Editorial
APOE-containing HDL: A New Window into the HDL Function and Atherosclerosis Progression
2026 年 33 巻 1 号 p. 24-25
詳細
2026 年 33 巻 1 号 p. 24-25
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 levels1), 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 of CETP inhibitors, which is independent of LDL receptor, is thought to be important for preventing arteriosclerotic disease2, 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 non-functional 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 atherosclerosis4) and they also reported that APOE-containing HDL was found to attenuate the impact of cholesterol-overloaded HDL on increased incident CHD risk5). 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 of apoE-containing HDL as a potentially effective biomarker for the anti-atherosclerotic function of HDL particles6).
A future challenge will be to go beyond HDL-C and utilize the HDL function to assess disease risk. The effectiveness of cholesterol efflux capacity, antioxidant capacity evaluation, and anti-inflammatory capacity evaluation has been reported, and it is thought that apoE-HDL can also be used. It has been reported that apoE-HDL does not show any significant fluctuations due to diet, and stable measurement results can thus be obtained7).
This study is associated with some limitations due to the fact that it did not analyze apoE isoforms or examine the effects of CETP deficiency, which is common in East Asia (nearly 10% have defective mutations in Japan). However, the relationship between apoE-HDL and atherosclerosis remains a question worthy of further investigation and it is expected to open a new window in the field of atherosclerosis research.
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