High-Density Lipoprotein Cholesterol

High-density lipoprotein (HDL) is often hailed as the "good" cholesterol, playing a crucial role in maintaining heart health and reducing the risk of cardiovascular diseases. 

HDL, or high-density lipoprotein, is a type of cholesterol-containing lipoprotein particle that helps remove cholesterol from your bloodstream.

HDL is known for its protective role in the cardiovascular system, as it transports cholesterol from the arteries to the liver for excretion, thereby reducing the risk of plaque buildup and heart disease.

This article delves into the definition and function of HDL. It also provides guidance on preparing for and interpreting HDL lab tests, understanding related biomarkers, and exploring natural ways to optimize HDL levels through diet, lifestyle, and supplementation.

Definition and Function of High Density Lipoprotein

Definition: What is High Density Lipoprotein, HDL?

HDL is a type of lipoprotein particle, which is responsible for shuttling cholesterol through the body.  

A lipoprotein particle is a biochemical assembly that contains both proteins and lipids, which are bound to the proteins. These particles are responsible for transporting lipids, such as cholesterol and triglycerides, throughout the bloodstream. 

The protein component, known as apolipoproteins, helps to stabilize the lipid molecules and also serves as a recognition signal for cellular receptors, facilitating the uptake and metabolism of the lipids carried by the lipoprotein particles. 

The different types of lipoprotein particles, such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL), have distinct roles and compositions, contributing to their specific functions in lipid transport and metabolism.

To understand the significance of HDL in health and disease, it is important to understand the different fractions of cholesterol present in the bloodstream.  

Overview of Cholesterol Lipoprotein Particle Types in the Bloodstream

Cholesterol is shuttled through the body in lipoprotein particles, and some types confer a higher risk of cardiovascular disease than others.  

There are five main types of lipoprotein particles: their individual cardiac risk, or atherogenicity, depends on their size, the direction in which they’re traveling (to or away from the liver), and the lipoproteins attached to them.  [11.]

Chylomicrons: chylomicrons contain lipids absorbed from the digestive system and are too large to have a direct effect on cardiovascular health

High-density lipoprotein (HDL): HDL particles contain the ApoA1 lipoprotein, among others, and tends to carry cholesterol back to the liver; therefore, HDL is considered “good” cholesterol.  [19.]

Non-HDL particles: these include very low-density lipoproteins [VLDL], intermediate-density lipoprotein [IDL], low-density lipoprotein [LDL], and lipoprotein(a), or Lp(a).  These particles all contain Apo-B lipoproteins, are traveling from the liver to peripheral tissues, and are small enough to cause atherosclerosis; for all of these reasons, they are considered to increase cardiovascular risk.  [3.]

In the basic lipid panel, the Total Cholesterol biomarker is used to describe the sum of HDL + Non-HDL particles.  Often, this is similar to HDL + LDL particles (the markers typically present on a standard lipid panel), but not always.  [11.]

Overview of HDL Structure, Production and Apolipoproteins  [2.]

High-density lipoprotein (HDL) particles are complex structures primarily involved in reverse cholesterol transport. They are composed of a core of cholesterol esters and triglycerides surrounded by a surface monolayer of phospholipids, free cholesterol, and various apolipoproteins. 

The main apolipoproteins present in HDL are:  [2.]

• Apo-AI: the primary structural protein of HDL, activates Lecithin–Cholesterol AcylTransferase (LCAT).

• Apo-AII: a structural protein in HDL, acts as an activator of hepatic lipase.

• Apo-AIV: its function is not fully understood.

• Apo-AV: activates lipoprotein lipase (LPL), responsible for triglyceride lipolysis.

• Apo-CI: activates LCAT.

• Apo-CII: activates LPL.

• Apo-CIII: inhibits LPL.

• Apo-E: serves as a ligand for the LDL receptor.

HDL particles are synthesized in the liver and intestines, starting with the production of Apo-AI. 

As HDL circulates, it acquires free cholesterol and phospholipids from peripheral tissues, chylomicrons, and very-low-density lipoprotein (VLDL). LCAT, activated by Apo-AI, converts free cholesterol on HDL's surface to cholesterol esters, which are then incorporated into HDL's core. 

HDL facilitates the return of cholesterol to the liver via several pathways, including direct uptake through receptors like SR-B1 and indirect transfer to other lipoproteins via the cholesterol ester transfer protein (CETP) pathway.

Function of HDL: What Does HDL Do in the Body?  [2., 4., 18.]

