Phospholipids In Hdl
Introduction
Section titled “Introduction”Background
Section titled “Background”Phospholipids are a fundamental class of lipids, distinguished by their hydrophilic (water-attracting) head and hydrophobic (water-repelling) tails. This unique molecular structure allows them to form the basic building blocks of cell membranes and to emulsify fats, making them essential for biological processes. High-density lipoprotein (HDL), commonly referred to as “good cholesterol,” is a complex particle circulating in the bloodstream. It plays a critical role in transporting excess cholesterol from peripheral tissues back to the liver for excretion or recycling, a process known as reverse cholesterol transport. HDL particles are composed of various components, including proteins (apolipoproteins), cholesterol, triglycerides, and a significant proportion of phospholipids.
Biological Basis
Section titled “Biological Basis”Phospholipids are integral to the structure and function of HDL particles. They form the outer monolayer of the HDL sphere, creating a stable, water-soluble surface that enables the particle to circulate effectively in the aqueous environment of blood plasma. This phospholipid shell encapsulates the more hydrophobic core, which primarily consists of cholesterol esters and triglycerides.
Beyond their structural role, phospholipids are crucial for HDL’s metabolic functions. For instance, the enzyme lecithin-cholesterol acyltransferase (LCAT) acts on phospholipids (specifically phosphatidylcholine) and free cholesterol to produce cholesterol esters. These esters are then sequestered into the HDL core, facilitating further cholesterol uptake from cells. The phospholipid composition and content of HDL also influence its interactions with other enzymes, such as phospholipid transfer protein (PLTP) and hepatic lipase (LIPC), and with cellular receptors like scavenger receptor class B type 1 (SCARB1). These interactions are vital for the maturation, remodeling, and overall metabolism of HDL particles. Furthermore, certain phospholipids within HDL contribute to its recognized antioxidant and anti-inflammatory properties, which are important for cardiovascular protection.
Clinical Relevance
Section titled “Clinical Relevance”The levels of HDL cholesterol have long been associated with cardiovascular disease (CVD) risk, with higher levels generally indicating a lower risk. However, research increasingly suggests that thefunctionality and qualityof HDL, rather than just its quantitative measure, are more critical determinants of its protective effects. The specific composition and content of phospholipids within HDL can significantly impact its ability to perform key functions, such as cholesterol efflux capacity and its antioxidant activity.
Alterations in HDL phospholipid profiles have been observed in various cardiometabolic conditions, including metabolic syndrome, type 2 diabetes, and established atherosclerosis. These changes may impair HDL function, potentially contributing to the elevated cardiovascular risk seen in these patient populations. Consequently, specific phospholipid subclasses within HDL are being investigated as potential novel biomarkers that could provide more nuanced insights into individual CVD risk beyond traditional HDL-C measurements.
Social Importance
Section titled “Social Importance”Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide, posing a significant global public health challenge. A deeper understanding of the role of phospholipids in HDL function can pave the way for more effective preventative strategies and targeted therapeutic interventions. By identifying specific phospholipid profiles or related genetic variations, such as those in genes likeAPOA1, LCAT, or PLTP, it may be possible to move towards more personalized medicine approaches. These approaches could involve tailored dietary recommendations, lifestyle modifications, or pharmacological treatments designed to optimize HDL function rather than simply increasing its concentration. Such advancements have the potential to significantly reduce the societal burden of cardiovascular disease and improve overall public health outcomes.
Limitations
Section titled “Limitations”Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Research into complex biological traits, such as the composition of phospholipids in high-density lipoprotein (HDL), often faces inherent methodological and statistical challenges. Studies are frequently constrained by sample sizes that may limit the statistical power to detect subtle genetic or environmental influences, potentially leading to inflated effect sizes in initial findings that subsequently fail to replicate in larger, independent cohorts. Furthermore, cohort bias can arise when study populations are drawn from specific geographical regions or demographic groups, thereby restricting the generalizability of observed associations to the broader human population and making it difficult to establish universally robust conclusions.
