Free Cholesterol In Medium Vldl
Introduction
Section titled “Introduction”Free cholesterol in very low-density lipoprotein (VLDL) refers to the unesterified cholesterol molecules transported within VLDL particles, which are a class of lipoproteins synthesized in the liver. These particles are crucial for distributing triglycerides and cholesterol from the liver to various tissues throughout the body. Understanding the dynamics of free cholesterol within specific VLDL subfractions, such as medium VLDL, offers a more nuanced view of lipid metabolism than broader cholesterol measures.
Biological Basis
Section titled “Biological Basis”VLDL particles are assembled in the liver and secreted into the bloodstream. Their primary role is to transport triglycerides, but they also contain cholesterol, phospholipids, and apolipoproteins. As VLDL circulates, enzymes like lipoprotein lipase remove triglycerides, causing the VLDL particles to shrink and become denser, eventually transforming into intermediate-density lipoproteins (IDL) and then low-density lipoproteins (LDL). Free cholesterol, unlike esterified cholesterol, can readily exchange between lipoproteins and cell membranes. The proportion and behavior of free cholesterol in different VLDL subfractions, including medium VLDL, reflect the metabolic state and the efficiency of lipid processing pathways. Variations in genes involved in lipid synthesis, transport, and catabolism can influence the composition and metabolism of these lipoproteins. For instance, studies have identified numerous genetic loci that contribute to variations in overall lipid concentrations, including LDL cholesterol and triglycerides, which are closely related to VLDL metabolism.[1]
Clinical Relevance
Section titled “Clinical Relevance”Elevated levels of VLDL and its components, including cholesterol, are associated with an increased risk of cardiovascular diseases (CVD). Dyslipidemia, characterized by abnormal levels of circulating lipids like high LDL cholesterol and triglycerides, is a major risk factor for atherosclerosis and coronary artery disease.[2]While traditional lipid panels often focus on total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, the specific measurement of free cholesterol within medium VLDL could provide finer insights into an individual’s atherogenic risk. Alterations in VLDL metabolism, which would impact free cholesterol content, are implicated in conditions such as metabolic syndrome, insulin resistance, and type 2 diabetes. Genetic variations influencing lipid levels, such as those found inHMGCR, APOB, PCSK9, and the CELSR2/PSRC1/SORT1 region, underscore the complex genetic architecture underlying dyslipidemia and its clinical consequences. [3]
Social Importance
Section titled “Social Importance”Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide, posing a significant public health burden. Understanding the genetic and metabolic factors that contribute to dyslipidemia, including the role of free cholesterol in medium VLDL, is crucial for developing more effective strategies for prevention, diagnosis, and treatment. Genetic studies, such as genome-wide association studies (GWAS), have advanced our knowledge of the genetic underpinnings of lipid levels, identifying common variants that contribute to polygenic dyslipidemia.[4]This knowledge can lead to personalized medicine approaches, allowing for risk stratification and targeted interventions based on an individual’s genetic profile and specific lipoprotein subfractions. Early identification of individuals at higher risk through such detailed lipid profiling could enable lifestyle modifications or pharmacological interventions, thereby reducing the societal impact of CVD.
Limitations
Section titled “Limitations”Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The large-scale genome-wide association studies (GWAS) on lipid phenotypes, which provide a framework for understanding complex traits like cholesterol fractions, are subject to various methodological and statistical constraints. While meta-analyses significantly boost statistical power, enabling the discovery of numerous loci, the initial sample sizes for individual cohorts in discovery stages (e.g., n = 8,589 for LDL cholesterol and n = 8,684 for triglycerides) may still limit the detection of variants with smaller effect sizes. [5] The combination of multiple studies into meta-analyses (e.g., totaling up to 19,840 individuals in stage 1 and up to 20,623 in stage 2 replication) helps mitigate this, but it also introduces heterogeneity in study design, genotyping platforms, and phenotyping protocols, even with efforts to standardize analyses. [6]Effect-size inflation, particularly for less robust signals, remains a possibility in early discovery stages before extensive replication, and while genomic control parameters were generally low (e.g., 1.03 for LDL cholesterol in meta-analysis), they suggest some residual confounding or relatedness.[4]
