Cholesterol Efflux Capacity

Introduction

Cholesterol efflux capacity refers to the ability of high-density lipoprotein (HDL) particles to accept and remove excess cholesterol from cells, particularly macrophages found in arterial walls. This process represents the initial and often rate-limiting step in reverse cholesterol transport (RCT), a vital pathway for maintaining cellular cholesterol homeostasis and preventing the accumulation of cholesterol that can lead to arterial plaque formation. While the total level of HDL cholesterol is a common metric for cardiovascular health, cholesterol efflux capacity is increasingly recognized as a more direct and functional indicator of HDL’s protective role

Methodological and Statistical Constraints

Studies on lipid-related traits often require very large sample sizes to achieve adequate statistical power, especially for detecting genetic variants with modest effects and for rigorous genome-wide significance thresholds. Small sample sizes can limit the discovery of new genetic loci and increase the risk of false-negative findings, meaning potentially relevant associations might be missed.^[1] The extent of multiple testing further exacerbates this challenge, necessitating even greater power to differentiate true associations from chance findings.^[2] While meta-analyses and replication stages are crucial for validating initial discoveries, the ability to replicate findings in independent cohorts is paramount and can sometimes be limited, particularly when relying on partial coverage of genetic variation.^[2] Despite statistical corrections like genomic control, some moderately strong associations might still represent false-positive results, requiring further validation beyond initial statistical support.^[1] Additionally, the process of imputing missing genotypes introduces a margin of error, which, while generally low, can influence the accuracy of allele calls and subsequent association analyses.^[1]

Generalizability and Phenotypic Nuances

A significant limitation stems from the predominant focus of many studies on cohorts of European ancestry.^[1] This narrow demographic focus can limit the generalizability of findings to other populations and may mask ancestry-specific genetic effects or gene-environment interactions.^[3] While some studies have expanded to multiethnic cohorts, broader representation is essential to capture the full spectrum of genetic variation influencing lipid-related traits across diverse human populations.^[1]Genetic risk profiles for lipid traits can differ markedly between males and females, reflecting known epidemiological and clinical variations in lipid values and cardiovascular disease prevalence.^[1] Many studies have not fully explored these sex-specific differences, potentially obscuring important genetic insights.^[1] Furthermore, variations in phenotypic definition and covariate adjustments (e.g., age, age squared, diabetes status, lipid-lowering therapy exclusion) across different cohorts can introduce heterogeneity and complicate meta-analyses, impacting the consistency and interpretation of results.^[1]

Unexplored Genetic and Environmental Influences

The influence of genetic variants on lipid-related phenotypes is often context-specific, being modulated by environmental factors such as diet or lifestyle.^[2] For instance, associations of ACE and AGTR2with left ventricular mass were reported to vary according to dietary salt intake, highlighting the importance of considering environmental factors.^[2] However, comprehensive investigations into these complex gene-environment interactions are frequently not undertaken, leaving a substantial gap in understanding how genetic predispositions manifest under varying environmental conditions.^[2] Fully characterizing these interactions is crucial for developing personalized prevention and treatment strategies.

Genome-wide association studies typically identify common single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium with, rather than necessarily being, the causal variants.^[3] Pinpointing the exact functional variant and elucidating the precise biological mechanisms by which it influences lipid metabolism requires extensive follow-up studies beyond initial association findings.^[1]This challenge also extends to understanding the broader impact of these variants on related health outcomes, such as longevity or stroke, which often necessitate additional dedicated research.^[1]

Variants

Genetic variations play a crucial role in determining an individual’s cholesterol efflux capacity, a key process in reverse cholesterol transport that removes excess cholesterol from cells. Several genes and their associated variants influence the intricate balance of lipid metabolism, impacting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. Understanding these variants helps to elucidate genetic predispositions to dyslipidemia and cardiovascular disease.

