Bridging the Gap Between the Bench and Bedside: Clinical Applications of High-density Lipoprotein Function

Abstract

Decades of research have reshaped our understanding of high-density lipoprotein (HDL) , shifting our focus from cholesterol (C) levels to multifaceted functionalities. Epidemiological studies initially suggested an association between HDL-C levels and cardiovascular disease (CVD) risk; however, such a simple association has not been indicated by recent studies. Notably, genome-wide studies have highlighted discrepancies between HDL-C levels and CVD outcomes, urging a deeper exploration of the role of HDL. The key to this shift lies in elucidating the role of HDL in reverse cholesterol transport (RCT), which is a fundamental anti-atherosclerotic mechanism. Understanding RCT has led to the identification of therapeutic targets and novel interventions for atherosclerosis. However, clinical trials have underscored the limitations of HDL-C as a therapeutic target, prompting the re-evaluation of the role of HDL in disease prevention. Further investigations have revealed the involvement of HDL composition in various diseases other than CVD, including chronic kidney disease, Alzheimer’s disease, and autoimmune diseases. The anti-inflammatory, antioxidative, and anti-infectious properties of HDL have emerged as crucial aspects of its protective function, opening new avenues for novel biomarkers and therapeutic targets. Omics technologies have provided insights into the diverse composition of HDL, revealing disease-specific alterations in the HDL proteome and lipidome. In addition, combining cell-based and cell-free assays has facilitated the evaluation of the HDL functionality across diverse populations, offering the potential for personalized medicine. Overall, a comprehensive understanding of HDL multifunctionality leads to promising prospects for future clinical applications and therapeutic developments, extending beyond cardiovascular health.

1.Introduction

In 1951, high-density lipoprotein (HDL) was first isolated by Eder¹⁾, marking the beginning of more than 70 years of research on this molecule. Research on HDL has progressed into two main categories: epidemiological studies focusing on HDL-cholesterol (HDL-C) and basic and clinical research focusing on the HDL function.

In epidemiological studies, such as the Framingham Heart Study and PROCAM study, HDL-C has been found to be negatively correlated with cardiovascular disease (CVD)^{2, 3)}, resulting in HDL being referred to as an anti-atherogenic lipoprotein. However, recent studies, including those from Japan, have demonstrated that markedly elevated HDL-C levels are unfavorably associated with CVD morbidity and mortality. For example, the Copenhagen City Heart Study and the Copenhagen General Population Study, including a total of approximately 100,000 participants, showed that the hazard ratio for all-cause mortality increased in individuals with very high HDL-C levels, specifically over 97 mg/dL for men and over 135 mg/dL for women⁴⁾. Similarly, a pooled analysis of 9 cohort studies in Japan involving approximately 40,000 participants found an increase in the hazard ratio for cardiovascular diseases in individuals with HDL-C levels of ≥ 90 mg/dL⁵⁾. Furthermore, genome-wide association studies (GWAS) have found that a loss-of-function variant (leucine replaces proline 376 [P376L] in SCARB1, the gene encoding SR-BI) elevated HDL-C levels and increased the risk of CVD⁶⁾. In addition, HDL-C elevation therapy using nicotinic acid or CETP inhibitors failed to prevent CVD events^{7, 8)}. Therefore, these studies cast doubt on the clinical significance of the HDL-C level. However, epidemiological studies have established low HDL-C levels as reliable predictors of atherosclerosis development.

Extensive studies have shown that HDL possesses various anti-atherosclerotic properties, including reverse cholesterol transport (RCT)⁹⁾, antioxidative functions¹⁰⁾, and anti-inflammatory¹¹⁾, anti-apoptotic¹²⁾, vasodilatory¹³⁾, and antithrombotic effects¹⁴⁾. Notably, RCT serves as a crucial anti-atherosclerotic mechanism by which HDL removes excess cholesterol from peripheral cells and transports it back to the liver, ultimately facilitating excretion into the feces. The initial step in extracting cholesterol from macrophages is the rate-limiting process of RCT, known as the cholesterol efflux capacity (CEC). Rader et al. were the first to demonstrate the importance of CEC as a predictor of CVD in a case-control study.