The primary function of high-density lipoprotein (HDL) is to transport cholesterol from peripheral tissues to the liver, a process known as reverse cholesterol transport (RCT). This role is crucial in maintaining lipid homeostasis and preventing the accumulation of cholesterol in blood vessels, which can lead to atherosclerosis. 

HDL particles are composed of various apolipoproteins, including Apo-AI, Apo-AII, Apo-AIV, Apo-AV, Apo-CI, Apo-CII, Apo-CIII, and Apo-E, each playing a distinct role in HDL function and metabolism.

Apo-AI, the main structural protein of HDL, is synthesized in the liver and intestines and is critical for the formation of nascent HDL particles. It activates the enzyme Lecithin–Cholesterol AcylTransferase (LCAT), which converts free cholesterol on the surface of HDL to cholesterol esters, allowing for its incorporation into the core of the HDL particle. 

Apo-AII acts as a structural component and activator of hepatic lipase, while Apo-AV stimulates lipoprotein lipase, crucial for triglyceride metabolism. 

Apo-CI, Apo-CII, and Apo-CIII are involved in the regulation of lipid metabolism, with Apo-CII activating lipoprotein lipase and Apo-CIII inhibiting it. 

Apo-E serves as a ligand for the LDL receptor, facilitating the uptake of HDL cholesterol by the liver.

In the liver, HDL cholesterol can be taken up via several pathways, including the scavenger receptor class B type 1 (SR-B1) pathway, which allows for the selective uptake of cholesterol without internalizing the entire HDL particle. 

The cholesterol ester transfer protein (CETP) pathway involves the exchange of cholesterol esters from HDL to apolipoprotein B-containing particles, such as very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), in exchange for triglycerides. 

This process enriches HDL in triglycerides and depletes its cholesterol ester core, leading to the formation of smaller HDL particles that can be metabolized by hepatic lipases or taken up by the liver through LDL receptors.

Overall, HDL plays a crucial role in lipid metabolism and cardiovascular health by facilitating the removal of excess cholesterol from peripheral tissues and its transport to the liver for excretion. Its anti-atherogenic and anti-inflammatory properties are attributed to its ability to reduce the size of atherosclerotic plaques and decrease inflammation associated with lipid accumulation.

Lab Testing for HDL Cholesterol Levels

General Testing Information and Sample Type

Typically, cholesterol assessment starts with a lipid panel, which includes the following biomarkers: total cholesterol, LDL and HDL cholesterols, and triglycerides, as well as the TC/HDL ratio.

People are increasingly aware of the benefits of advanced testing for cholesterol levels in order to support wellness, reduce their risk of cardiovascular disease, and inform personalized medical decisions.  To address the desire for more information about cholesterol health, lab companies are increasingly offering more comprehensive assessments.  

A few examples include:

The Cardiometabolic Profile by Doctor’s Data

The CadioPro Advanced Profile by Access Medical Labs

The Cardiometabolic Comprehensive Profile by BostonHeart Diagnostics

The LPP Plus by Spectracell Laboratories

These tests, including the standard lipid profile, are all blood tests that require a venipuncture.  Fasting is typically recommended for these tests.  In some cases, a mobile phlebotomist can come to you to have the blood draw performed from the home or office, and the sample can then be taken to the lab by the phlebotomist. 

Interpreting Test Results

Reference Range for HDL Cholesterol

Reference ranges may vary among labs, so it is important to interpret test results according to the individual lab company used.

Generally, the reference ranges for HDL-C are as follows:  [26.] 

Male: >45 mg/dL or >0.75 mmol/L (SI units)

Female: >55 mg/dL or >0.91 mmol/L (SI units)

Clinical Significance of High Levels of HDL Cholesterol  [6.] 

Elevated HDL cholesterol levels are considered > 80 mg/dL (>2.1 mmol/L).

High levels of high-density lipoprotein (HDL) cholesterol are generally considered beneficial for cardiovascular health due to HDL's role in reverse cholesterol transport and its anti-inflammatory and anti-oxidative properties. 

However, recent studies suggest that extremely high HDL cholesterol levels may not always be protective and could, in some cases, increase the risk of cardiovascular disease (CVD). [6., 23., 33.] 

This has led to a shift in focus from merely the quantity of HDL to the quality and functionality of HDL particles. [1.]

The size and composition of HDL particles, including the presence of specific proteins and lipids, are now recognized as crucial factors influencing their protective effects. Smaller, denser HDL particles, for example, are believed to be more effective in cholesterol efflux and exhibit greater anti-inflammatory capacity than larger, less dense particles.