Variants within the APOE-APOC1 gene cluster are central to lipid metabolism, influencing how lipoproteins are processed and cleared from the bloodstream. The APOEgene provides instructions for apolipoprotein E, a component of various lipoproteins that mediates their binding to receptors, whileAPOC1(apolipoprotein C-I) modulates lipid transfer and receptor interactions. Variants likers445925 and rs141622900 in the APOC1-APOC1P1 region can alter the function of these apolipoproteins, thereby affecting LDL cholesterol concentrations and overall cholesterol efflux. For instance, the APOE/APOC cluster is strongly associated with LDL cholesterol levels, with specific variants linked to significant increases in LDL cholesterol.^[1] These genetic differences ultimately impact the efficiency of cholesterol removal from peripheral tissues and its transport back to the liver.

The enzymes LPL(Lipoprotein Lipase) andLIPC(Hepatic Lipase) are critical for breaking down triglycerides and remodeling lipoprotein particles.LPL hydrolyzes triglycerides in chylomicrons and very-low-density lipoproteins (VLDL), making fatty acids available to tissues and influencing HDL formation.^[1] Variants such as rs77069344 in LPLcan alter this enzymatic activity, impacting triglyceride levels and, consequently, HDL cholesterol and cholesterol efflux capacity. Similarly,LIPCplays a significant role in the metabolism of HDL cholesterol and triglycerides, influencing the size and composition of HDL particles crucial for reverse cholesterol transport. The variantrs2070895 , which is located in a region encompassing ALDH1A2 and LIPC, may affect LIPC activity, thereby modulating HDL cholesterol levels and cholesterol efflux.^[1] CETP(Cholesteryl Ester Transfer Protein) is another key player in lipid metabolism, facilitating the exchange of cholesteryl esters from HDL to other lipoproteins in return for triglycerides. This process is central to the dynamics of reverse cholesterol transport and directly impacts cholesterol efflux capacity. Variants inCETP, such as rs247616 in the HERPUD1-CETP region, can significantly influence HDL cholesterol concentrations.^[1] For example, specific CETP variants are strongly associated with higher HDL cholesterol levels.^[1] Furthermore, the variant rs964184 , associated with ZPR1 and located near the APOA5-APOA4-APOC3-APOA1cluster, is linked to increased triglyceride concentrations.^[1] While ZPR1 is involved in cell proliferation and survival, its genetic proximity to the apolipoprotein A5 cluster suggests potential indirect effects on lipid processing, which can influence the overall lipid environment critical for cholesterol efflux.

Beyond core lipid-processing genes, other genetic regions can also contribute to cholesterol efflux capacity through broader metabolic or cellular functions. TheCDKAL1 gene, with variants such as rs118065692 and rs117835232 , is primarily recognized for its role in pancreatic beta-cell function and susceptibility to type 2 diabetes. These variants can indirectly influence lipid metabolism through effects on insulin secretion and glucose homeostasis, which are interconnected with lipid pathways.^[2] ALDH1A2 is involved in the synthesis of retinoic acid, a powerful signaling molecule with widespread regulatory effects on gene expression, including those implicated in lipid metabolism. The variant rs261290 in ALDH1A2 may alter retinoic acid levels, thereby subtly influencing cholesterol efflux pathways.^[1] Lastly, the RBFOX3-MIR4739 region, including variant rs4889908 , is involved in neuronal development and microRNA regulation, respectively. While not directly part of the canonical lipid metabolic pathways, genetic variations in such regions can have pleiotropic effects on overall metabolic health and cellular function, indirectly impacting cholesterol homeostasis and efflux capacity.

The researchs material does not contain specific information regarding the classification, definition, and terminology of ‘cholesterol efflux capacity’.

Key Variants

RS ID	Gene	Related Traits
rs118065692	CDKAL1	cholesterol efflux capacity measurement
rs117835232	CDKAL1	cholesterol efflux capacity measurement
rs964184	ZPR1	very long-chain saturated fatty acid measurement coronary artery calcification vitamin K measurement total cholesterol measurement triglyceride measurement
rs247616	HERPUD1 - CETP	high density lipoprotein cholesterol measurement lipoprotein-associated phospholipase A(2) measurement coronary artery disease HDL cholesterol change measurement, response to statin phosphatidylcholine 34:3 measurement
rs445925	APOE - APOC1	coronary artery calcification atherosclerosis clinical ideal cardiovascular health lipoprotein-associated phospholipase A(2) measurement Red cell distribution width
rs261290	ALDH1A2	level of phosphatidylethanolamine level of phosphatidylcholine high density lipoprotein cholesterol measurement triglyceride measurement, high density lipoprotein cholesterol measurement VLDL particle size
rs141622900	APOC1 - APOC1P1	level of phosphatidylcholine triglyceride measurement diacylglycerol 36:4 measurement diacylglycerol 36:5 measurement diacylglycerol 36:3 measurement
rs77069344	LPL	sphingomyelin measurement triglyceride measurement diacylglycerol 34:2 measurement diacylglycerol 34:1 measurement metabolic syndrome
rs2070895	ALDH1A2, LIPC	high density lipoprotein cholesterol measurement total cholesterol measurement level of phosphatidylcholine level of phosphatidylethanolamine triglyceride measurement, depressive symptom measurement
rs4889908	RBFOX3 - MIR4739	cholesterol efflux capacity measurement