Since then, many clinical studies, including cohort studies, have confirmed that the HDL function with regard to the CEC is a negative risk factor for CVD, bringing about a paradigm shift from the HDL-C to the HDL function. Clinical studies targeting inflammation, such as the Colchicine Cardiovascular Outcomes Trial (COLCOT)¹⁵⁾ and the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)¹⁶⁾, have found that HDL reduces CVD events. Although these studies did not focus on the anti-inflammatory function of HDL, increased attention has been paid to this aspect¹⁷⁾.

In this review, we provide a comprehensive summary of the role of HDL-C in humans, based on both basic and clinical studies. In addition, we explore the recently discovered novel aspects of HDL.

2.Reverse Cholesterol Transport

In 1968, Glomset proposed the concept of RCT as a major function of HDL¹⁸⁾. Subsequently, Oram et al. demonstrated the ability of HDL to extract cholesterol from cells using fibroblasts¹⁹⁾, establishing HDL as a mediator of cholesterol handling in the peripheral tissues. In addition, low HDL-C levels were identified as an independent predictor of CVD in the Framingham study. These findings have led many researchers to explore the role of HDL and HDL-C in the development of CVD.

RCT plays a role in inhibiting the progression of atherosclerosis²⁰⁾. An animal model of RCT, commonly known as in vivo RCT, was established by Dr. Rader’s group at the University of Pennsylvania, demonstrating improved RCT in apolipoprotein A-I (apoA-I) transgenic mice²¹⁾. After its establishment, further research was conducted to identify the factors that regulate RCT. For example, liver X receptor (LXR) agonists were initially considered promising therapeutic targets for atherosclerosis because they promote in vivo RCT and suppress atherosclerosis²²⁾. However, concerns regarding the hepatosteatosis associated with these agonists have prevented their clinical application. Other studies have reported that miR-33 ²³⁾, Farnesoid X receptor (FXR)²⁴⁾, and low-density lipoprotein receptor-related protein 1 (LRP-1)²⁵⁾ are involved in modulating RCT activity. Our laboratory demonstrated that ezetimibe, an inhibitor of Niemann-Pick C1-Like1 ²⁶⁾, and probucol-oxidized products, spiroquinone and diphenoquinone, enhance RCT²⁷⁾. Another research group has developed a system for measuring macrophage-specific RCT in humans and attempted its clinical application²⁸⁾. However, such assays have not been widely adopted because of their complex protocols.

3.CEC and its Clinical Application for CVD

The process by which HDL removes cholesterol from peripheral tissues is necessary for transferring cholesterol from the extravascular compartment to the intravascular compartment. ATP-binding cassette subfamily A member 1 (ABCA1) transports peripheral cholesterol to lipid-poor apolipoproteins, such as apoA1 or apoE, while discoidal HDL (nascent HDL), ATP-binding cassette subfamily G member 1 (ABCG1) and scavenger receptor class B member 1 (SR-B1)²⁹⁾ transport it to cholesteryl ester-rich HDL (mature HDL).

Regarding the clinical application of CEC, Rader et al. established an assay using human serum for HDL CEC³⁰⁾. Subsequently, in the Dallas Heart Study, Khera et al. demonstrated that CEC, distinct from HDL-C, serves as an independent prognostic factor for CVD³¹⁾, indicating the importance of the role of HDL in the development of coronary artery disease (CAD). Following this, our laboratory validated the utility of CEC in Japanese patients and demonstrated a decrease in CEC among those with coronary artery disease³²⁾. Furthermore, Ogura et al. revealed that CEC is independently and inversely associated with the presence of CVD in patients with heterozygous familial hypercholesterolemia³³⁾. Thus, identifying the factors that promote RCT, including CEC, might be a novel therapeutic strategy for atherosclerosis.

