Lysophosphatidylcholine
Background
Section titled “Background”Lysophosphatidylcholine (LPC) is a class of glycerophospholipids, which are fundamental components of biological membranes and play various roles in cellular processes , primarily draws from studies conducted in populations of European ancestry.[1]This demographic focus limits the direct generalizability of these findings to diverse global populations. Genetic architecture, allele frequencies, and linkage disequilibrium patterns can vary significantly across different ancestral groups, meaning that variants identified in one population may not have the same effect size or even be present in others.[2] For instance, even within broad ancestry groups, discrepancies have been noted in associations of certain genetic loci, suggesting that population-specific factors or subtle genetic differences can influence outcomes.[2] Furthermore, some studies include individuals from founder populations, such as the Kosrae islanders, which, while valuable for identifying strong genetic signals due to reduced genetic heterogeneity, may not fully represent the genetic landscape of outbred populations.[2]This specificity necessitates caution when extrapolating findings related to lysophosphatidylcholine metabolism across diverse ethnic and geographical backgrounds without explicit replication in those groups. The lack of comprehensive multi-ethnic data for lysophosphatidylcholine specifically means that the full spectrum of genetic influences on its levels across humanity remains largely unexplored, potentially leading to an incomplete understanding of its role in health and disease globally.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The power of genome-wide association studies (GWAS) to detect genetic variants influencing lysophosphatidylcholine levels is inherently linked to sample size and rigorous statistical analysis. While some studies have achieved genome-wide significance for related metabolic traits through large meta-analyses, the specific associations with lysophosphatidylcholine, such as thers174548 variant, could still benefit from even larger cohorts to identify additional variants of smaller effect or to refine effect size estimates.[1]A fundamental challenge in GWAS is the prioritization of identified single nucleotide polymorphisms (SNPs) for follow-up and the need for independent replication to validate initial findings and confirm true genetic associations.[3]Without such external validation, particularly for lysophosphatidylcholine, the robustness of some associations remains to be fully established, impacting the confidence in their general applicability.
Additionally, the methodologies employed in these studies, such as the common assumption of an additive mode of inheritance for SNP effects, might overlook complex non-additive genetic interactions that could contribute to lysophosphatidylcholine variation.[1]Phenotype measurement also presents challenges; while sophisticated metabolomics platforms are used to quantify lysophosphatidylcholine species, the precise analytical methods, potential for measurement error, and the need for statistical transformations to normalize skewed distributions can influence the reported associations.[4]Although adjustments for common confounders like age and sex are typically performed, residual confounding from unmeasured or imperfectly adjusted variables cannot be entirely excluded, potentially influencing the observed genetic effects on lysophosphatidylcholine concentrations.
Unexplained Variance and Mechanistic Complexity
Section titled “Unexplained Variance and Mechanistic Complexity”Despite significant genetic associations, such as the rs174548 variant explaining up to 10% of the variance in certain glycerophospholipids including lyso-phosphatidylcholine.[5]a substantial portion of the variability in lysophosphatidylcholine levels remains genetically unexplained. This “missing heritability” suggests that many other genetic factors, including rare variants, structural variations, or complex epistatic interactions not captured by current GWAS designs, likely contribute to the trait.[6]The interplay between genetic predispositions and environmental factors, such as diet and lifestyle, is also crucial but often not fully elucidated. Lysophosphatidylcholine, being a lipid metabolite, is directly influenced by dietary intake and metabolic pathways, making gene-environment interactions significant confounders that are difficult to comprehensively account for.[2] Furthermore, while some identified genetic associations are functionally plausible, like the link between FADS1variants and fatty acid desaturation affecting lysophosphatidylcholine derivatives, the precise molecular mechanisms for many other associated loci are still emerging.[5]Functional follow-up studies are essential to translate statistical associations into a deeper biological understanding of how specific genetic variants mechanistically impact lysophosphatidylcholine synthesis, breakdown, or transport.[3]Without a complete picture of these complex regulatory networks, the full clinical implications of genetic findings related to lysophosphatidylcholine for disease risk and therapeutic intervention remain constrained.