Biological Background

Cholesterol efflux capacity, a critical component of lipid metabolism, represents the ability of cells to remove excess cholesterol, primarily from macrophages, and is a key process in preventing atherosclerotic plaque formation. This complex biological trait is influenced by an intricate network of molecular and cellular pathways, genetic mechanisms, and pathophysiological processes that collectively regulate cholesterol homeostasis throughout the body. Understanding these underlying biological aspects is crucial for comprehending the systemic consequences of dysregulated cholesterol efflux and its impact on human health.

Cellular Cholesterol Dynamics and Efflux Mechanisms

Cellular cholesterol homeostasis is maintained through a delicate balance of synthesis, uptake, and efflux. A primary mechanism for cholesterol efflux involves the ATP-binding cassette transporterABCA1, which facilitates the transfer of cholesterol and phospholipids from cells to lipid-poor apolipoproteins, primarily apolipoprotein A-I (APOA1), forming nascent high-density lipoprotein (HDL) particles.^[1] This process is vital for reverse cholesterol transport, where cholesterol is returned from peripheral tissues to the liver for excretion. Concurrently, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) regulates the mevalonate pathway, the primary route for endogenous cholesterol synthesis, while the low-density lipoprotein receptor (LDLR) mediates the uptake of cholesterol from plasma into cells.^[3] These interconnected molecular pathways ensure that intracellular cholesterol levels are tightly controlled, with a decrease in HMGCR activity leading to lower cellular synthesis and a compensatory increase in LDLR-mediated uptake to maintain balance.^[3]

Genetic Regulation of Lipid Metabolism

The intricate regulation of lipid profiles, including cholesterol efflux capacity, is significantly influenced by an individual’s genetic makeup, with family studies suggesting that roughly half of the variation in these traits is genetically determined.^[4]Genome-wide association studies (GWAS) have identified numerous genetic variants and loci associated with lipid concentrations and the risk of coronary artery disease, including genes likeABCA1, APOB, CETP, HMGCR, LDLR, LIPC, LPL, and PCSK9.^[1] Beyond gene presence, regulatory elements and gene expression patterns play a crucial role, exemplified by transcription factors such as hepatocyte nuclear factor 4alpha (HNF4A) and hepatocyte nuclear factor-1alpha (HNF1A), which are essential for maintaining hepatic gene expression, lipid homeostasis, and regulating bile acid and plasma cholesterol metabolism.^[5] Furthermore, alternative splicing, such as that observed in HMGCR (affecting exon13) or APOB (affecting exon27), provides an additional layer of post-transcriptional control, influencing enzyme activity and the production of functional proteins critical for cholesterol regulation.^[3]

Key Proteins in Lipoprotein Dynamics and Remodeling

Several key biomolecules are integral to the formation, remodeling, and clearance of lipoproteins, directly impacting cholesterol efflux and overall lipid transport. Lecithin-cholesterol acyltransferase (LCAT) is an enzyme critical for the esterification of cholesterol in HDL particles, a process vital for mature HDL formation and efficient reverse cholesterol transport; defects in LCATactivity, as seen in fish eye disease, lead to severe dyslipidemia.^[6] Cholesterol ester transfer protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides between lipoproteins, influencing the composition and size of HDL and LDL particles.^[7]Lipoprotein lipase (LPL) and hepatic lipase (LIPC) are crucial enzymes involved in the hydrolysis of triglycerides in circulating lipoproteins, thereby modulating the levels of HDL and triglycerides.^[8] Additionally, proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a significant role in regulating LDLR levels, accelerating its degradation and consequently impacting plasma LDL cholesterol concentrations.^[9]