Furthermore, the reliance on an additive model of inheritance for genotype-phenotype association analyses, while standard, might not fully capture complex genetic architectures involving dominant, recessive, or epistatic interactions. [6] The process of imputing untyped SNPs using reference panels like HapMap CEU, while expanding coverage, introduces a degree of uncertainty and relies on the genetic architecture of the reference population. [4] Replication gaps, where signals from initial discovery are not consistently replicated across all follow-up cohorts or show borderline significance, highlight the challenge of confirming true associations, especially when proxy SNPs are used with imperfect linkage disequilibrium. [1]
Phenotype Definition and Generalizability
Section titled “Phenotype Definition and Generalizability”The precise definition and measurement of lipid phenotypes across diverse cohorts present inherent limitations for generalizability. For instance, LDL cholesterol was often calculated using the Friedewald formula, with specific exclusions for individuals with high triglyceride levels, and adjustments for covariates like age, gender, and diabetes status.[6] While necessary for standardization, these adjustments and exclusions could influence the observable genetic effects and their interpretation. The exclusion of individuals on lipid-lowering therapy, or imputation of untreated values, aims to isolate genetic effects but might not fully reflect real-world population variability. [4]
A significant limitation pertains to the ancestry and generalizability of findings. The majority of individuals included in the discovery and meta-analysis cohorts were of European ancestry (e.g., from Utah residents with ancestry from northern and western Europe (CEU) HapMap samples, London Life Sciences Prospective Population Cohort, FINRISK97). [4] While some studies included multiethnic cohorts or investigated linkage disequilibrium patterns between different ancestries, the predominant focus on European populations means that the identified genetic variants and their effect sizes may not be directly transferable or have similar frequencies and impacts in other ancestral groups. [3] This limits the broad applicability of these findings to a global population and underscores the need for more diverse genomic studies to capture a fuller spectrum of genetic influences on lipid traits.
Environmental Confounders and Remaining Knowledge Gaps
Section titled “Environmental Confounders and Remaining Knowledge Gaps”Understanding the genetic architecture of lipid traits is further complicated by unmeasured environmental or gene–environment confounders and the presence of significant missing heritability. Despite adjusting for known factors like age, sex, and sometimes ancestry-informative principal components, numerous unmeasured environmental influences (e.g., diet, physical activity, socioeconomic status) can significantly modulate lipid concentrations and interact with genetic predispositions.[4] Such interactions are complex and often not fully captured in current GWAS designs, leading to potential confounding or an incomplete picture of causal pathways.
The observed genetic variants explain only a fraction of the total phenotypic variance for lipid traits (e.g., 7.7% for LDL cholesterol and 7.4% for triglycerides), indicating substantial “missing heritability”. [4] This gap suggests that a large proportion of genetic influence remains undiscovered, possibly attributable to rare variants, structural variations, epigenetic factors, or complex gene-gene and gene-environment interactions not detectable by common SNP arrays and current statistical models. [6]Therefore, while significant progress has been made in identifying common variants, a comprehensive understanding of the polygenic nature of dyslipidemia and the full spectrum of factors influencing specific lipid fractions like free cholesterol in medium VLDL requires further research employing advanced sequencing technologies, deeper phenotyping, and sophisticated analytical approaches.
Variants
Section titled “Variants”Several genetic variants and their associated genes play crucial roles in regulating lipid metabolism, significantly influencing the levels of free cholesterol within medium very-low-density lipoprotein (VLDL) particles. These genes affect processes ranging from lipoprotein assembly and secretion to their catabolism and uptake.