While elevated HDL cholesterol levels typically indicate a reduced risk of CVD, certain genetic disorders associated with high HDL cholesterol may not offer the same protective benefits due to accompanying lipid and metabolic abnormalities.  [34.]

Primary causes of elevated HDL cholesterol include genetic mutations that lead to overproduction or decreased clearance of HDL cholesterol. Secondary causes can include conditions such as alcohol use disorder without cirrhosis, hyperthyroidism, primary biliary cirrhosis, and the use of certain medications like corticosteroids, insulin, phenytoin, and estrogen.

Cholesteryl ester transfer protein (CETP) deficiency, a rare autosomal recessive disorder caused by mutations in the CETP gene, is characterized by extremely high HDL cholesterol levels (> 150 mg/dL or > 3.9 mmol/L) but without proven protection from cardiovascular disorders. 

Familial hyperalphalipoproteinemia, an autosomal dominant condition resulting from various genetic mutations, is usually diagnosed incidentally with plasma HDL cholesterol levels exceeding 80 mg/dL (> 2.1 mmol/L). Patients with these conditions typically do not exhibit symptoms or signs related to their elevated HDL cholesterol levels, and no specific treatment is necessary.

Possible causes of elevated HDL cholesterol levels include: 

Genetic Factors: as noted above, certain genetic mutations can lead to elevated HDL levels.

Physical Activity: regular exercise, especially aerobic activities, can increase HDL cholesterol.  [13.]

Diet: a diet rich in healthy fats, such as those found in olive oil, nuts, and fatty fish, can raise HDL levels.  [7.] 

‍Alcohol Consumption: moderate alcohol intake, particularly red wine, is associated with higher HDL levels.  [5.]

‍Medications: some medications including certain fibrates and niacin, can increase HDL cholesterol.  [20.] 

Weight Loss: losing excess weight, particularly in individuals with obesity, can lead to an increase in HDL levels.  [28.]

Hormonal Factors: changes in hormone levels, such as during menopause or with hormone replacement therapy, can affect HDL cholesterol.  [9., 21.]

Smoking Cessation: quitting smoking can result in an increase in HDL cholesterol levels.  [14.]

Liver Disease: certain liver conditions, such as primary biliary cirrhosis, can lead to elevated HDL levels.  [32.]

Clinical Significance of Low Levels of HDL Cholesterol 

A low HDL cholesterol level is typically considered to be below 40 mg/dL.  [22.]

Traditionally, low levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of cardiovascular disease (CVD).  While new research uncovers the nuances of the relationship between optimal levels of HDL cholesterol and cardiovascular health, it is still accepted that low levels of HDL cholesterol may confer increased risk of cardiovascular disease.  [15.]

Low HDL cholesterol levels can lead to the accumulation of cholesterol in the arteries, forming plaques that narrow and harden the arteries, a condition known as atherosclerosis. This can increase the risk of heart attacks, strokes, and peripheral artery disease.

Several factors can contribute to low HDL cholesterol levels. Genetic factors play a significant role, with some individuals inheriting conditions that result in low HDL cholesterol. Lifestyle factors are also crucial, with poor diet, physical inactivity, obesity, and smoking being major contributors to low HDL levels. A diet high in saturated and trans fats can lower HDL cholesterol, while regular physical activity and maintaining a healthy weight can help increase HDL levels.

Medical conditions and certain medications can also lead to low HDL cholesterol levels. For example, type 2 diabetes, metabolic syndrome, chronic kidney disease, and inflammatory conditions such as rheumatoid arthritis and lupus can all result in lower HDL cholesterol. Additionally, medications such as beta-blockers, anabolic steroids, and progestins can also decrease HDL cholesterol levels.

What is an Optimal HDL Cholesterol Level?

Research continues to shed light on optimal levels of cholesterol markers and overall human health.  A range of HDL cholesterol between 40-60 mg/dL is given as an optimal level.  [22.] 

Research increasingly shows increased risk of cardiovascular disease and events with HDL levels above 80 mg/dL, indicating that this may be the upper threshold of optimal HDL levels.  [6., 23., 33.] 

Related Biomarkers: What Should Be Tested Besides Total Cholesterol?

The standard lipid panel is a good place to begin to evaluate an individual’s risk of developing heart disease.  There are a variety of other biomarkers available that can provide increased information above and beyond a standard lipid panel.  Some of these include: 

VLDL Particles: very-low-density lipoprotein (VLDL) particles are a precursor to LDL particles and play a crucial role in lipid metabolism. Elevated VLDL levels are associated with increased risk of atherosclerosis and cardiovascular disease.  [8.]