Pathophysiological Consequences of Dysregulated Cholesterol Efflux

Disruptions in the intricate pathways governing cholesterol efflux and metabolism can lead to a spectrum of pathophysiological conditions, including polygenic dyslipidemia and an increased risk of coronary artery disease (CAD).^[9] For instance, rare variants in LDLR and APOB genes, as well as common variants in APOE, are strongly associated with elevated LDL cholesterol and heightened susceptibility to CAD.^[8] Beyond generalized dyslipidemia, specific defects in cholesterol transport can lead to distinct disorders, such as sitosterolemia, caused by mutations in ABC transporters, which results in the accumulation of dietary cholesterol.^[10] Similarly, the hepatic cholesterol transporter ABCG8has been identified as a susceptibility factor for human gallstone disease.^[11] The body attempts to compensate for these disruptions, but genetic variants can influence these responses; for example, common variants in HMGCR have been associated with reduced efficacy of statin therapy, highlighting how genetic factors can modulate therapeutic outcomes.^[1] The interplay of these genetic and molecular factors ultimately determines an individual’s susceptibility to lipid-related diseases, with tissue-level effects in organs like the liver and pancreas playing central roles in systemic lipid homeostasis.^[12]

Pathways and Mechanisms

Cholesterol efflux capacity, a crucial component of reverse cholesterol transport, involves a complex interplay of signaling cascades, metabolic pathways, and regulatory mechanisms that collectively maintain systemic lipid homeostasis. These processes are tightly controlled at multiple levels, from gene expression to protein activity, and their dysregulation can significantly impact cardiovascular health.

Transcriptional and Post-Translational Control of Lipid Homeostasis

Cholesterol efflux capacity is intricately governed by robust transcriptional and post-translational regulatory mechanisms. Transcription factors like the Hepatocyte Nuclear Factors (HNF) play a central role, with HNF4α being essential for maintaining hepatic gene expression and overall lipid homeostasis, while HNF1α specifically regulates bile acid and plasma cholesterol metabolism.^[5] These factors orchestrate the expression of numerous genes involved in lipid processing, thereby exerting hierarchical control over metabolic pathways. Furthermore, the sterol regulatory element-binding protein 2 (SREBP-2) is a key regulator influencing isoprenoid and adenosylcobalamin metabolism, highlighting its role in cholesterol biosynthesis and related pathways.^[13] Post-translational modifications and protein interactions also significantly impact cholesterol dynamics. For instance, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting enzyme in the mevalonate pathway for cholesterol biosynthesis, is subject to regulation including alternative splicing of its exon13, which can affect cellular cholesterol homeostasis and plasma cholesterol levels.^[3] Similarly, Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) accelerates the degradation of the Low-Density Lipoprotein Receptor (LDLR) in a post-endoplasmic reticulum compartment, effectively reducing LDLR protein levels and thus impacting LDL cholesterol uptake.^[14]An amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) can lead to a selective loss of its alpha-activity, causing conditions like fish eye disease and impairingHDL-mediated cholesterol efflux.^[15]

Key Metabolic Enzymes and Transporters in Cholesterol Dynamics

The direct movement and processing of cholesterol and other lipids are facilitated by a suite of specialized enzymes and transporters. The ATP-binding cassette transportersABCG5 and ABCG8 form a functional heterodimeric complex essential for the efflux of dietary cholesterol and noncholesterol sterols from both the intestine and the liver, playing a crucial role in preventing excessive sterol absorption.^[1] Dysfunctional variants in these transporters lead to abnormal accumulation of sterols, as seen in sitosterolemia, underscoring their importance in maintaining systemic lipid balance.^[1]Enzymes like lipoprotein lipase (LPL) and hepatic lipase (LIPC) are fundamental for the catabolism of triglycerides within lipoproteins and the remodeling of high-density lipoproteins (HDL), respectively, directly influencing the availability of cholesterol for efflux.^[8]Cholesteryl ester transfer protein (CETP) further regulates the distribution of cholesterol esters and triglycerides among lipoproteins, affecting HDL cholesterol levels and the overall efficiency of reverse cholesterol transport.^[7] Beyond direct enzymatic action, proteins like SORT1(Sortilin 1) mediate the endocytosis and degradation of lipoprotein lipase, thereby indirectly controlling lipid flux and the availability of fatty acids for cellular processes.^[16]These metabolic pathways work in concert to ensure controlled movement and processing of lipids, which is vital for effective cholesterol efflux capacity.

