HDL Function and Its Role in Cardiovascular Health

Written by Mark Houston, MD, and Sara Gottfried, MD

High-density lipoprotein (HDL) plays a vital role in lipid biology and coronary heart disease (CHD) pathophysiology. However, we’re witnessing a major paradigm shift in the medical community regarding the role of HDL-cholesterol (HDL-C) in dyslipidemia and dyslipidemia-induced cardiovascular disease, especially CHD and myocardial infarction (MI). (4)

What is HDL?

HDLs are complex nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. HDL is best known for its ability to scavenge for and ferry low-density lipoprotein cholesterol (LDL-C) away from the arteries and back to the liver for redistribution, metabolism, and elimination. (4)

HDL: the paradigm shift in the role

LDL is essentially a “garbage”-type particle that deposits cholesterol in cells all over the body, while HDL is like a “garbage” collector. The HDL particle literally takes excess cholesterol out of tissue to remove it from the body, usually through the liver. (4)

Epidemiological studies, ranging from the Framingham Study and continuing through to the Atherosclerosis Risk in Communities (ARIC) Study, demonstrated that HDL-C is inversely associated with CHD and MI. (9)(30) Specifically, as the calculation was extended, CHD risk increased by 3% in men and 2% in women for every 1 mg/dL decrement in HDL-C. (8) Patients were told high HDL-C meant high “reverse cholesterol transport (RCT),” the body’s ability to bring cholesterol back to the liver for removal. It was believed that as long as HDL-C levels were above a threshold, a patient was protected from having CHD and/or MI.

New research compels us to update that perception, as evidence points to a more nuanced model. Pharmacological interventions in randomized trials that raise HDL-C by two- to threefold have failed to produce the anticipated reduction in cardiovascular risk. (2)(1)(29)(12)(7) Additionally, HDL-associated apolipoprotein A-I (apoA-I) levels in HDL subtypes are a better predictor of cardiovascular risk than HDL-C concentration. (35) The anti-atherogenic capacity of HDL seems to be mediated by function, such as cholesterol efflux capacity (CEC), which is a superior predictor of risk than total HDL-C concentration, (22) though not all data are concordant. Data from genome-wide association studies (GWAS) show that lower HDL-C may not cause CHD, high HDL-C may not be protective from CHD, and heterogeneity of HDL structure and function may be more to blame. (34)(33)

In other words, if HDL is the garbage collector, there’s a range of options in the fleet. Some garbage trucks look good but don’t perform. Some have flat tires. But some of the garbage trucks are top of the line, some have large carrying capacity, others have small carrying capacity, and others are highly dependable and perform beyond expectations—that’s the spectrum of HDL function.

We can no longer rely on high HDL-C alone for heart health protection because experts are now questioning the composition and function of the various types of HDL.

What is HDL function?

Static measurement of HDL-C fails to reflect the dynamics of the HDL particle, its remodeling process, the HDL cargo load, HDL interconversions in the lipid pathway, the hepatic unloading, and resulting function.

Until recently HDL function could not be measured. We only had “indicative markers of HDL function,” such as myeloperoxidase (MPO) and inflammatory and oxidative stress markers, but not direct assessments of HDL function. However, a new lab in beta testing may soon be available to measure to determine HDL function simply. Investigators demonstrated that assessment of CEC is one metric of HDL function and may in fact be a predictor of atherosclerosis and cardiovascular disease risk. (6)

New research is painting a broader picture that HDL function may be impaired by systemic inflammation or oxidative stress, such as that from autoimmunity, suggesting that improvement in HDL function may help beyond cardiovascular risk. (17)

HDL mapping of various subspecies of HDL

There are five forms of HDL particles. “HDL mapping” is a test which includes α-1, α-2, α-3, α-4, and pre-β HDL. Emphasis on the importance was placed on large HDLs such as α-1 and, to a degree, α -2. This concept has since changed. Small HDL may be just as important as they transform into larger HDL, which removes more LDL. All types of HDL may play a role in this process.

But without proper function, even size doesn’t matter. A patient may have a normal level of all HDL sizes with HDL mapping, but his HDL function can be abnormal. Think of it like a garbage truck with four flat tires. That’s why function is the key factor. (27)

The importance of HDL particle number

The benefits of HDL also depend on the number of HDL particles. This is called HDL particle number (HDL-P). Based on recent research, the higher the HDL particle number, the more protected the person is from CHD and MI. (16) Many researchers agree HDL function and particle number are the two most important factors when measuring HDL. In fact, in many studies, the HDL-P and HDL function measurements are equally predictive of CHD and MI.

Nutritional protocol for HDL function

Supplementation can play a key role in HDL management. There are very few pharmaceutical agents that modify HDL. Most won‘t affect the lab parameters we’ve covered. However, various nutraceutical supplement and nutritional changes can modify at least one of these key factors.

Variety of foods

Increased intake of virgin olive oil, nuts, legumes, whole grains, and fish improves HDL function. (11) Specifically, olive oil and whole-grain consumption raise CEC. Nut and legume intake improve PON-1 activity. Legumes decrease cholesteryl ester transfer protein activity. Fish consumption increases PON-1 activity and declines in cholesteryl ester transfer protein activity, HDL-C concentrations, and functions related to HDL (CEC).

Pomegranate

Pomegranate can change some of the enzymes, such as paraoxonase 1 (PON-1), in the HDL particle, allowing it to better transport cholesterol and improve HDL’s anti-oxidant capacity. (28)(10)

Niacin

Niacin shows promise, though data is mixed. It appears to raise HDL-C, and HDL-P, however some researchers found this did not significantly affect HDL function. (20)(13)(32)(25)

Lycopene

Lycopene-rich diet or lycopene increased apoA-I and other proteins associated with HDL function. (18)(31)

Green tea extract

Green tea extract, or EGCG, can change the protein or lipid content of HDL, reducing the effects of oxidative stress or inflammation, thereby reducing the risk of HDL dysfunction. (3)

Flavonoids

Flavonoids, such as anthocyanin, positively change serum biomarkers related to HDL function in several patient populations, including dyslipidemic, hypertensive, and diabetic individuals. This results in not only increased HDL cholesterol levels, but also HDL anti-oxidant and CEC. (19)

Additional bioactives for HDL function

Quercetin, glutathione, resveratrol, and phosphatidyl serine may improve HDL function, though several of the studies are underpowered, and more functional data is needed. (23)(26)(36)(5)(24)

Track patient progress

As HDL-C provides almost no information on HDL function, other measurements are needed to track whether interventions are effective. Biomarkers of low-grade inflammation (e.g., hs-CRP) and oxidative stress (MPO) give information on HDL particle dysfunction risk. Advanced lipid panels (e.g., HDL-P) and HDL mapping provide additional information on the health of HDL particles. Patients’ results will guide or alter a supplement and lifestyle protocol. Close follow-up and repeat testing should be run every two to four months. When a patient achieves optimal levels of all three components, a reduction in the event rate for CHD and MI should be seen. (14)

The bottom line

The latest discoveries on the key parameters of HDL efficiency have led to promising new treatment methods for better patient outcomes. Recognizing and measuring HDL type, size, function, and particle number are key factors in protecting patients from CHD and MIs. Through proper nutrition and lifestyle protocols, we can better protect our patient populations from the perils of heart-related health concerns.