However, while CEC is indeed a valuable assay target, standardizing its measurement poses challenges owing to the need for radioisotopes and cells, as well as facility constraints. Consequently, efforts are underway to enhance CEC standardization. Shimizu et al. established a new CEC measurement technique using stable isotope-labeled cholesterol instead of the conventional radioactive isotope-labeled cholesterol³⁴⁾. They incubated J774 cells labeled with [d7] cholesterol in apoB-depleted patient serum and quantified the extracted cholesterol by liquid chromatography/quadrupole time-of-flight mass spectrometry. This new method provides more accurate measurements of CEC levels than radioactive isotope or fluorescence methods and is recommended for use in future clinical studies.

Another barrier to standardization is the use of cells. Therefore, cell-free assays have been developed. In this regard, a research group from Kobe University developed a new cell-free assay for the cholesterol uptake capacity (CUC). Assaying CUC involves separating HDL from patient serum using anti-apoA-1 antibodies, adding fluorescent cholesterol, and evaluating the ability of HDL to capture cholesterol based on the resulting fluorescence intensity. This assay has been applied in clinical research using optical coherence tomography, finding a significant correlation between CUC measurements, the lipid index, and the macrophage score³⁵⁾. In addition, serum CUC levels were independently associated with subsequent revascularization after percutaneous coronary intervention³⁶⁾. However, while CUC seems relevant to clinical studies, caution should be exercised as to whether the “uptake” is identical or similar to “efflux.”

Another research group focused on phospholipid exchange in HDL using fluorescence-tagged phosphatidylethanolamine (PE) and developed a cell-free phospholipid efflux assay called the HDL-SPE assay. They validated the HDL-SPE assay in three clinical studies, including the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, and demonstrated that HDL-SPE was independently associated with CAD in Japanese patients³⁷⁾.

The use of cell-free assays makes measurements feasible for a large number of samples. However, as mentioned earlier, cholesterol efflux consists of three pathways (involving ABCA1, ABCG1, and SR-B1), making it challenging to evaluate efflux using these assays. By combining cell-based and cell-free assays, it is possible to identify the causes of disease-related HDL dysfunction and other contributing factors, thereby providing useful information for the development of therapeutic interventions.

4.Analyzing the Role of HDL and its Clinical Applications in other Diseases

Altered cholesterol homeostasis contributes to the progression of not only atherosclerosis but also several other diseases, including chronic kidney disease, Alzheimer’s disease, and diabetes mellitus (DM)³⁸⁾. Researchers have explored the role of HDL in lipotoxicity by assessing the CEC in patients with these diseases. DM is associated with low HDL-C dyslipidemia and an increased risk of CVD morbidity and mortality³⁹⁾. Substantial evidence indicates that DM significantly alters the HDL functionality. Cavallero et al. reported that DM affected the phospholipid composition of HDL and disrupted RCT⁴⁰⁾. Furthermore, ABCA1-mediated cholesterol efflux from small HDL is impaired in type 2 DM, and alterations in SERPINA1 levels in the HDL proteome are closely related to ABCA1-mediated cholesterol efflux⁴¹⁾.

Yamamoto et al. were the first to investigate HDL dysfunction in patients with end-stage renal disease (ESRD) undergoing dialysis⁴²⁾. Subsequently, Holzer et al. analyzed the HDL functionality and composition in patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) in comparison with a healthy control group. Their findings revealed that CEC was significantly lower in both HD and PD groups than in the control group. This suggests that HDL dysfunction may play a pivotal role in atherogenicity associated with ESRD⁴³⁾.

Another study investigated the HDL functionality in Alzheimer’s disease. They had been prompted by Previous studies have shown that apoA-1 deficiency contributes to the cerebral accumulation of amyloid and memory deficits, and that the overexpression of apoA-1 attenuates neuroinflammation in vivo^{44, 45)}, implicating the contribution of the role of HDL in Alzheimer’s pathogenesis. Their results indicated attenuated CEC in the cerebral fluid of individuals with Alzheimer’s disease, suggesting the potential involvement of altered cholesterol homeostasis in this disease⁴⁶⁾.