Systems-Level Regulation of Lipoprotein Dynamics

Cholesterol efflux capacity is not an isolated process but an integral component of a broader, interconnected network of lipoprotein metabolism. Pathway crosstalk is evident in the regulation ofLDL receptor levels, where PCSK9 directly influences LDLR degradation, thereby impacting the clearance of LDL cholesterol from circulation and illustrating a critical feedback mechanism within the lipid network.^[17]Genetic variants within key lipoprotein gene clusters, such as theAPOE-APOC cluster and the APOA5-APOA4-APOC3-APOA1 cluster, demonstrate complex network interactions by associating with varying levels of LDL cholesterol and triglycerides, respectively.^[8]These clusters represent a hierarchical regulation where multiple apolipoproteins, each with distinct roles in lipoprotein structure and metabolism, collectively determine the overall lipid profile. For instance, a null mutation inAPOC3 has been shown to confer a favorable plasma lipid profile and apparent cardioprotection, revealing the emergent properties of genetic variations within these integrated systems.^[18] Furthermore, angiopoietin-like proteins, such as ANGPTL3 and ANGPTL4, regulate lipid metabolism, with variations in ANGPTL4 specifically reducing triglycerides and increasing HDL, underscoring the broad systemic impact of these regulatory proteins on lipoprotein dynamics and, consequently, cholesterol efflux capacity.^[19]

Genetic Variation and Disease Relevance

Genetic variations significantly contribute to individual differences in cholesterol efflux capacity and susceptibility to dyslipidemia. CommonSNPs in genes such as HMGCR can influence its alternative splicing, affecting cellular cholesterol homeostasis and ultimately plasma cholesterol levels, making it a well-established therapeutic target for statins.^[3] Similarly, variants within the FADS gene cluster (FADS1, FADS2, FADS3) are associated with the composition of fatty acids in phospholipids, highlighting a genetic predisposition to altered lipid profiles.^[20] Dysregulation of these pathways is directly linked to various lipid disorders; for example, mutations in ABCG5 cause sitosterolemia, a rare monogenic disorder characterized by abnormal absorption of cholesterol and other sterols.^[1] Conversely, specific genetic variations can confer protection, as seen with sequence variations in PCSK9 that are associated with lower LDLlevels and protection against coronary heart disease, positioningPCSK9 as a significant therapeutic target.^[21]Understanding these disease-relevant mechanisms, including compensatory responses and pathway dysregulation, is crucial for identifying novel therapeutic strategies aimed at improving cholesterol efflux capacity and mitigating cardiovascular risk.

Genetic Risk Assessment and Prognosis for Cardiovascular Disease

Genetic risk profiles, particularly those encompassing multiple loci associated with Total Cholesterol (TC), demonstrate significant prognostic value in assessing cardiovascular health. These comprehensive profiles enhance the prediction of clinically defined hypercholesterolemia and the progression of intima media thickness (IMT) beyond what is achievable with traditional risk factors such as age, sex, and Body Mass Index (BMI).^[1]While these genetic scores improve the discriminative accuracy for dyslipidemia and are associated with incident Coronary Heart Disease (CHD), some studies suggest that the association with CHD may be largely mediated through the circulating lipid levels themselves.^[1]Nevertheless, the integration of genetic information into risk assessments can aid in identifying individuals at higher risk for dyslipidemia and subsequent cardiovascular complications, thereby facilitating earlier and more targeted preventive strategies.