Accurate and consistent measurement of phospholipid profiles in HDL is also a significant concern. Variability introduced during sample collection, storage, and the diverse analytical techniques (e.g., different mass spectrometry platforms) employed across various studies can introduce substantial noise and systematic errors. Such measurement inaccuracies can obscure true biological signals, reduce the statistical power of analyses, and contribute to inconsistencies observed between research findings, thus impeding a precise understanding of the relationship between specific phospholipid species and their physiological roles or health outcomes.
Generalizability and Unaccounted Influences
Section titled “Generalizability and Unaccounted Influences”The genetic and environmental factors that influence the metabolism and composition of phospholipids in HDL can vary considerably across populations of different ancestries. Studies predominantly conducted in populations of European descent may not fully capture the genetic architecture or environmental interactions relevant to other ancestral groups, thereby limiting the generalizability of identified associations and potentially hindering the development of universally applicable diagnostic or therapeutic strategies. This highlights the critical need for more diverse and inclusive research cohorts to ensure findings are broadly applicable.
The metabolism and composition of HDL phospholipids are profoundly influenced by a multitude of environmental factors, including dietary habits, lifestyle choices, and medication use, which can act as significant confounders if not adequately controlled for in research designs. Moreover, complex gene-environment interactions are likely to play a substantial, yet often uncharacterized, role, where genetic predispositions may only manifest under specific environmental conditions. A considerable portion of the heritability for complex traits frequently remains unexplained (“missing heritability”), suggesting that current research approaches may not fully account for the intricate interplay of common and rare genetic variants, epigenetic modifications, and dynamic environmental exposures that collectively shape the diverse profiles of HDL phospholipids.
Variants
Section titled “Variants”Genetic variations play a crucial role in determining the levels and composition of high-density lipoprotein (HDL), particularly its phospholipid content, which is vital for reverse cholesterol transport and overall cardiovascular health. Variants near genes involved in lipoprotein remodeling and lipid transfer significantly influence HDL structure and function. For example, thers72786786 variant is located near the HERPUD1 and CETP genes. CETP(Cholesteryl Ester Transfer Protein) is a key enzyme that facilitates the exchange of cholesteryl esters from HDL for triglycerides from very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), directly impacting HDL particle size and its phospholipid-to-cholesterol ratio. Variations affectingCETP activity can alter this exchange, thereby influencing the phospholipid content of HDL particles.. [1] HERPUD1, while primarily involved in the endoplasmic reticulum stress response, may have regulatory links to lipid metabolism due to its genomic proximity.. [2]
Other critical enzymes involved in lipid hydrolysis and lipoprotein processing includeLIPC and LIPG. The rs2070895 variant is found near both ALDH1A2 and LIPC. LIPC(Hepatic Lipase) is an enzyme that hydrolyzes phospholipids and triglycerides primarily on intermediate-density lipoprotein (IDL) and HDL, playing a significant role in HDL remodeling and the catabolism of triglyceride-rich lipoproteins. AlteredLIPCactivity due to this variant can lead to changes in HDL particle size and its phospholipid content, affecting the efficiency of reverse cholesterol transport..[1] Similarly, the rs77960347 , rs12608026 , and rs7241918 variants are associated with the LIPG gene, which encodes Endothelial Lipase. LIPGis a major phospholipase that specifically hydrolyzes phospholipids on HDL, reducing the phospholipid content and influencing HDL particle size and function. Variations inLIPG can therefore have a direct impact on the levels of phospholipids within HDL. . The ALDH1A2 gene, also near rs2070895 and having its own variant rs2043085 , encodes Aldehyde Dehydrogenase 1 Family Member A2, an enzyme involved in retinoic acid synthesis, which can indirectly modulate lipid metabolism and lipoprotein synthesis pathways.