Recently, there have been significant advances in the research on HDL in the field of autoimmune diseases, specifically exploring its role in autoimmunity. HDL plays a crucial role in inhibiting inflammation, facilitating cholesterol metabolism, and maintaining a healthy immune response by interacting with immune cells^47-49). For example, Holzer et al. reported altered CEC in patients with psoriasis and found an inverse association between CEC and the Psoriasis Area and Severity Index (PASI) score. However, subsequent research on psoriasis has failed to confirm this finding. Nonetheless, an increase in oxidized HDL levels was observed, suggesting a potential role for HDL in the atherogenicity of psoriasis⁵⁰⁾.

Rheumatoid arthritis (RA) is an autoimmune disease that increases the risk of atherosclerosis. Karpouzas et al. revealed an inverse association between ABCG1-mediated cholesterol efflux and non-calcified plaques and excessive plaques in RA, which is known to be associated with CVD⁵¹⁾. Diseases that induce lipotoxicity may affect HDL functionality, and there is potential for its clinical application as a biomarker for stratifying risk and predicting the prognosis of diseases, such as RA.

5.Other Functions of HDL: Antioxidative, Vasodilatory, Anti-Thrombotic, and Anti-Infectious Effects

In addition to its RCT function, HDL exerts antioxidative, vasodilatory, anti-thrombotic, and anti-infectious effects as well as anti-inflammatory and anti-apoptotic effects. HDL functions as an antioxidant by clearing lipid hydroperoxide (LOOH) and oxidized phospholipids (oxPL) from atherogenic oxidized low-density lipoprotein (oxLDL). This mechanism involves HDL-associated hydrolases, such as paraoxonase (PON1), platelet-activating factor acetyl hydrolase (PAF-AH), and lecithin-cholesterol acyltransferase (LCAT)⁵²⁾. Several apolipoproteins within HDL, including apoA-I, apoA-II, apoD, apoF, apoJ, apoL1, and apoM, contribute to lipid peroxidation⁵³⁾.

HDL also plays a pivotal role in the regulation of the endothelial function and inhibition of thrombosis. It enhances endothelial nitric oxide synthase (eNOS) activity, promoting nitric oxide (NO) production and vasodilation⁵⁴⁾. Furthermore, HDL modulates platelet activity and coagulation cascades, affecting proteins such as Proteins C and S¹⁴⁾.

The anti-infectious effects of HDL are particularly evident in sepsis patients. It binds to lipopolysaccharide (LPS) to neutralize endotoxins produced by Gram-negative bacteria⁵⁵⁾. Studies have indicated that HDL-associated proteins such as apoA-I play a pivotal role in improving survival rates in sepsis models⁵⁶⁾. The anti-infectious effect of HDL is particularly useful when clinically applied for the treatment of sepsis. Guo et al. revealed that synthetic HDL inhibited the inflammatory pathways induced by LPS in sepsis mouse models, suggesting that HDL may have the potential to regulate cytokine storm in sepsis⁵⁷⁾.

6.Research Focusing on HDL Particles: Proteome, Lipidome, and MicroRNA

HDL comprises several apolipoproteins (A-I, A-II, and E) and lipid components, including cholesterol, phospholipids, and triglycerides (TG). Recent research utilizing lipidomics, proteomics, and transcriptomics has revealed disease-associated heterogeneity of HDL. Advances in proteomics analyses have shown that over 200 proteins are present in the HDL proteome, and they are summarized in the HDL Proteome Watch⁵⁸⁾. This has led to reports of disease-specific alterations in the HDL proteome associated with CAD^{59, 60)}, chronic heart failure⁶¹⁾, chronic kidney disease^{62, 63)}, and COVID-19 ⁶⁴⁾. In addition, inflammatory remodeling of the HDL proteome associated with increased serum amyloid A (SAA) levels directly impairs CEC⁶⁵⁾, suggesting that an altered HDL proteome may be directly linked to HDL dysfunction. Furthermore, in a study that focused on the HDL proteome in stroke, Puebell et al. revealed changes in the HDL proteome from the acute phase to the recovery state⁶⁶⁾. This suggests that the HDL proteome undergoes dynamic changes in composition owing to changes in disease conditions, and further elucidation of the respective mechanisms is expected in the future.

