2. Microparticles and Their Emerging Role in the Regulation of Lipid … – PubMed ↩

Natural treatment options for hyperlipidemia

Hyperlipidemia, characterized by elevated cholesterol and triglyceride levels, can increase the risk of cardiovascular diseases. However, there are natural ways to help manage and improve lipid levels in your body.

One of the most effective natural strategies is to incorporate a healthy diet rich in fruits and vegetables. These plant-based food items contain essential nutrients, fiber, and cholesterol-blocking molecules like sterols and stanols. Be sure to consume a wide variety of colorful fruits and vegetables, as their vibrant pigments offer added health benefits.

Another recommendation is to include wild fatty fish such as salmon, tuna, and mackerel in your meal plan. These fish are abundant in omega-3 fatty acids, which can help lower LDL (bad) cholesterol levels and improve overall heart health. However, don’t consume the farm-rasied varieties of these fish as they lack abundant omega-three fatty acids.  Instead, purchase only “wild” options. Similarly, seeds and nuts are excellent sources of healthy fats and proteins, offering additional support in managing hyperlipidemia.

Stay physically active and maintain a regular exercise routine. Engaging in at least 150 minutes of moderate-intensity aerobic exercise per week can help lower LDL cholesterol and increase HDL (good) cholesterol levels.

Lastly, consider integrating cholesterol-lowering supplements in your daily regimen. Some potential options include berberine, plant sterols, and stanols. A non-flushing form of niacin (B3) is often used to reduce excess lipids, specifically LDLs.  It is best to take niacin with a good B-complex to minimize any issues with homocysteine elevation that can occur as you reduce LDLs. Remember to consult with a qualified healthcare professional before beginning a supplement regimen, as they can provide personalized advice based on your specific needs and potential interactions with other medications.

Incorporating these natural treatment options for hyperlipidemia can support your journey towards better health. By prioritizing a nutrient-rich diet, regular exercise, and appropriate supplementation, you can effectively manage and improve your lipid profile.

When are statins necessary?

Statins are cholesterol-lowering medications that can help prevent heart attacks, strokes, and other cardiovascular events. Your doctor may recommend statins if you have a history of heart disease or are at high risk for developing these conditions. For instance, individuals with LDL cholesterol levels above 190 mg/dL or those with a high calculated 10-year risk of cardiovascular disease may be prescribed statins as a preventive measure ¹.

People aged 40 years and older without known cardiovascular disease can also benefit from statins if they have risk factors such as diabetes, high blood pressure, or a family history of heart disease ². In these cases, statins are prescribed for primary prevention to reduce their long-term risk of heart attacks and strokes ³.

Statins are not without their risks.  A very common side effect is muscle pain.  If ignored, this can lead to protective movement patterns which can lead to falls.  Fatigue, headache, digestive problems and dizziness can occur.  Less commonly (but more concerning), statins may cause liver damage 4.

It’s important to keep in mind that the decision to start statin therapy should always be based on a thorough evaluation of your individual risk factors and a discussion with your healthcare provider. They will help you weigh the potential benefits and risks of statin use based on your unique circumstances.

Lifestyle changes, such as adopting a heart-healthy diet, exercising regularly, and maintaining a healthy weight, should always be a primary line of defense against high cholesterol and cardiovascular disease. However, if these efforts are not sufficient to reduce your risk, statins can provide additional protection and help you maintain good cardiovascular health ⁵.

Remember that taking statins is not a substitution for following a healthy lifestyle. Combining statin therapy with smart lifestyle choices can lead to even better outcomes in terms of cardiovascular risk reduction.

Conclusion

In summary, lipid phenotyping is a crucial method for understanding our personal lipid profiles. Lipid phenotyping can reveal detailed associations between individual lipids and their role in disease risk factors, as well as our overall health. Understanding these connections can lead to improved diagnostic tools and personalized treatment options.

Footnotes

1. https://www.ncbi.nlm.nih.gov/books/NBK279314/ ↩
2. https://www.acc.org/latest-in-cardiology/articles/2022/08/23/18/48/uspstf-releases-updated-statin-guidelines-for-primary-prevention-of-cvd ↩
3. https://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/statins/art-20045772 ↩
4. https://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/in-depth/statin-side-effects/art-20046013 
5. https://www.uptodate.com/contents/statins-actions-side-effects-and-administration ↩

Frequently Asked Questions

Who Should Have a Lipid Phenotype Test Performed?

If you have cardiac symptoms, a family history of cardiac events, are post-menopausal, and/or are over 50 and would like a baseline, ask your doctor to order a lipid phenotype test for you. 

How are proteins and lipids sorted and trafficked in cells?

Your cells utilize a system called vesicular trafficking to sort and transport proteins and lipid droplets within the cell. Vesicles, or small membrane-enclosed sacs, are responsible for carrying proteins, lipids, and other cellular components to their target locations. The process begins with the membrane-bound compartments, such as the endoplasmic reticulum and Golgi apparatus, where proteins and lipids are synthesized and modified. Vesicles then bud-off, carrying their cargo to their destination, such as the plasma membrane or other organelles within the cell.

What abnormalities can occur in lipid metabolism?

Various abnormalities can occur in lipid metabolism, leading to different types of diseases and disorders. These include lipid storage diseases, which result from the improper breakdown or accumulation of lipids, leading to organ dysfunction. Additionally, disruptions in cholesterol metabolism can lead to cardiovascular diseases, such as atherosclerosis. Genetic determinants of lipids, like familial hypercholesterolemia, can also result in abnormalities in lipid metabolism and an increased risk of cardiovascular issues.

What is the primary method for lipid profiling?

The primary method for plasma lipid profiling is a high-throughput, direct infusion high-resolution mass spectrometry (DIHRMS), which is a novel technique that enables rapid and accurate profiling of hundreds of lipids in human serum without prior chromatography. This method allows for in-depth lipid phenotyping in large epidemiological studies, revealing the detailed associations of individual lipids with health risk factors, for example, coronary heart disease.  This method separates lipids within each overall lipid category and different lipid classes, creating a lipoprotein phenotyping profile.

What research has been done on disease prevention and lipid phenotyping in clinical research?

There have bene numerous studies showing the relationships between lipid subclasses, deviations for each lipid, and issues associates with lipid profiles.  This includes a Pakistan risk of myocardial infarction study and studies done by the Institute for Health Research Cambridge, National Institute for Health Research, the Blood Institute, The European Research Council, and the UK Medical Research Council.  These studies looked for quantitative and statistically significant information on a broad panel of complex lipid species across populations, including the association of lipids with obesity.  The overall lipid category most strongly associated with obesity was low-density lipoprotein cholesterol.

Which lipids have the most significant impact on health?

The lipids with the most significant impact on your health are cholesterol and triglycerides. Both are essential components of your cells, but an imbalance in their levels can lead to various health issues. Differences in lipid species detected – such as abnormal lipoprotein distribution and concentration – are the cornerstone of this approach for circulatory lipid phenotyping. High levels of low-density lipoprotein (LDL) cholesterol, known as “bad” cholesterol, can contribute to the formation of arterial plaque, increasing the risk of cardiovascular disease. On the other hand, high-density lipoprotein (HDL) cholesterol, called “good” cholesterol, helps protect against heart disease. Additionally, elevated triglyceride levels may contribute to the development of diabetes, liver disease, and heart disease.  Correlations of these lipids is a partial determinant of your coronary heart disease risk factors and your risk of acute pancreatitis.