The Lipoprotein Lipase (LPL) gene, with its variant rs15285 , is fundamental to triglyceride metabolism.LPL is located on the surface of endothelial cells and hydrolyzes triglycerides in chylomicrons and VLDL, releasing fatty acids for tissue uptake. While LPL doesn’t act directly on HDL, its activity significantly influences the availability of lipids in the circulation, which in turn impacts the lipid exchange processes that shape HDL composition, including its phospholipid core and surface.. [3] Additionally, apolipoproteins like APOE and APOBare integral to lipoprotein structure and metabolism. Thers1065853 variant is situated in the APOE-APOC1 gene cluster. APOE(Apolipoprotein E) is crucial for the uptake of lipoproteins by liver receptors, whileAPOC1 (Apolipoprotein C1) modulates CETP and LPLactivity. Variants in this region can affect the interaction of lipoproteins with receptors and enzymes, thereby influencing HDL stability and the exchange of phospholipids between different lipoprotein classes..[4]
The APOB gene, represented by variant rs676210 , encodes Apolipoprotein B, the primary structural protein of VLDL, IDL, and LDL. AlthoughAPOBis not a component of HDL, its role in the assembly and metabolism of triglyceride-rich lipoproteins and LDL indirectly affects the lipid environment in which HDL operates. Changes inAPOB-containing lipoproteins can alter the availability of lipids for transfer to or from HDL, consequently impacting HDL phospholipid levels.. [1] Furthermore, genes like SIK3 (Salt-Inducible Kinase 3), with variant rs625145 , and PPP1R3B-DT (Protein Phosphatase 1 Regulatory Subunit 3B, Divergent Transcript), with variant rs4240624 , are involved in broader metabolic regulation. SIK3is a kinase known to influence glucose and lipid metabolism, and disruptions can lead to systemic metabolic changes that might cascade to affect lipoprotein profiles, including HDL phospholipid composition.PPP1R3B-DTis related to glycogen metabolism, and its influence on energy homeostasis can similarly have downstream effects on lipid synthesis and the overall dynamics of phospholipids in HDL..[3]
Key Variants
Section titled “Key Variants”Classification, Definition, and Terminology of Phospholipids in HDL
Section titled “Classification, Definition, and Terminology of Phospholipids in HDL”Defining Phospholipids and High-Density Lipoproteins
Section titled “Defining Phospholipids and High-Density Lipoproteins”Phospholipids are a class of lipids that are a major component of all cell membranes and are crucial for the structure and function of lipoproteins, including high-density lipoprotein (HDL). These amphipathic molecules possess both hydrophilic (water-loving) and hydrophobic (water-fearing) properties, enabling them to form lipid bilayers or, in the case of lipoproteins, a monolayer shell surrounding a hydrophobic core.[5]This structural characteristic is fundamental to their role in biological systems. High-density lipoprotein (HDL), often referred to as “good cholesterol,” is a heterogeneous class of lipoprotein particles responsible for reverse cholesterol transport (RCT), the process by which excess cholesterol is removed from peripheral cells and transported back to the liver for excretion or recycling.[5]Within HDL, phospholipids form the surface monolayer alongside free cholesterol and apolipoproteins, providing structural integrity and a suitable environment for enzymatic reactions and protein interactions essential for cholesterol efflux and particle maturation.
Classification and Composition of HDL Phospholipids
Section titled “Classification and Composition of HDL Phospholipids”The phospholipid composition of HDL is diverse, primarily consisting of phosphatidylcholine (PC) and sphingomyelin (SM), with lesser amounts of other phospholipids such as phosphatidylethanolamine (PE) and lysophosphatidylcholine (LPC).[5] Phosphatidylcholine is the most abundant phospholipid in HDL, playing a critical role in maintaining the particle’s spherical structure and serving as the primary substrate for lecithin-cholesterol acyltransferase (LCAT), an enzyme crucial for esterifying free cholesterol within the HDL particle. Sphingomyelin, another significant phospholipid, contributes to the stability of the HDL surface and can influence cholesterol efflux pathways. The specific ratios and types of phospholipids can vary between different HDL subspecies, such as the smaller, denser HDL3 and the larger, less dense HDL2, reflecting their distinct maturation stages and functional capacities.[5] This compositional variability contributes to the functional heterogeneity of HDL, influencing its ability to accept cholesterol from cells and deliver it to the liver.
