APOE-containing HDL - A New Window into the HDL Function and Atherosclerosis Progression

Sep 30, 2026

HDL particles protect against atherosclerosis, yet therapies that raise HDL-C often fail to deliver expected benefits, making HDL function a more relevant target. The editorial discusses why CETP deficiency and CETP inhibition may be informative, and why evaluating HDL function rather than HDL-C alone is important in high-risk coronary heart disease groups. ApoE-HDL is highlighted as an indicator linked to apoA1 changes, cholesterol metabolism, and biomarker potential for anti-atherosclerotic effects.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages2

Reading Time5 min

AccessFree to download

Editorial

HDL-C vs HDL function

Roles of apoA1 and apoE in lipoproteins

ApoE-HDL as a biomarker and future directions

Limitations and disclosures

References

The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Editorial J Atheroscler Thromb, 2026; 33: 24-25. [http://doi.org/10.5551/jat.ED293](http://doi.org/10.5551/jat.ED293) APOE-containing HDL: A New Window into the HDL Function and Atherosclerosis Progression Atsushi Nohara Department of Clinical Genetics, Ishikawa Prefectural Central Hospital, Kanazawa, Japan See article vol. 33: 40-54 Epidemiological evidence has clearly shown that HDL particles are lipoproteins that act to protect against atherosclerosis. However, various types of therapeutic intervention that increase HDL-C often do not produce the expected effects, and the HDL function is thought to be important. CETP deficiency, which has been discovered in Japanese individuals, shows markedly elevated HDL-C levels and reduced LDL-C levels 1), and CETP inhibitors are therefore expected to become an effective lipid treatment drug. In recent years, obicetrapib has been undergoing clinical trials, and the LDL-C lowering effect ofCETP inhibitors, which is independent of LDL receptor, is thought to be important for preventing arteriosclerotic disease 2, 3) . Although some research reports have suggested that HDL-C is merely a marker, the function of HDL particles easily declines with either inflammation or metabolic disorders among CHD high risk groups, it is reasonable to consider that it is important to evaluate the HDL function rather than HDL-C. ApoE-HDL may also be an indicator that reflects some related function. ApoA1, which is specific to HDL, is understood to be important for the HDL function as the starting point for reverse cholesterol transport from peripheral tissues, and apoA1 deficiency results in extremely low HDL levels and a susceptibility to develop atherosclerosis. On the other hand, apoE is contained in many lipoproteins other than LDL. Because the nonfunctional isoform ε2/2 is the cause of type III hyperlipidemia, its importance in the metabolism of TG-rich lipoproteins, such as remnants, is well established and easy to clinically understand. However, the importance of apoE contained in HDL remains a matter of debate. HDL particles in cerebrospinal fluid function via apoE, not apoA1, and it is well known that ε4 is a risk factor for Alzheimer’s disease. So how does apoE-HDL increase or decrease in the peripheral blood, and how does it affect atherosclerotic disease? In HDL particles, an increase in apoE may decrease apoA1, but what is the impact? HDL containing only apoE is larger in size and it contains more cholesterol than apoA1-HDL. It has been reported that in CETP deficiency (or CETP inhibition), the apoE-containing subfraction in HDL increases. Furthermore, apoE-HDL has been shown to have a higher receptor binding capacity than LDL, and since a significant number of HDL particles contain apoE, it may have a significant impact on the cholesterol metabolism. Qi Y, Liu J, and colleagues have previously published important reports on apoE-HDL. They demonstrated that cholesterol-overloaded HDL particles are independently associated with the progression of carotid atherosclerosis 4) and they also reported that APOE-containing HDL was found to attenuate the impact of cholesterol-overloaded HDLon increased incident CHD risk 5) . In this issue of the journal, Ni P et al. prospectively followed the 5-year progression of carotid plaque in an asymptomatic, cardiovascular disease-free general cohort and reported the potential ofapoE-containing HDL as a potentially effective biomarker for the anti-atherosclerotic function of HDL particles 6) . A future challenge will be to go beyond HDL-Cand utilize the HDL function to assess disease risk. The effectiveness of cholesterol efflux capacity, antioxidant capacity evaluation, and antiinflammatory capacity evaluation has been reported, and it is thought that apoE-HDL can also be used. It has been reported that apo

FAQs

Why does the editorial emphasize evaluating HDL function rather than HDL-C alone?

HDL function declines with inflammation or metabolic disorders in high-risk CHD groups, while HDL-C–raising therapies often do not yield the expected protective effects. Therefore, HDL function is considered important to assess disease risk.

What is the role of CETP deficiency or CETP inhibitors discussed in the editorial?

CETP deficiency in Japanese individuals markedly increases HDL-C and reduces LDL-C. CETP inhibitors, including obicetrapib under clinical trials, are expected to contribute to lipid treatment and arteriosclerotic disease prevention through mechanisms such as LDL-C lowering independent of the LDL receptor.

How does apoE-HDL relate to atherosclerosis progression and biomarker potential?

The editorial notes that apoE-containing HDL may influence cholesterol metabolism due to higher receptor binding capacity and prevalence among HDL particles. It also summarizes reports suggesting associations between cholesterol-overloaded HDL and carotid atherosclerosis progression, and highlights a study on apoE-containing HDL as a potentially effective biomarker for anti-atherosclerotic HDL function.

Sep 30, 2026

Uploaded by Valentina