Diagnostic Utility and Personalized Prevention Strategies

Genetic risk scores offer valuable diagnostic utility by improving the classification of Coronary Heart Disease (CHD) risk when considered alongside traditional clinical risk factors.^[1]These genetic profiles help identify individuals predisposed to various dyslipidemias, including elevated Total Cholesterol (TC), Low-Density Lipoprotein (LDL) cholesterol, High-Density Lipoprotein (HDL) cholesterol, or triglycerides.^{[1], [8], [9]}Early identification of these high-risk groups, including those with polygenic dyslipidemia, enables the implementation of personalized prevention strategies, which may involve earlier lifestyle interventions or pharmacotherapy before the advanced stages of cardiovascular disease develop.^{[1], [9]}For instance, alleles consistently associated with increased LDL cholesterol concentrations are linked with an elevated risk of Coronary Artery Disease (CAD), underscoring their potential as markers for refined risk stratification.^[8]

Treatment Response and Comorbidity Considerations

Genetic variants can significantly influence an individual’s response to lipid-lowering therapies, particularly statins. For example, common variants in the HMGCR gene, which encodes the rate-limiting enzyme for cholesterol synthesis and is the primary target of statins, have been associated with reduced efficacy of pravastatin therapy and contribute to variations in LDL cholesterol response to statin treatment.^{[1], [3]} This pharmacogenetic insight is critical for advancing personalized medicine, as it can guide treatment selection and optimize therapeutic outcomes for patients. Furthermore, genetic influences on lipid levels can exhibit sex-specific effects, with distinct differences observed for genes such as HMGCR and NCAN, reflecting known epidemiological disparities in lipid values and cardiovascular disease prevalence between males and females.^[1] Understanding these genetic associations and their phenotypic variations is essential for tailoring monitoring strategies and recognizing overlapping lipid-related comorbidities in patient care.

References

[1] 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.

[2] Benjamin, E. J., et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, 2007, p. S11.

[3] Burkhardt, R, et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 1, 2009, pp. 153-160.

[4] Heller, D.A., et al. “Genetic and environmental influences on serum lipid levels in twins.” N Engl J Med, vol. 328, 1993, pp. 1150–1156.

[5] Hayhurst, G. P., et al. “Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.” Molecular and Cellular Biology, vol. 21, 2001, pp. 1393–1403.

[6] “A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity.”Proc. Natl. Acad. Sci. USA, vol. 88, 1991, pp. 4855–4859.

[7] Hiura, Y., et al. “Identification of genetic markers associated with high-density lipoprotein-cholesterol by genome-wide screening in a Japanese population: the Suita study.”Circ J, vol. 73, no. 5, 2009, pp. 886-892.

[8] 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.

[9] Kathiresan, S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nature Genetics, vol. 40, no. 12, 2008, pp. 1419-1427.

[10] Berge, K. E., et al. “Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.” Science, vol. 290, 2000, pp. 1771–1775.

[11] Buch, S., et al. “A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.”Nat. Genet., vol. 39, 2007, pp. 995–999.

[12] Odom, D. T., et al. “Control of pancreas and liver gene expression by HNF transcription factors.” Science, vol. 303, 2004, pp. 1378–1381.

[13] Murphy, C., et al. “Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism.” Biochemical and Biophysical Research Communications, vol. 355, 2007, pp. 359–364.

[14] Maxwell, K. N., et al. “Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, 2005, pp. 2069–2074.

[15] Kuivenhoven, J. A., et al. “The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes.” Journal of Lipid Research, vol. 38, 1997, pp. 191–205.

[16] Nielsen, M. S., et al. “Sortilin/neurotensin receptor-3 binds and mediates degradation of lipoprotein lipase.”The Journal of Biological Chemistry, vol. 274, 1999, pp. 8832–8836.

[17] Benjannet, S., et al. “NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.”The Journal of Biological Chemistry, vol. 279, 2004, pp. 48865–48875.

[18] 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.

[19] Koishi, R., et al. “Angptl3 regulates lipid metabolism in mice.” Nature Genetics, vol. 30, 2002, pp. 151–157.

[20] Malerba, G., et al. “SNPs of the FADS Gene Cluster are Associated with Polyunsaturated Fatty Acids in a Cohort of Patients with Cardiovascular Disease.”Lipids, vol. 43, 2008, pp. 289–299.

[21] Cohen, J. C., et al. “Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.”The New England Journal of Medicine, vol. 354, 2006, pp. 1264–1272.