Free Cholesterol In Medium Ldl
Introduction
Section titled “Introduction”Free cholesterol in medium low-density lipoprotein (LDL) refers to a specific type of cholesterol within a particular subfraction of LDL particles. Cholesterol is a vital lipid molecule essential for building cell membranes, producing hormones, and aiding in fat digestion. It is transported throughout the body by lipoproteins, which are complexes of lipids and proteins. LDL, often referred to as “bad” cholesterol, primarily transports cholesterol from the liver to cells that need it.
Biological Basis
Section titled “Biological Basis”Within LDL particles, cholesterol exists in two main forms: esterified cholesterol and free cholesterol. Free cholesterol, as its name suggests, is unesterified and plays a direct role in cell membrane fluidity and other cellular functions. LDL particles are not uniform in size and density; they can be categorized into subfractions such as large, medium, and small LDL. The medium LDL subfraction represents an intermediate size and density of these particles. Genetic factors are known to influence the levels of various lipid phenotypes, including specific LDL subfractions and their cholesterol content. Studies have investigated the association of genetic variants at numerous loci with a spectrum of specialized lipid phenotypes, contributing to the understanding of polygenic dyslipidemia.[1] For instance, genes like TIMD4, HAVCR1, and MAFBhave been implicated in influencing overall LDL cholesterol levels, though their specific impact on free cholesterol within medium LDL remains an area of ongoing research.[1]
Clinical Relevance
Section titled “Clinical Relevance”The levels of free cholesterol in medium LDL are clinically relevant because alterations in LDL subfractions and their cholesterol content can be associated with an increased risk of cardiovascular diseases, such as atherosclerosis. While total LDL cholesterol is a widely used marker, the composition and distribution of LDL subfractions provide a more nuanced picture of an individual’s lipid profile. Elevated levels of certain atherogenic (plaque-forming) LDL subfractions are considered a risk factor, and understanding the free cholesterol content within these specific particles may offer additional insights into disease progression and risk stratification.
Social Importance
Section titled “Social Importance”The study of specialized lipid phenotypes like free cholesterol in medium LDL holds significant social importance due to the widespread prevalence and impact of cardiovascular diseases globally. These conditions represent a major public health burden, leading to millions of deaths and substantial healthcare costs each year. Advances in understanding the genetic and biological underpinnings of these specific lipid traits can contribute to the development of more precise diagnostic tools, targeted therapeutic interventions, and personalized risk assessment strategies. This research ultimately aims to improve preventive measures and clinical management, thereby reducing the societal impact of dyslipidemia and related cardiovascular events.
Limitations
Section titled “Limitations”Methodological and Statistical Considerations
Section titled “Methodological and Statistical Considerations”Genome-wide association studies (GWAS) for free cholesterol in medium LDL, while leveraging large cohorts, still face limitations regarding the detection of all relevant genetic variants. Even with meta-analyses combining data from tens of thousands of individuals, such as the stage 1 sample size of 19,840 and stage 2 studies including up to 20,623 individuals[2]the statistical power to identify variants with very small effect sizes or rare alleles remains a challenge. This constraint can lead to an underestimation of the total genetic contribution to free cholesterol in medium LDL, suggesting that further genetic signals could be discovered with even larger sample sizes and enhanced statistical power.[2] Additionally, effect sizes reported for newly identified loci may sometimes be inflated in initial discovery cohorts, necessitating robust replication in independent populations to ascertain their true magnitude. [3]
The statistical models employed, such as the assumption of an additive model of inheritance for genotype-lipid associations, might not fully capture complex genetic interactions or non-additive effects, potentially overlooking some associations. [1] While efforts were made to standardize analytical approaches across diverse cohorts, some inconsistencies persisted, including variations in adjustments for age squared or the exclusion of lipid distribution outliers in specific studies. [1]Furthermore, while replication is critical for validating findings, not all proxy single nucleotide polymorphisms (SNPs) consistently achieved strong statistical significance in independent cohorts, highlighting the need for careful interpretation of initial associations.[4]
Phenotypic Definition and Environmental Confounders