Variations within the APOE-APOC1-APOC4-APOC2 cluster and the LDLRgene are central to lipoprotein clearance. TheAPOE gene (Apolipoprotein E) encodes a key component of VLDL and chylomicrons, acting as a ligand for receptors like the Low-Density Lipoprotein Receptor (LDLR), facilitating the uptake of these particles by the liver. The rs7412 variant in APOEis associated with the ε4 allele, which can impair VLDL remnant clearance, leading to higher circulating VLDL levels and consequently impacting free cholesterol content in medium VLDL.[5] Similarly, the rs584007 variant, located within the APOE-APOC1 region, can influence the expression or function of APOC1 (Apolipoprotein C1), which inhibits the binding of APOE-containing lipoproteins to receptors, thus affecting VLDL metabolism. [4] The rs73015024 variant near LDLR (Low-Density Lipoprotein Receptor) is likely to affect the efficiency of VLDL and LDL particle removal from the bloodstream. Reduced LDLRactivity, whether due to genetic variation or other factors, can lead to an accumulation of VLDL remnants and an altered free cholesterol profile in medium VLDL due to prolonged circulation.[5]
Other significant loci directly influence triglyceride metabolism and VLDL production. Thers115849089 variant, located in or near the LPL gene (Lipoprotein Lipase), affects the activity of this crucial enzyme that hydrolyzes triglycerides in circulating VLDL and chylomicrons. Reduced LPLactivity results in higher triglyceride-rich lipoprotein levels, including VLDL, and can alter their free cholesterol composition.[5] Similarly, the rs116843064 variant in ANGPTL4 (Angiopoietin-like 4) can modulate LPL activity, as ANGPTL4 acts as an endogenous inhibitor of LPL. Variants that reduce ANGPTL4function typically lead to lower triglycerides and can influence free cholesterol in VLDL by enhancing triglyceride clearance.[7] The rs1260326 variant in GCKR (Glucokinase Regulator) is strongly associated with higher triglyceride concentrations. This variant impacts hepatic glucose metabolism andde novolipogenesis, thereby influencing the liver’s production of VLDL particles and their associated free cholesterol.[5] Furthermore, variants like rs2954021 and rs112875651 in the TRIB1 gene (Tribbles Homolog 1) are associated with lower triglycerides and LDL cholesterol, and higher HDL cholesterol. TRIB1plays a role in regulating hepatic lipid synthesis and VLDL secretion, thereby influencing the pool of circulating VLDL and its free cholesterol content.[6]
The structural integrity and assembly of VLDL particles are also influenced by genetic factors. The APOB gene (Apolipoprotein B) provides the primary structural protein for VLDL and LDL. Variants such as rs693 in APOBare linked to both LDL cholesterol and triglyceride levels. This variant can affect the number or composition of VLDL particles secreted by the liver, thereby influencing the free cholesterol carried within medium VLDL.[6] The rs58542926 variant in TM6SF2 (Transmembrane 6 Superfamily Member 2) is a notable example, as it affects hepatic VLDL assembly and secretion. This variant is associated with reduced VLDL secretion, leading to lower circulating triglycerides and LDL cholesterol, which directly impacts the quantity of VLDL particles and their free cholesterol load.[5] Lastly, the rs13225450 variant in the BCL7B-TBL2region has been associated with lipid traits, including triglycerides and HDL cholesterol. This region’s influence on lipid metabolism could affect VLDL particle dynamics and, consequently, their free cholesterol content.[6]
Key Variants
Section titled “Key Variants”Causes
Section titled “Causes”Genetic Influences on Lipid Metabolism
Section titled “Genetic Influences on Lipid Metabolism”The amount of free cholesterol in medium VLDL particles is significantly influenced by an individual’s genetic makeup. Research has identified common genetic variants across numerous loci that contribute to polygenic dyslipidemia, a condition characterized by abnormal lipid levels.[4]These inherited variations can affect the synthesis, transport, and catabolism of lipids, thereby impacting the overall distribution and composition of cholesterol within various lipoprotein fractions, including VLDL.[5]The cumulative effect of these genetic factors establishes a predisposition to altered lipid concentrations, influencing the availability of free cholesterol for incorporation into VLDL particles.
Further studies have pinpointed newly identified genetic loci that specifically influence lipid concentrations and, consequently, the risk of coronary artery disease.[5]These genetic determinants play a crucial role in regulating the enzymes and proteins involved in VLDL assembly and metabolism, directly affecting the amount of free cholesterol present within these particles. Understanding these genetic underpinnings is essential for comprehending the variability in an individual’s lipid profile and their susceptibility to dyslipidemia.
Lifestyle, Diet, and Related Metabolic Conditions
Section titled “Lifestyle, Diet, and Related Metabolic Conditions”Beyond genetic predispositions, lifestyle and dietary habits exert a substantial influence on free cholesterol in medium VLDL. Classic risk factors, which encompass elements like diet and physical activity, have been shown to contribute to trends in coronary event rates, indicating their impact on lipid metabolism.[8]Diets high in certain fats and carbohydrates can lead to elevated triglyceride levels, which are intrinsically linked to VLDL production and, by extension, the free cholesterol content within these lipoproteins.[4]
Furthermore, metabolic conditions that often arise from a combination of lifestyle and genetic factors, such as high triglycerides, can significantly alter VLDL composition. These conditions are recognized as risk factors for heart disease mortality, with cholesterol fractions and apolipoproteins playing key roles.[9]The interplay between dietary intake, metabolic health, and the body’s lipid processing pathways directly impacts the synthesis and remodeling of VLDL particles, thereby influencing the concentration of free cholesterol they carry.