Total LDL Particles (LDL-P): measuring the number of LDL particles gives different information than LDL-C, which is the amount of cholesterol that’s carried by LDL particles.  

Knowing the number of LDL particles present in the bloodstream provides a more comprehensive assessment of cardiovascular risk than LDL-C alone because the size of LDL particles also confers cardiovascular risk, with smaller LDL particles being more atherogenic.  

Therefore, in two people with the same LDL-C number, the person with a higher LDL-P (and therefore more small LDL particles present in his or her bloodstream) has a higher risk for a cardiovascular event than the person with the lower LDL-P.  [24.]

Remnant Lipoprotein: remnant lipoproteins, remnants of VLDL and chylomicrons after triglyceride hydrolysis, are atherogenic particles associated with increased risk of cardiovascular events, even in individuals with normal LDL cholesterol levels.  [25., 35.]

Dense LDL III and Dense LDL IV: small dense LDL (sdLDL) subfractions, particularly LDL III and LDL IV, are more atherogenic than larger, buoyant LDL particles. Measuring these subfractions provides additional information for assessing cardiovascular risk beyond traditional lipid panels.  [27.]

Buoyant HDL 2b: buoyant HDL 2b particles are considered particularly cardioprotective due to their role in reverse cholesterol transport. Higher levels of buoyant HDL 2b are associated with reduced risk of cardiovascular events.  [17.]

Lipoprotein(a): Elevated lipoprotein(a) levels are an independent risk factor for cardiovascular disease, particularly in individuals with a family history of premature heart disease.  It is important to note that Lp(a) levels are genetically determined and change little, if at all, in response to diet and lifestyle.  [30.]

Apolipoprotein B (ApoB): Apolipoprotein B is a structural component of atherogenic cholesterol particles including VLDL, IDL, LDL and Lp(a)  particles and is considered a more accurate predictor of cardiovascular risk compared to LDL cholesterol levels alone, particularly in the setting of insulin resistance and diabetes.  [3.]

‍Apolipoprotein A1 (apoA1): apoA1 is attached to the surface of HDL particles, and is associated with a cardioprotective effect.  Elevated apoA1 levels are associated with improved HDL functionality and reduced cardiovascular risk, while low levels are independently linked to increased risk of cardiovascular events. 

Monitoring apoA1 levels allows for better risk prediction and assessment of therapeutic efficacy in managing cardiovascular disease risk. [19.]

hs-CRP (High-Sensitivity C-Reactive Protein): elevated hs-CRP levels are indicative of systemic inflammation and are associated with increased risk of cardiovascular events, including myocardial infarction and stroke.  [12.]

Homocysteine: elevated homocysteine levels are associated with increased risk of cardiovascular disease, including atherosclerosis, stroke, and venous thromboembolism.  [29.]

How to Support Healthy Cholesterol Levels

Lifestyle Modifications

• Maintain a healthy weight through regular physical activity and a balanced diet.  [28.]

• Reduce sedentary behavior and incorporate more movement throughout the day to support a healthy metabolism.

• Manage stress levels through relaxation techniques such as meditation or yoga. High stress has been correlated with metabolic dysfunction.  [36.]

• Ensure adequate sleep duration and quality to support metabolic health.  [31.]

Dietary Changes  [7.]

• Consume a diet rich in whole foods, including fruits, vegetables, whole grains, lean proteins, and healthy fats.  
• Limit intake of highly processed foods, sugary beverages, and foods high in saturated and trans fats.
• Increase fiber intake from sources like legumes, nuts, seeds, and whole grains to promote satiety and regulate blood sugar levels.
• Monitor portion sizes and practice mindful eating to prevent overeating and promote weight management.
• Follow a plant-based diet, and reduce intake of high-fat animal products. 

Exercise Recommendations  [13.]

• Engage in a combination of aerobic exercise, strength training, and flexibility exercises to improve metabolic function.
• Aim for regular physical activity throughout the week, incorporating both cardiovascular exercise and resistance training sessions.
• Gradually increase exercise intensity and duration over time to challenge the body and promote fitness gains.
• Incorporate activities you enjoy to increase adherence to exercise routines and maintain long-term consistency.
• Consult with a healthcare provider or fitness professional to develop a personalized exercise plan based on individual fitness levels and health goals.

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