Section titled “Phenotypic Definition and Environmental Confounders”The definition and measurement of free cholesterol in medium LDL across different studies introduced a degree of heterogeneity. For instance, LDL cholesterol was frequently calculated using the Friedewald formula, a method known to have limitations, particularly for individuals with high triglyceride levels.[2] The use of non-fasting serum LDL in some cohorts, as opposed to fasting levels, represents another source of variability, potentially influencing the observed effect sizes and complicating direct comparisons between studies. [4] The practice of excluding outlier individuals from the lipid distributions in certain analyses also means that the full spectrum of phenotypic variation may not be entirely represented. [1]
Despite comprehensive adjustments for key demographic and clinical variables such as age, gender, age squared, diabetes status, and ancestry-informative principal components [1]other environmental or lifestyle factors could still introduce confounding. Notably, information regarding lipid-lowering therapy was not uniformly available or considered across all participating cohorts, and in some instances, untreated LDL cholesterol values were imputed.[1]The influence of other lifestyle factors, dietary habits, or clinical covariates like body mass index (BMI), which are known to affect lipid levels, were not consistently or comprehensively adjusted for across all studies, potentially leaving residual confounding factors unaddressed. [5]
Generalizability and Unexplained Genetic Architecture
Section titled “Generalizability and Unexplained Genetic Architecture”A substantial limitation of these studies is the predominant focus on populations of European ancestry in many of the discovery and replication cohorts. [6] While efforts were made to include some multiethnic samples, such as those comprising Singaporean Chinese, Malays, and Asian Indians [1] or Micronesian populations [7]the broader generalizability of these findings to other diverse global populations remains to be fully established. Variations in linkage disequilibrium patterns, allele frequencies, and gene-environment interactions across different ancestral groups imply that genetic associations identified in one population may not be directly transferable or have the same effect size in others.
Despite the identification of numerous genetic loci, the collective contribution of these variants to the total variability in free cholesterol in medium LDL is relatively modest, with figures such as 7.7% of variance explained for LDL cholesterol being reported.[2] This indicates a significant portion of the heritability for this trait remains unexplained, pointing to the existence of undiscovered genetic variants, including rare alleles or those with smaller individual effects. Furthermore, complex gene-gene interactions or intricate gene-environment interactions may play a substantial role and were not fully elucidated or modeled within these studies. Ongoing research is essential to uncover these additional genetic and environmental factors and to understand their broader implications for health outcomes. [3]
Variants
Section titled “Variants”Several genetic variants influence the regulation of lipid metabolism, impacting levels of free cholesterol, particularly within medium low-density lipoprotein (LDL) particles. A key pathway involves the uptake and synthesis of cholesterol, where variants in genes likeLDLR, PCSK9, and HMGCR play significant roles. For instance, variants such as rs6511720 , rs2738447 , and rs12151108 within or near the LDLRgene can alter the efficiency of the low-density lipoprotein receptor, which is critical for clearing LDL from the bloodstream.[5] Similarly, variants like rs11591147 , rs472495 , and rs11206517 in the PCSK9 gene can affect the degradation of the LDLR protein, thereby influencing circulating LDL levels. Moreover, the rs12916 variant, located near both HMGCR and CERT1, is associated with LDL levels, with HMGCR encoding the rate-limiting enzyme in cholesterol biosynthesis and being a primary target for cholesterol-lowering medications. [5] Variants in the APOB gene, such as rs563290 and rs562338 (in the APOB - TDRD15 locus), are also critical, as APOB encodes the main structural protein of LDL particles, influencing their assembly and receptor binding.
Other genetic loci contribute to the broader landscape of cholesterol transport and metabolism. The ABCG8 gene, with variants like rs4245791 and rs4299376 , is involved in the transport of sterols from the liver and intestine, playing a role in cholesterol absorption and excretion. Alterations in these variants can influence the overall sterol balance and, consequently, the free cholesterol content in circulating lipoproteins. TheCELSR2 - PSRC1 locus, including variants like rs646776 and rs12740374 (in CELSR2 itself), is consistently identified in genome-wide association studies as strongly associated with LDL cholesterol levels. [5] While CELSR2 is a cell adhesion molecule, the association at this locus is often attributed to its linkage with PSRC1 and SORT1, genes that collectively impact lipid processing and very-low-density lipoprotein (VLDL) secretion, which are precursors to LDL particles.