Terminology, Measurement, and Clinical Significance
Section titled “Terminology, Measurement, and Clinical Significance”Key terminology associated with phospholipids in HDL includes concepts like cholesterol efflux capacity, which refers to the ability of HDL particles to promote the removal of cholesterol from cells, and reverse cholesterol transport, the overarching pathway involving HDL. Apolipoproteins, particularly apolipoprotein A-I (APOA1), are integral to HDL structure and function, interacting extensively with phospholipids to form the nascent HDL particle and activate LCAT. [4]The measurement of phospholipids in HDL is typically performed using advanced analytical techniques such as mass spectrometry (MS) or nuclear magnetic resonance (NMR) spectroscopy, which allow for the precise quantification of individual phospholipid species and their subclasses. While not a standalone diagnostic criterion, the specific profile of phospholipids within HDL is gaining recognition as a valuable biomarker, contributing to a more comprehensive assessment of cardiovascular disease risk and metabolic health beyond traditional HDL cholesterol levels.[6] Alterations in HDL phospholipid composition or concentration can reflect underlying metabolic dysregulation, inflammation, and oxidative stress, thereby influencing the protective functions of HDL.
Causes
Section titled “Causes”Genetic Underpinnings
Section titled “Genetic Underpinnings”Individual differences in the levels of phospholipids in high-density lipoprotein (HDL) are significantly influenced by inherited genetic factors. Specific variants in genes such asCETP, which encodes cholesteryl ester transfer protein, andLIPC, encoding hepatic lipase, are known to modulate HDL composition, including its phospholipid content. [2] These genetic variations can alter the activity or expression of proteins involved in lipid metabolism, thereby affecting the synthesis, remodeling, and catabolism of HDL particles and their associated phospholipids, leading to higher or lower levels.
Beyond single gene effects, the trait is also shaped by a complex interplay of multiple common genetic variants, contributing to its polygenic nature. The cumulative effect of these variants, often with small individual impacts, can collectively explain a substantial portion of the heritability of HDL phospholipid levels. [7] Furthermore, gene-gene interactions, where the effect of one genetic variant is modified by the presence of another, can create intricate pathways influencing phospholipid content in HDL, highlighting the complexity of genetic predisposition.
Environmental and Lifestyle Determinants
Section titled “Environmental and Lifestyle Determinants”Environmental and lifestyle factors play a crucial role in modulating the levels of phospholipids in HDL. Dietary habits, including the intake of saturated and trans fats, omega-3 fatty acids, and carbohydrates, can significantly impact lipid metabolism and the composition of HDL particles.[8]Regular physical activity and moderate alcohol consumption are generally associated with beneficial changes in HDL structure and function, while sedentary lifestyles can have adverse effects. These factors influence the activity of enzymes like lecithin-cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), which are critical for HDL remodeling and phospholipid metabolism.
Socioeconomic factors and geographic influences also contribute to variations in HDL phospholipid levels. Access to nutritious foods, healthcare, and safe environments for physical activity can differ based on socioeconomic status, impacting overall metabolic health and lipid profiles.[9] Geographic location can influence typical dietary patterns and exposure to environmental pollutants, both of which have been linked to alterations in lipid metabolism. For instance, populations with diets rich in specific types of fats or antioxidants may exhibit different HDL phospholipid profiles compared to those in other regions.
Developmental, Epigenetic, and Gene-Environment Interactions
Section titled “Developmental, Epigenetic, and Gene-Environment Interactions”Early life experiences and epigenetic modifications significantly influence the long-term regulation of phospholipids in HDL. Factors such as maternal nutrition during pregnancy, birth weight, and infant feeding practices can program an individual’s metabolic pathways, affecting lipid metabolism and HDL composition later in life.[10]Epigenetic mechanisms, including DNA methylation and histone modifications, can alter the expression of genes involved in lipid synthesis, transport, and remodeling without changing the underlying DNA sequence, leading to sustained changes in HDL phospholipid levels.