Pharmacological and Age-Related Modifiers
Section titled “Pharmacological and Age-Related Modifiers”The concentration of free cholesterol in medium VLDL can also be significantly altered by pharmacological interventions and natural physiological changes associated with aging. Lipid-lowering therapies, such as statins, are well-established for their ability to reduce low-density lipoprotein (LDL) cholesterol, but they also have broader effects on overall lipid metabolism, which can indirectly influence VLDL cholesterol levels.[10]Individuals undergoing such treatment often experience changes in their lipoprotein profiles, reflecting the drug’s impact on cholesterol synthesis and clearance.[4]
Age-related changes in the body’s metabolic processes also contribute to variations in cholesterol fractions. Research indicates that cholesterol fractions and apolipoproteins act as risk factors for heart disease mortality, particularly in older individuals.[9]As individuals age, their lipid metabolism can become less efficient, potentially leading to altered VLDL production and clearance rates, and consequently, changes in the free cholesterol content of medium VLDL particles.
Biological Background
Section titled “Biological Background”Lipoprotein Structure and Cholesterol Dynamics
Section titled “Lipoprotein Structure and Cholesterol Dynamics”Very Low-Density Lipoprotein (VLDL) particles are essential for transporting various lipids, including free cholesterol, throughout the bloodstream. These complex structures feature a core primarily composed of triglycerides and cholesterol esters, encased by a surface layer of phospholipids, free cholesterol, and specific apolipoproteins.[11]Free cholesterol, positioned on the outer surface of VLDL, is unesterified and plays a crucial role in maintaining membrane fluidity and facilitating interactions with cellular receptors and enzymes. The continuous exchange of free cholesterol between lipoproteins and cell membranes is a fundamental process vital for maintaining systemic lipid balance.
VLDL Metabolism and its Regulation
Section titled “VLDL Metabolism and its Regulation”VLDL particles are synthesized and secreted by the liver, subsequently entering the circulation to deliver triglycerides to peripheral tissues for energy or storage. As VLDL circulates, it undergoes a remodeling process that includes the removal of triglycerides by lipoprotein lipase and the dynamic exchange of apolipoproteins and lipids with other lipoprotein classes.[11]Apolipoprotein C-III, or_APOC3_, acts as a critical regulator of VLDL metabolism by inhibiting lipoprotein lipase activity and impeding the liver’s uptake of triglyceride-rich lipoproteins.[12] Therefore, _APOC3_significantly influences the circulating concentrations of VLDL and its associated free cholesterol.
Genetic Influences on Lipid Profiles
Section titled “Genetic Influences on Lipid Profiles”Genetic variations can profoundly affect the structure and function of proteins involved in lipid metabolism, thereby impacting an individual’s plasma lipid profile. For instance, research indicates that a null mutation in the human _APOC3_ gene results in a favorable plasma lipid profile. [12]Such genetic alterations, including substitutions at critical amino acid positions, can lead to changes in protein structure and function, consequently altering their biological activity.[13] These genetic mechanisms, through their influence on proteins like _APOC3_, intricately regulate the expression and activity of enzymes and receptors responsible for managing VLDL and cholesterol levels in the body.
Pathophysiological Implications
Section titled “Pathophysiological Implications”Disruptions in VLDL metabolism and the regulation of free cholesterol levels can lead to significant pathophysiological consequences, upsetting systemic lipid homeostasis. Elevated levels of VLDL cholesterol are frequently linked to an increased risk of cardiovascular diseases. Conversely, a beneficial plasma lipid profile, characterized by lower VLDL and triglyceride levels, is associated with a reduced risk of these conditions.[12] The presence of a null mutation in _APOC3_, which leads to diminished _APOC3_ function, contributes to apparent cardioprotection by enhancing the overall lipid profile. [12]This illustrates how specific molecular changes can initiate compensatory responses that protect against the development of disease.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Lipoprotein Metabolism and Catabolism
Section titled “Lipoprotein Metabolism and Catabolism”Very low-density lipoprotein (VLDL) particles are synthesized in the liver and serve as crucial carriers for triglycerides and free cholesterol throughout the body. These particles are characterized by their apolipoprotein components, includingAPOB, APOC3, and APOE, which dictate their fate and interactions within the circulatory system. [12]The primary enzyme responsible for breaking down the triglycerides within VLDL is lipoprotein lipase (LPL), which hydrolyzes triglycerides into fatty acids that can be taken up by peripheral tissues. [2]