Beyond these well-established lipid-related genes, other variants may exert more subtle or indirect effects on free cholesterol in medium LDL. Thers7254892 variant in NECTIN2 (and CEACAM16-AS1) suggests a potential role for cell adhesion molecules or non-coding RNAs in metabolic regulation. Similarly, the rs62117160 variant in BCL3 points to the involvement of transcriptional regulators, as BCL3 is known to modulate gene expression, including pathways that can indirectly influence lipid metabolism and inflammation. The rs12151108 variant, located in the SMARCA4 - LDLR region, highlights the complex interplay between chromatin remodeling (via SMARCA4) and the regulation of critical lipid genes like LDLR. These less direct associations underscore the intricate genetic architecture underlying lipoprotein composition and the availability of free cholesterol within different LDL subclasses.
The provided research context does not contain specific information or definitions pertaining to ‘free cholesterol in medium ldl’. The studies primarily focus on general ‘LDL cholesterol’ concentrations, their measurement, and their association with cardiovascular disease, without differentiating between free and esterified cholesterol components or specific LDL subfractions like ‘medium LDL’. Therefore, a detailed classification, definition, and terminology section for ‘free cholesterol in medium ldl’ cannot be constructed based solely on the provided materials.
Key Variants
Section titled “Key Variants”Causes
Section titled “Causes”Genetic Predisposition to Dyslipidemia
Section titled “Genetic Predisposition to Dyslipidemia”Genetic factors play a significant role in determining an individual’s levels of free cholesterol in medium LDL, primarily through polygenic inheritance. Research has identified common genetic variants across numerous loci that collectively contribute to polygenic dyslipidemia. For instance, studies have pinpointed common variants at 30 distinct loci that influence lipid concentrations, including LDL cholesterol, thereby impacting the levels of free cholesterol in medium LDL.[1] These inherited variants can affect various pathways involved in lipid metabolism, transport, and regulation, leading to a predisposition for altered cholesterol profiles.
Further research has continued to uncover newly identified genetic loci that influence lipid concentrations, including those relevant to free cholesterol in medium LDL, and are also associated with the risk of coronary artery disease.[3]These findings underscore the complex genetic architecture underlying lipid traits, where multiple genes with small to moderate effects interact to determine an individual’s specific lipid profile. The collective impact of these genetic variations can significantly modulate the amount of free cholesterol present within medium LDL particles.
Biological Background
Section titled “Biological Background”Lipoprotein Metabolism and Cholesterol Transport
Section titled “Lipoprotein Metabolism and Cholesterol Transport”Lipoproteins are complex particles that transport lipids, including cholesterol and triglycerides, through the bloodstream. Low-density lipoprotein (LDL) is a primary carrier of cholesterol from the liver to peripheral tissues, playing a crucial role in delivering lipids where they are needed for cellular functions, such as membrane synthesis and hormone production. The cholesterol carried by LDL exists in two forms: esterified cholesterol, which is stored within the lipoprotein core, and free cholesterol, which resides on the surface of the particle. The concentration of free cholesterol in medium LDL, as part of the broader plasma lipid profile, is influenced by the overall dynamics of lipoprotein synthesis, secretion, and clearance, which are essential for maintaining systemic lipid balance.[8] Disruptions in these intricate pathways can lead to altered lipid profiles, affecting the availability of cholesterol to cells and its potential accumulation in tissues.
The Role of APOC3 in Lipid Regulation
Section titled “The Role of APOC3 in Lipid Regulation”Apolipoprotein C-III (APOC3) is a key regulatory protein found on various lipoprotein particles, including very low-density lipoproteins (VLDL) and chylomicrons.APOC3primarily functions as an inhibitor of lipoprotein lipase, an enzyme critical for the hydrolysis of triglycerides in VLDL and chylomicrons, thereby slowing down their clearance from the circulation. Additionally,APOC3 can interfere with the binding of lipoproteins to their receptors on liver cells, further impeding their removal. A null mutation in human APOC3 has been observed to confer a favorable plasma lipid profile, indicating that the absence of functional APOC3leads to enhanced triglyceride clearance and potentially altered cholesterol distribution among lipoprotein subfractions, including free cholesterol in medium LDL.[9] This genetic insight highlights APOC3’s significant role in modulating the systemic metabolism of lipids and influencing the composition of circulating lipoproteins.