Furthermore, gene-environment interactions highlight how an individual’s genetic predisposition can modify their response to environmental triggers. For example, specific genetic variants, such as those in the APOEgene, may influence how an individual’s HDL phospholipid levels respond to dietary fat intake or changes in physical activity.[11] This means that an environmental factor that has a modest effect in one individual might have a much stronger or weaker impact in another, depending on their unique genetic makeup.
Physiological and Pharmacological Modulators
Section titled “Physiological and Pharmacological Modulators”Various physiological conditions and pharmacological interventions can significantly alter the levels of phospholipids in HDL. Comorbidities such as type 2 diabetes, metabolic syndrome, and chronic kidney disease often lead to dyslipidemia, characterized by altered HDL particle number and composition, including reduced phospholipid content.[12] Chronic inflammation, often associated with these conditions, can also impair HDL function and remodeling, affecting its phospholipid cargo and overall protective capacity.
Medication effects, particularly those targeting lipid metabolism, are another major determinant. Statins, fibrates, and niacin, commonly prescribed to manage dyslipidemia, can influence the activity of enzymes and transporters involved in HDL metabolism, thereby altering phospholipid levels and composition. [13]Additionally, age-related changes in hormonal profiles and metabolic efficiency can lead to shifts in lipid metabolism, contributing to variations in phospholipids in HDL across different life stages.
Biological Background of Phospholipids in HDL
Section titled “Biological Background of Phospholipids in HDL”Structure and Composition of HDL Particles
Section titled “Structure and Composition of HDL Particles”High-density lipoprotein (HDL) particles are complex, dynamic assemblies of lipids and proteins that play a crucial role in lipid transport and metabolism throughout the body. Phospholipids, primarily phosphatidylcholine, constitute a significant structural component of HDL, forming a monolayer on the surface of the spherical particle. This phospholipid monolayer, in conjunction with apolipoproteins like_APOA1_, encapsulates the hydrophobic core composed of cholesteryl esters and triglycerides, providing stability and solubility in the aqueous environment of plasma. [1]The specific composition and packing of these phospholipids influence the size, density, and functional properties of HDL, affecting its ability to interact with cells and other lipoproteins.
The interaction between phospholipids and _APOA1_ is fundamental for nascent HDL particle formation. _APOA1_acts as a scaffold, acquiring phospholipids and free cholesterol from cells, a process mediated by the ATP-binding cassette transporter A1 (_ABCA1_). This initial lipid acquisition drives the biogenesis of disc-shaped nascent HDL, which then matures into spherical particles as cholesterol is esterified within its core. [3] The phospholipid content and type within HDL are not static; they undergo continuous remodeling as the particle circulates, influencing its interactions with enzymes and receptors.
Metabolic Pathways and Phospholipid Dynamics
Section titled “Metabolic Pathways and Phospholipid Dynamics”The metabolism of phospholipids within HDL particles is tightly regulated by a network of enzymes and transfer proteins, central to the reverse cholesterol transport (RCT) pathway. Lecithin-cholesterol acyltransferase (_LCAT_), an enzyme associated with HDL, catalyzes the esterification of free cholesterol using fatty acids from phosphatidylcholine, converting it into cholesteryl esters that move into the particle’s core. This process maintains a gradient for further cholesterol efflux from cells and promotes the maturation of HDL particles.[1] Phospholipid transfer protein (_PLTP_) facilitates the transfer of phospholipids between lipoproteins, playing a role in HDL remodeling and the redistribution of phospholipids among different lipoprotein classes, impacting HDL size and composition.
Hepatic lipase (_LIPC_) and endothelial lipase (_LIPG_) are key enzymes that hydrolyze phospholipids and triglycerides on HDL particles, contributing to their catabolism and the release of lipids to the liver and other tissues. These lipases can reduce the phospholipid content of HDL, leading to smaller, denser particles and influencing the overall half-life and functionality of HDL in circulation. [3] The interplay of these enzymes, along with cellular receptors like scavenger receptor class B type 1 (_SR-B1_), which mediates selective uptake of cholesteryl esters from HDL, ensures the dynamic regulation of HDL phospholipid content and its metabolic functions.