Variants
Section titled “Variants”The Fatty Acid Desaturase (FADS) gene cluster, comprising FADS1, FADS2, and FADS3, is a critical genomic region influencing the body’s ability to synthesize long-chain polyunsaturated fatty acids (LCPUFAs) from essential dietary precursors. Variants within this cluster, such as rs174548 , rs174550 , rs174549 , rs174546 , rs174547 , rs174545 , rs1535 , rs174583 , rs174601 , rs174455 , rs1000778 , and rs7394871 , are strongly associated with variations in lipid profiles, including levels of lysophosphatidylcholine.[1] Specifically, FADS1encodes delta-5 desaturase, a key enzyme in the metabolic pathways that convert omega-3 and omega-6 fatty acids into more complex forms like arachidonic acid (C20:4).[5] The minor allele of rs174548 , for instance, is associated with reduced efficiency of this desaturase enzyme, leading to lower concentrations of LCPUFAs and their derivatives, particularly arachidonic acid and its lyso-phosphatidylcholine derivative (PC a C20:4).[5] Furthermore, rs102275 , which is in strong linkage disequilibrium with rs174547 , is also implicated in lipid metabolism, influencing transcript levels in the liver and contributing to the overall genetic impact on fatty acid composition.[1]This cluster’s variants collectively modulate the balance of glycerophospholipid species, impacting cellular membrane fluidity, signaling, and overall lipid homeostasis.
The TMEM258 gene (Transmembrane Protein 258) and MYRF (Myelin Regulatory Factor) also host variants relevant to metabolic phenotypes. While TMEM258 is thought to play a role in cellular membrane processes or intracellular transport, its variant rs102275 shows high linkage disequilibrium with rs174547 within the FADS region, suggesting an indirect influence on fatty acid desaturation.[1] Other TMEM258 variants, such as rs102274 , rs174538 , rs174535 , rs108499 , and rs174532 , may contribute to metabolic regulation through their impact on membrane function or broader cellular processes. MYRF, primarily known as a transcription factor for myelination, could indirectly affect lipid metabolism through its regulatory functions or by influencing cell types involved in lipid transport and storage, potentially impacting lysophosphatidylcholine levels through complex gene networks.[5] Further genetic contributions come from other less characterized genes. The FEN1 gene (Flap Endonuclease 1), with its variant rs4246215 , is involved in DNA replication and repair, and its genomic proximity to FADS2 suggests a possible regulatory or functional interaction that could influence fatty acid metabolism.[5] PDXDC1 (Pyridoxal Dependent Decarboxylase Domain Containing 1), represented by rs1121 , is a gene with less defined metabolic roles, yet its variants may subtly affect how the body processes various compounds, including lipids. Similarly, variants in RAB3IL1 (RAB3A Interacting Protein 1 Like), such as rs174471 , rs174478 , and rs174479 , may play roles in membrane trafficking and vesicle transport, processes essential for cellular lipid secretion and communication, thereby indirectly impacting circulating lipid species.[5] Lastly, the MYCL - Y_RNA region, including rs7529794 , highlights the involvement of non-coding RNAs in gene regulation, which can fine-tune the expression of genes involved in lipid synthesis and breakdown, affecting the overall metabolic profile and lysophosphatidylcholine concentrations.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs102275 rs102274 rs174538 | TMEM258 | coronary artery calcification Crohn’s disease fatty acid amount high density lipoprotein cholesterol measurement, metabolic syndrome phospholipid amount |
| rs174550 rs174548 rs174549 | FADS2, FADS1 | blood glucose amount HOMA-B fatty acid amount, linoleic acid measurement omega-6 polyunsaturated fatty acid measurement triacylglycerol 54:4 measurement |
| rs174546 rs174547 rs174545 | FADS1, FADS2 | C-reactive protein measurement, high density lipoprotein cholesterol measurement triglyceride measurement, C-reactive protein measurement triglyceride measurement low density lipoprotein cholesterol measurement high density lipoprotein cholesterol measurement |
| rs1535 rs174583 rs174601 | FADS2 | inflammatory bowel disease high density lipoprotein cholesterol measurement, metabolic syndrome response to statin level of phosphatidylcholine level of phosphatidylethanolamine |