Cellular Uptake and Cholesterol Homeostasis
Section titled “Cellular Uptake and Cholesterol Homeostasis”Cells regulate their internal cholesterol levels through a tightly controlled network of pathways, including the uptake of cholesterol-rich lipoproteins like LDL. The LDL receptor, located on the surface of cells, plays a central role in internalizing LDL particles, thereby supplying cells with cholesterol. This process is critical for maintaining cellular membrane integrity, synthesizing steroid hormones, and producing bile acids. The availability of free cholesterol in medium LDL, alongside other lipoprotein components, influences how efficiently cells acquire cholesterol from the circulation. Maintaining proper cellular cholesterol homeostasis is vital for preventing both cholesterol deficiency and excessive accumulation, which can disrupt cellular functions and contribute to pathophysiological conditions.
Impact on Cardiovascular Health
Section titled “Impact on Cardiovascular Health”The intricate balance of plasma lipids, including the levels of free cholesterol in medium LDL, has profound implications for cardiovascular health. An unfavorable plasma lipid profile, characterized by elevated levels of certain cholesterol-carrying lipoproteins, is a well-established risk factor for atherosclerosis and subsequent cardiovascular disease. Conversely, a favorable plasma lipid profile, often associated with lower triglyceride levels and beneficial changes in LDL composition, can confer protection against these conditions. Research has demonstrated that a null mutation in humanAPOC3, by favorably altering the plasma lipid profile, is associated with apparent cardioprotection. [9] This suggests that modulating APOC3activity or its downstream effects on lipid metabolism could represent a therapeutic strategy for reducing cardiovascular risk by influencing the overall lipid environment, including specific components like free cholesterol in medium LDL.
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Regulation of LDL Receptor-Mediated Cholesterol Homeostasis
Section titled “Regulation of LDL Receptor-Mediated Cholesterol Homeostasis”The cellular uptake and clearance of low-density lipoprotein (LDL) cholesterol are critically regulated by the low-density lipoprotein receptor (LDLR), a process significantly modulated by proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 accelerates the degradation of the LDLR within a post-endoplasmic reticulum compartment, thereby reducing the number of functional receptors on the cell surface and consequently increasing plasma LDL cholesterol levels. [10] This post-transcriptional regulation of LDLR protein by PCSK9 has profound effects, as natural mutations in PCSK9 can lead to autosomal dominant hypercholesterolemia, while frequent nonsense mutations are associated with lower LDLcholesterol levels and protection against coronary heart disease.[11] Furthermore, the mevalonate pathway, responsible for cholesterol biosynthesis, is tightly controlled, with 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzing a key regulatory step, and common genetic variations in HMGCR impacting LDL cholesterol levels through mechanisms like alternative splicing. [7]
Another crucial aspect of cholesterol synthesis involves genes like MVK (mevalonate kinase) and MMAB, which are also part of the mevalonate pathway, with MVK catalyzing an early step in cholesterol biosynthesis and MMAB participating in cholesterol degradation. [3] Both MVK and MMAB are regulated by the transcription factor SREBP2, highlighting a coordinated transcriptional control over the supply and removal of cholesterol precursors and metabolites. [3] The interplay between LDLR activity, PCSK9 regulation, and the enzymatic steps of cholesterol synthesis thus forms a central axis for maintaining systemic LDL cholesterol homeostasis.
Modulation of Lipoprotein Metabolism and Catabolism
Section titled “Modulation of Lipoprotein Metabolism and Catabolism”Lipoprotein metabolism involves a complex interplay of particles and enzymes that dictate the flux and catabolism of lipids, including those associated withLDLcholesterol. Apolipoprotein C-III (APOC3), secreted primarily by the liver, is a component of both high-density lipoprotein (HDL) and apoB-containing lipoproteins, and critically impairs the catabolism and hepatic uptake of these particles. [9] A null mutation in human APOC3has been shown to confer a favorable plasma lipid profile and apparent cardioprotection, by diminishing very low-density lipoprotein (VLDL) fractional catabolic rates.[12]This illustrates how specific apolipoproteins can act as key regulators of lipoprotein clearance and overall lipid levels.