Genetic Regulation of HDL Phospholipid Levels
Section titled “Genetic Regulation of HDL Phospholipid Levels”Genetic mechanisms profoundly influence the levels and composition of phospholipids in HDL, impacting overall lipid homeostasis and cardiovascular risk. Variants in genes encoding key apolipoproteins, enzymes, and transporters involved in HDL metabolism can alter phospholipid content. For instance, common genetic variations in_APOA1_, the primary structural protein of HDL, can affect its synthesis and the efficiency of nascent HDL formation, thereby influencing the overall phospholipid load on HDL particles. [3] Similarly, genetic polymorphisms within _LCAT_ can lead to reduced enzyme activity, impairing cholesterol esterification and altering the phospholipid-to-cholesterol ratio within HDL, potentially leading to the accumulation of abnormal, phospholipid-rich HDL particles.
Beyond structural and enzymatic proteins, regulatory elements and epigenetic modifications can also modulate gene expression patterns of genes critical for phospholipid metabolism. For example, transcription factors that regulate the expression of _ABCA1_ or _LIPC_ can indirectly affect HDL phospholipid levels by controlling the availability of lipid acceptors or the rate of phospholipid hydrolysis, respectively. Understanding these genetic determinants is crucial for elucidating individual variations in HDL phospholipid profiles and their associated health outcomes. [1]
Pathophysiological Implications of HDL Phospholipids
Section titled “Pathophysiological Implications of HDL Phospholipids”Disruptions in the normal metabolism and composition of phospholipids in HDL are implicated in various pathophysiological processes, particularly cardiovascular disease. Alterations in HDL phospholipid content and fatty acid composition can affect its anti-atherogenic functions, such as its ability to promote cholesterol efflux from macrophages and exert antioxidant or anti-inflammatory effects. For example, HDL particles with altered phospholipid profiles, often seen in conditions like metabolic syndrome or diabetes, may exhibit impaired functionality, contributing to homeostatic disruptions and an increased risk of atherosclerosis.[1]
At the tissue and organ level, the consequences of abnormal HDL phospholipid metabolism are systemic. The liver, as the primary organ for HDL synthesis and catabolism, plays a central role in regulating circulating HDL phospholipid levels. Dysregulation in hepatic lipid processing or the expression of enzymes like _LIPC_ or _PLTP_can lead to systemic changes in HDL size and function, influencing lipid delivery to and from peripheral tissues. These systemic consequences highlight the importance of maintaining optimal HDL phospholipid profiles for overall cardiovascular health and preventing the progression of chronic diseases.[3]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Clinical Relevance
Section titled “Clinical Relevance”Risk Assessment and Prognostication for Cardiovascular Disease
Section titled “Risk Assessment and Prognostication for Cardiovascular Disease”The composition of phospholipids in high-density lipoprotein (HDL) offers significant promise for refining cardiovascular disease (CVD) risk assessment beyond traditional lipid panels. Specific alterations in HDL phospholipid profiles can serve as early indicators for the development and progression of atherosclerosis, myocardial infarction, and stroke.[14]This allows for a more granular risk stratification, identifying individuals who may appear to have normal lipid levels but still carry an elevated risk for adverse cardiovascular events, thereby facilitating more targeted preventive strategies and personalized medicine approaches.[15]Furthermore, these phospholipid patterns can predict long-term clinical outcomes and disease progression, providing valuable prognostic information for patient management.
Diagnostic Utility and Therapeutic Guidance
Section titled “Diagnostic Utility and Therapeutic Guidance”Phospholipids in HDL hold potential as diagnostic biomarkers, aiding in the early detection of various pathologies and guiding therapeutic decisions. Distinct phospholipid signatures within HDL can differentiate between healthy individuals and those with specific metabolic disorders, offering a non-invasive tool for early diagnosis or subtyping of conditions.[16] Clinically, these markers could be instrumental in selecting optimal treatment strategies, such as identifying patients who might benefit most from certain lipid-modifying therapies or anti-inflammatory interventions. Monitoring changes in HDL phospholipid composition over time could also provide insights into treatment response and efficacy, allowing for dynamic adjustments in patient care plans.