In addition to proteins, HDL contains a diverse array of phospholipids and sphingolipids, which are associated with its function⁶⁷⁾. For instance, lipid fluidity, caused by changes in phospholipid composition, has been found to be a determinant of cholesterol efflux. In this regard, Rothblat et al. established that HDL phosphatidylcholine content is correlated with SR-B1-mediated cholesterol efflux in vitro⁶⁸⁾. The phospholipid components of HDL also influence its anti-inflammatory activity. Among them, 1-palmitoyl-2-linoleyl PC deactivates T cells via dendritic cells⁶⁹⁾. In addition, HDL-associated sphingolipids and sphingosine-1-phosphate (S1P) play pivotal roles in the anti-apoptotic effect on endothelial cells as well as in their vasodilatory activity⁷⁰⁾. Further investigation confirmed that S1P binds to HDL rather than albumin, allowing it to reduce TNFα-induced NF-κB activation and increase the expression of intercellular adhesion molecule 1 (ICAM1)⁷¹⁾.

HDL lipidomic analyses have seen notable advances, particularly with the integration of the HDL lipidome, nuclear magnetic resonance (NMR) features, HDL proteome, and CEC analyses by Arnold von Eckardstein’s group in patients with diabetes. Their findings revealed sphingomyelin SM 42:3 (SM42:3) to be a novel determinant of the HDL functionality. This phospholipid inhibits starvation-induced apoptosis in human aortic endothelial cells (HAECs)⁷²⁾. Integrated analyses of other diseases are expected to lead to the discovery of new determinants of the HDL functionality. Interestingly, in contrast to the findings of such omics analyses, Vickers et al. revealed for the first time the ability of HDL to transport microRNA⁷³⁾. They also found that HDL-transferred microRNA-223 regulated ICAM-1 expression in endothelial cells⁷⁴⁾, suggesting that HDL-transferred miRNA contributes to the anti-inflammatory function of HDL.

7.Research on Inflammation and HDL

High-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, has been recognized as a predictor of CVD in numerous clinical studies, suggesting that inflammation contributes to atherosclerosis progression⁷⁵⁾. In addition, treatments targeting inflammation, such as those in the CANTOS trial¹⁶⁾, have reduced the risk of CVD in secondary prevention. This indicates that inflammation is not merely a marker but also holds promise as a target for therapeutic strategies. Considering this trend in HDL research, Tietge devised an anti-inflammatory assay for HDL to evaluate VCAM-1 mRNA expression. This assay was validated by its correlation with incident CVDs in the PREVEND study¹⁷⁾. The findings of this research suggest that the anti-inflammatory capacity of HDL shows promise in providing pertinent information for CVD risk assessments.

Previous in vivo and in vitro studies have revealed that HDL exhibits cholesterol-efflux-dependent and cholesterol-efflux-independent anti-inflammatory effects by inhibiting TLR4 signaling and TRIF-related pathways⁷⁶⁾. For instance, Yvan-Charvet et al. initially reported that macrophages lacking ABCA1 and ABCG1 exhibited notably heightened inflammatory responses, particularly to LPS, which is a ligand for TLR4 ⁷⁷⁾. This highlights the potential of apoA-1 to mitigate inflammation in macrophages. Smoak et al. demonstrated that myeloid differentiation primary response protein 88 (MyD88), an adaptor protein of TLR4, is involved in apoA-1-mediated cholesterol efflux from macrophages and in vivo RCT⁷⁸⁾. Further adding to their findings, Suzuki et al. revealed that HDL inhibits the type I response in LPS-treated macrophages⁷⁹⁾.