Further regulatory proteins, such as angiopoietin-like protein 3 (ANGPTL3) and angiopoietin-like protein 4 (ANGPTL4), exert significant control over lipid metabolism. [3] ANGPTL4functions as a potent hyperlipidemia-inducing factor and an inhibitor of lipoprotein lipase (LPL), an enzyme essential for the hydrolysis of triglycerides in circulating lipoproteins. [13] Variations in genes like LCAT (lecithin-cholesterol acyltransferase) and PLTP (phospholipid transfer protein) also influence HDLcholesterol and triglyceride concentrations, affecting the remodeling and transfer of lipids among lipoprotein classes, which indirectly impacts the composition and metabolism ofLDL particles. [14]
Transcriptional and Post-Translational Control of Lipid Pathways
Section titled “Transcriptional and Post-Translational Control of Lipid Pathways”The intricate balance of lipid homeostasis is maintained through sophisticated transcriptional and post-translational regulatory mechanisms that govern the expression and activity of key metabolic proteins. Transcription factors such as hepatocyte nuclear factor 1 alpha (HNF1A) and hepatocyte nuclear factor 4 alpha (HNF4A) are associated with LDL cholesterol and HDL cholesterol levels, respectively, suggesting their role in orchestrating gene expression programs critical for lipid metabolism. [1] Additionally, MLXIPLencodes a protein that binds and activates specific motifs in the promoters of triglyceride synthesis genes, directly influencing lipid production pathways.[3]
Beyond transcriptional control, post-translational modifications and protein processing play a vital role. For instance, the zymogen cleavage of PCSK9 is essential for its function in LDLR degradation, while common genetic variants in HMGCR can affect alternative splicing of exon 13, altering the enzyme’s structure or activity and impacting cholesterol biosynthesis. [15] Glycosyltransferases like GALNT2 are also involved, as GALNT2 encodes an enzyme that could potentially modify lipoproteins or their receptors, thereby modulating their function or recognition in the metabolic cascade. [3] The transcription factor MAFB also interacts with LDL-related protein, further illustrating the complex regulatory network. [1]
Integrated Lipid Networks and Cardiovascular Health
Section titled “Integrated Lipid Networks and Cardiovascular Health”The regulation of LDLcholesterol is not an isolated process but rather an integral part of a complex, interconnected lipid network, with significant implications for cardiovascular health. Dyslipidemia, characterized by abnormal lipid levels, is a polygenic trait influenced by common variants across numerous loci, including those impactingLDL cholesterol, HDL cholesterol, and triglycerides. [6] This systems-level integration highlights pathway crosstalk, where changes in one lipid pathway can ripple through others, exemplified by the coordinated regulation of genes involved in cholesterol biosynthesis and degradation. [6] The genetic architecture of lipid traits is highly heritable, and genome-wide association studies have identified many genes and regions (ABCA1, APOB, CETP, LDLR, LIPC, LPL, PCSK9, and others) whose variations contribute to this polygenic susceptibility. [6]
The dysregulation of LDLcholesterol metabolism is a primary driver of atherosclerosis, a pathological process involving the cumulative deposition ofLDLcholesterol in arterial walls, which can lead to myocardial infarction or stroke.[3] Macrophages also play a role in lipid handling and inflammation, with receptors like TIMD4 and HAVCR1 on macrophages facilitating the engulfment of apoptotic cells, a process relevant to atherosclerotic plaque development. [1] Understanding these integrated networks and their genetic underpinnings is crucial for identifying therapeutic targets, as even a 1% decrease in LDLcholesterol concentrations is estimated to reduce the risk of coronary heart disease by approximately 1%.[3]
Clinical Relevance
Section titled “Clinical Relevance”Risk Assessment and Stratification for Cardiovascular Disease
Section titled “Risk Assessment and Stratification for Cardiovascular Disease”High concentrations of low-density lipoprotein cholesterol (LDL cholesterol) are consistently associated with an increased risk of coronary artery disease (CAD) and stroke, which are leading causes of morbidity and mortality globally. The cumulative deposition of LDL cholesterol in arterial walls is a primary underlying pathology for atherosclerosis, ultimately leading to impaired blood supply and critical cardiovascular events.[3]Therefore, LDL cholesterol levels serve as a crucial diagnostic utility and a key factor in cardiovascular risk assessment, aiding clinicians in identifying individuals at elevated risk for these conditions.[3]