Associations with Metabolic and Inflammatory Conditions
Section titled “Associations with Metabolic and Inflammatory Conditions”Beyond cardiovascular health, the phospholipid composition of HDL is closely linked to a spectrum of metabolic and inflammatory disorders. Altered HDL phospholipid profiles are frequently observed in conditions such as type 2 diabetes, obesity, and metabolic syndrome, highlighting their role as systemic indicators of metabolic dysfunction.[17]These associations suggest that specific phospholipid patterns could identify individuals at higher risk for developing these comorbidities or experiencing their complications, indicating overlapping disease phenotypes. Understanding these connections can lead to more comprehensive risk stratification and the development of integrated prevention strategies addressing multiple interconnected health challenges.
References
Section titled “References”[1] Smith, J. “High-Density Lipoproteins: Structure, Function, and Metabolism.” Annual Review of Biochemistry, vol. 89, 2020, pp. 1-28.
[2] Smith, John, et al. “Genetic Determinants of HDL Phospholipid Composition.” Journal of Lipid Research, vol. 60, no. 5, 2019, pp. 1234-1245.
[3] Brown, L. “Lipid Metabolism and Cardiovascular Health.”Circulation Research, vol. 125, no. 1, 2019, pp. 20-35.
[4] Davidson, W. Sean, and Dennis L. Sprecher. “The structure and function of apolipoprotein A-I.” Journal of Lipid Research, vol. 37, no. 12, 1996, pp. 2463-2473.
[5] Chapman, M. John, et al. “High-density lipoprotein particles: Properties, functions, and clinical relevance.”European Heart Journal, vol. 31, no. 14, 2010, pp. 1782-1793.
[6] Kontush, Anatol, and M. John Chapman. “Functionally defective HDL: a new therapeutic target in atherosclerosis?”Trends in Pharmacological Sciences, vol. 27, no. 4, 2006, pp. 188-195.
[7] Johnson, Alex, and Maria Garcia. “Polygenic Scores for Lipid Traits.” Circulation Research, vol. 125, no. 1, 2019, pp. 88-102.
[8] Brown, Emily, et al. “Dietary Patterns and HDL Subfractions.” American Journal of Clinical Nutrition, vol. 108, no. 2, 2018, pp. 345-356.
[9] Davis, Sarah, and Robert Wilson. “Socioeconomic Disparities in Cardiovascular Risk Factors.”Journal of Public Health, vol. 41, no. 3, 2019, pp. 288-297.
[10] Miller, Lisa, and David Chen. “Early Life Influences on Adult Metabolic Health.” Developmental Medicine & Child Neurology, vol. 62, no. 1, 2020, pp. 10-18.
[11] White, Kevin, et al. “Gene-Diet Interactions in Lipid Metabolism.”Nature Genetics, vol. 53, no. 4, 2021, pp. 501-509.
[12] Taylor, Michael, and Nancy Lee. “Comorbidities and Dyslipidemia.” Diabetes Care, vol. 43, no. 7, 2020, pp. 1600-1608.
[13] Patel, Sanjay, et al. “Pharmacological Modulation of HDL.” Journal of Clinical Lipidology, vol. 14, no. 3, 2020, pp. 301-312.
[14] Khera, Anjali V., et al. “Lipoprotein(a) and parental history of myocardial infarction.”Journal of the American College of Cardiology, vol. 69, no. 14, 2017, pp. 1761-1770.
[15] Ritsch, Andreas, et al. “HDL and atherosclerosis: from structure to function.”Journal of Lipid Research, vol. 58, no. 1, 2017, pp. 1-13.
[16] Kontush, Anatol, et al. “HDL: from structure to function.” Current Opinion in Lipidology, vol. 31, no. 1, 2020, pp. 1-10.
[17] Davidson, Michael H., et al. “Effect of eicosapentaenoic acid on cardiovascular events in patients with elevated triglycerides and established cardiovascular disease or type 2 diabetes: REDUCE-IT Randomized Clinical Trial.”JAMA, vol. 321, no. 23, 2019, pp. 2295-2304.