Focusing on the mechanism underlying these anti-inflammatory effects, another research group found that HDL suppressed the expression of TLR-induced cytokines in macrophages by regulating the transcription factor ATF3 ⁸⁰⁾. Regarding cells other than macrophages, Murphy et al. found that HDL and ApoA-1 mitigated neutrophil activation both in vitro and in vivo⁸¹⁾. In addition, Wang et al. observed that HDL and apoA-1 suppressed T cell activation by disrupting lipid rafts⁸²⁾. Furthermore, Thacker observed that HDL was able to inhibit inflammasome activation triggered by cholesterol crystals⁸³⁾.

From a different perspective, modulation of ABCA1- and ABCG1-mediated cholesterol efflux by HDL is influenced by immune cell responses. Previous studies have indicated that myeloid ABCA1/ABCG1 deficiency stimulates myeloid cell proliferation⁸⁴⁾ and Nrp3 inflammasomes⁴⁷⁾, and T-cell ABCA1/ABCG1 deficiency induces T-cell activation and senescence⁸⁵⁾. HDL exerts anti-inflammatory effects by affecting various factors involved in inflammation, both in vitro and in vivo.

Although much attention has been paid to the anti-inflammatory effects of HDL, some groups have also reported the pro-inflammatory effects of HDL. For example, in murine and human macrophages, HDL enhances TLR-induced proinflammatory responses, thereby increasing the ability of mice to eliminate P. aeruginosa bacterial infection⁸⁶⁾. In contrast, within atherosclerotic plaques, the anti-inflammatory effects of HDL seem to surpass its pro-inflammatory effects, indicating that HDL functions synergistically to exert protective effects in the body¹¹⁾. Single-cell analyses revealed the presence of various immune cells in atherosclerotic plaque lesions, each of which plays a role in the inflammation and progression of atherosclerosis⁸⁷⁾.

Future research is needed to evaluate how HDL interacts with various immune cell populations within plaques and elucidate the underlying mechanisms. Investigating this is crucial for understanding how HDL suppresses or augments inflammatory responses and atherosclerosis progression, which may lead to the development of new approaches and treatments for the management and prevention of atherosclerotic lesions.

8.Clinical Applications using ApoA-1 Mimetics

Previous studies have shown that apoA-1 and apoA-1 mimetics promote RCT and inhibit atherosclerosis progression in vivo^{21, 88, 89)}. Therefore, apoA-1 mimetics are a potential therapeutic option for the treatment of atherosclerosis. Nissen et al. previously demonstrated a preventive effect of the recombinant apoA-I milano/phospholipid complex (ETC-216) on coronary atheroma burden, as measured by intravascular ultrasound (IVUS)⁹⁰⁾. However, another apoA-1 mimetic (CER-001) failed to reduce coronary atherosclerosis, possibly because of the small sample size⁹¹⁾. As the two trials were small in scale, high expectations were placed on large-scale apoA-1 mimetic trials on CSL112 and apoA-I Event Reducing in Ischemic Syndromes II (AEGIS-II)⁹²⁾.

Although CSL112 failed to reduce the risk of a composite of myocardial infarction, stroke, and death from CVD in high-risk acute myocardial infarction participants, it did reduce the risk of myocardial infarction at the secondary endpoint of 180 days. These results suggest a potential reduction in the risk of CVD with long-term administration⁹³⁾.

Furthermore, there has been growing hope in recent years regarding the potential therapeutic application of synthetic HDL in sepsis, cancer, and other diseases^94-96).

9.Conclusion

Decades of research have reshaped our understanding of HDL, and attention has shifted to HDL functionality, particularly its role in RCT and anti-inflammatory and antioxidative pathways. HDL involvement extends beyond CVD to other conditions, such as kidney disease, Alzheimer’s disease, and autoimmune diseases. Furthermore, advances in omics technologies have revealed the diverse composition of HDL and its potential utility as a biomarker. Overall, the multifaceted functions of HDL may offer promising avenues for future clinical applications and therapeutic developments.

Statement of Conflict of Interest

The authors confirm that no known conflicts of financial interest or personal relationships could have influenced the work presented in this manuscript.

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