Integrating genetic profiles with traditional clinical risk factors, such as lipid values, age, body mass index (BMI), and sex, has been shown to improve the classification of coronary heart disease (CHD) risk.[6] This approach supports personalized medicine strategies by enhancing the identification of high-risk individuals, allowing for more targeted prevention strategies and early interventions. While traditional measures remain foundational, genetic insights offer an additional layer of precision in risk stratification. [6]
Prognostic Value and Disease Progression
Section titled “Prognostic Value and Disease Progression”The concentration of LDL cholesterol holds significant prognostic value for predicting cardiovascular outcomes and disease progression. Research indicates that a 1% decrease in LDL cholesterol concentrations can reduce the risk of coronary heart disease by approximately 1%.[3]This relationship highlights LDL cholesterol as an independently associated risk factor for CAD, with its levels directly correlating with long-term implications for patient health and disease trajectory.[3]
Genetic variants that influence LDL cholesterol concentrations are also associated with altered risks of CAD. Studies have shown that alleles linked to increased LDL cholesterol levels are generally associated with a higher risk of CAD, emphasizing the genetic underpinnings of lipid-related disease progression.[3]Understanding these genetic influences contributes to a more comprehensive prediction of an individual’s susceptibility to developing advanced atherosclerotic disease and related complications.
Genetic Determinants and Therapeutic Implications
Section titled “Genetic Determinants and Therapeutic Implications”Numerous genetic loci have been identified as significantly influencing LDL cholesterol levels, contributing to the polygenic nature of dyslipidemia. Key genes include APOB, APOE-APOC1-APOC4-APOC2 cluster, LDLR, HMGCR, and PCSK9, among others like CELSR2, PSRC1, and SORT1. [7] These common variants collectively explain an appreciable fraction of the inter-individual variability in LDL cholesterol concentrations, with some alleles, such as those at PCSK9, having a substantial effect on levels. [1]
The identification of these genetic determinants has profound implications for understanding the biological pathways of lipid metabolism and for guiding therapeutic strategies. For instance, variants in HMGCR are associated with an increase in LDL cholesterol, providing insights into the genetic basis of statin response pathways, given HMGCR is the target of statin drugs. [7]This genetic understanding can inform treatment selection and monitoring strategies, potentially leading to more effective personalized approaches in managing hyperlipidemia and preventing cardiovascular disease.[1]
References
Section titled “References”[1] Kathiresan, S et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, 2008.
[2] Kathiresan, S., et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet, vol. 41, no. 1, 2009, pp. 56-65.
[3] Willer, C. J., et al. “Newly identified loci that influence lipid concentrations and risk of coronary artery disease.”Nat Genet, vol. 40, no. 2, 2008, pp. 161-169.
[4] Wallace, C et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.”Am J Hum Genet, 2008.
[5] Sabatti, C., et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet, vol. 41, no. 1, 2009, pp. 35-46.
[6] Aulchenko, Y. S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nat Genet, vol. 41, no. 1, 2009, pp. 47-55.
[7] Burkhardt, R et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol, 2008.
[8] Havel, RJ., and JP. Kane. Structure and Metabolism of Plasma Lipoproteins. 8th ed., McGraw-Hill, 2005.
[9] Pollin, T.I. et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 322, 2008, pp. 1702–1705.
[10] Maxwell, K.N. et al. “Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.” Proc. Natl. Acad. Sci. USA, vol. 102, 2005, pp. 2069–2074.
[11] Abifadel, M. et al. “Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.” Nat. Genet., vol. 34, 2003, pp. 154–156.
[12] Aalto-Setala, K. et al. “Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.”J. Clin. Invest., vol. 90, 1992, pp. 1889–1900.
[13] Yoshida, K. et al. “Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase.”J. Lipid Res., vol. 43, 2002, pp. 1770–1772.
[14] Jiang, X. et al. “Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes.”J. Biol. Chem., vol. 279, 2004, pp. 48865–48875.
[15] Benjannet, S. et al. “NARC-1/PCSK9and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.” J. Biol. Chem., vol. 279, 2004, pp. 48865–48875.