Apolipoprotein C-III (APOC3), predominantly secreted by the liver, is a critical regulator of VLDL metabolism. It functions as an inhibitor of LPL activity, thereby impeding the efficient catabolism and hepatic clearance of apoB-containing lipoproteins, including VLDL. [12] A null mutation in human APOC3has been shown to confer a favorable plasma lipid profile, characterized by lower triglyceride and VLDL levels, and is associated with apparent cardioprotection.[12] Beyond APOC3, other proteins like angiopoietin-like protein 3 (ANGPTL3) are recognized as major regulators of lipid metabolism, and rare variants in ANGPTL4have been linked to variations in HDL and triglyceride concentrations, highlighting a complex regulatory network governing lipoprotein catabolism.[5]
Cholesterol Biosynthesis and Regulation
Section titled “Cholesterol Biosynthesis and Regulation”The maintenance of cellular free cholesterol levels relies heavily on its tightly regulated biosynthesis, primarily through the mevalonate pathway. This pathway initiates with the crucial enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), which catalyzes a rate-limiting step in cholesterol production. [3] The activity of HMGCR is pivotal for regulating the overall flux of intermediates through the mevalonate pathway, thus directly impacting the amount of cholesterol produced. [3]
Regulation of cholesterol biosynthesis also involves transcriptional control mechanisms. For instance, the genes encoding mevalonate kinase (MVK), another enzyme in the cholesterol synthesis pathway, and MMAB, which is involved in cholesterol degradation, are both regulated by sterol regulatory element-binding protein 2 (SREBP2). [5]Furthermore, genetic variations, such as common single nucleotide polymorphisms (SNPs) inHMGCR, can influence LDL cholesterol levels by altering the alternative splicing of specific exons. [3] This demonstrates that cholesterol metabolism is controlled at multiple levels, from gene expression to post-transcriptional processing, ensuring dynamic adaptation to metabolic demands.
Genetic Regulation and Post-Translational Control
Section titled “Genetic Regulation and Post-Translational Control”Beyond the direct synthesis, the cellular uptake and catabolism of circulating lipoproteins are also subject to sophisticated regulatory mechanisms, particularly involving the low-density lipoprotein receptor (LDLR) pathway. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key player in this regulation, accelerating the degradation of LDLR protein within a post-endoplasmic reticulum compartment. [14] This post-translational modification by PCSK9 reduces the abundance of LDLR on the cell surface, thereby diminishing the uptake of LDL cholesterol from the bloodstream. [15] Genetic variants in PCSK9, including nonsense mutations, are associated with lower LDL cholesterol levels and provide protection against coronary heart disease.[16]
Transcriptional regulation also exerts significant influence on plasma lipid profiles. MLXIPLencodes a protein that activates specific motifs in the promoters of triglyceride synthesis genes, directly impacting plasma triglyceride concentrations.[17] Other transcription factors, such as TCF1, are implicated in the regulation of genes like HAVCR1, while MAFB interacts with LDL-related proteins, highlighting complex transcriptional networks that modulate lipid metabolism. [4] Additionally, the enzyme GALNT2, a glycosyltransferase, could potentially modify lipoproteins or their receptors, adding another layer of post-translational regulation to lipoprotein function and clearance.[5]
Systems-Level Integration and Disease Relevance
Section titled “Systems-Level Integration and Disease Relevance”The intricate web of lipid metabolism involves extensive crosstalk and hierarchical regulation among various pathways. For example, APOC3 not only inhibits the catabolism of apoB-containing lipoproteins like VLDL but also contributes to the catabolism of HDL, illustrating its broad impact on systemic lipid homeostasis. [12] Genome-wide association studies (GWAS) have elucidated the polygenic nature of dyslipidemia, identifying numerous common genetic variants that collectively contribute to variations in circulating lipid levels. [4] These studies have pinpointed key genes and gene clusters, including ABCA1, APOB, CETP, LDLR, LPL, PCSK9, and the APOA5-APOA4-APOC3-APOA1 cluster, as significant determinants of plasma lipid concentrations. [2]
Dysregulation within these interconnected lipid pathways is a major underlying cause of cardiovascular diseases. The cumulative deposition of LDL cholesterol in arterial walls leads to atherosclerosis, a pathological process that can result in myocardial infarction and stroke.[5]High concentrations of LDL cholesterol are strongly associated with an increased risk of coronary artery disease, whereas higher HDL cholesterol levels are generally considered protective.[5] A detailed understanding of these molecular mechanisms, such as the PCSK9-LDLR pathway or the inhibitory role of APOC3, is crucial for identifying effective therapeutic targets to manage dyslipidemia and mitigate cardiovascular risk.[6]
References
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