| rs174535 rs108499 rs174532 | TMEM258, MYRF | ankylosing spondylitis, psoriasis, ulcerative colitis, Crohn’s disease, sclerosing cholangitis fatty acid amount, oleic acid measurement triacylglycerol 56:7 measurement cholesteryl ester 18:3 measurement docosapentaenoic acid measurement |
| rs4246215 | FEN1, FADS2 | fatty acid amount, linoleic acid measurement inflammatory bowel disease alpha-linolenic acid measurement eicosapentaenoic acid measurement docosapentaenoic acid measurement |
| rs174455 rs1000778 rs7394871 | FADS3 | esterified cholesterol measurement phosphatidylcholine 38:5 measurement level of phosphatidylcholine sphingomyelin measurement triglyceride measurement |
| rs1121 | PDXDC1 | cholesteryl ester 20:3 measurement level of phosphatidylcholine lysophosphatidylcholine measurement polyunsaturated fatty acids to total fatty acids percentage degree of unsaturation measurement |
| rs174471 rs174478 rs174479 | RAB3IL1 | level of phosphatidylcholine triglyceride measurement diacylglycerol 38:4 measurement diacylglycerol 38:3 measurement lysophosphatidylcholine measurement |
| rs7529794 | MYCL - Y_RNA | 2-linoleoylglycerophosphocholine measurement level of Phosphatidylcholine (16:0_0:0) in blood serum level of Phosphatidylcholine (18:1_0:0) in blood serum level of Phosphatidylcholine (18:2_0:0) in blood serum level of Phosphatidylethanolamine (18:0_0:0) in blood serum |
Definition and Chemical Structure
Section titled “Definition and Chemical Structure”Lysophosphatidylcholine (LPC) represents a class of glycerophospholipids that structurally differ from conventional phosphatidylcholines (PC) by possessing only a single fatty acid acyl chain attached to the glycerol backbone.[5] This distinguishing feature contrasts with diacyl phosphatidylcholines, which typically bear two fatty acid residues.[5]A notable example, lysophosphatidylcholine PC a C20:4, is specifically characterized as a derivative of phosphatidylcholine formed from a single arachidonyl-moiety.[5] The unique mono-acylated configuration of LPCs is crucial for their distinct biochemical properties and diverse biological functions within cellular membranes and signaling pathways.
Nomenclature and Classification
Section titled “Nomenclature and Classification”The nomenclature for lysophosphatidylcholines employs a standardized system that precisely describes their molecular composition. Lysophosphatidylcholine species are often abbreviated as “PC a Cx:y,” where “PC” denotes phosphatidylcholine, and the “a” signifies the presence of a single acyl fatty acid residue, indicating its lysophosphatidylcholine classification.[5] The “Cx:y” component provides specific details about the attached fatty acid side chain, with ‘x’ representing the total number of carbon atoms and ‘y’ indicating the number of double bonds within that chain.[5]For instance, “PC a C20:4” refers to a lysophosphatidylcholine with a 20-carbon fatty acid chain containing four double bonds, specifically identifying an arachidonyl-moiety.[5] This systematic approach allows for accurate identification and classification of various LPC subtypes based on their acyl chain characteristics.
Biological Significance and Measurement Criteria
Section titled “Biological Significance and Measurement Criteria”Lysophosphatidylcholine species are recognized for their significant roles in various biological processes, acting as key signaling molecules and components of cell membranes. The concentrations of specific lysophosphatidylcholines, such as PC a C20:4, are of particular scientific interest due to their strong association with genetic variants in genes likeFADS1.[5] Research has shown that increased copy numbers of the minor allele in FADS1are linked to a significant reduction in the levels of PC a C20:4, as well as its precursor, arachidonic acid.[5] These findings underscore the utility of lysophosphatidylcholines as measurable biomarkers, often quantified through metabolomic profiling in serum, to assess an individual’s metabolic status and genetic predisposition related to essential fatty acid metabolism.
Biological Background of Lysophosphatidylcholine
Section titled “Biological Background of Lysophosphatidylcholine”Lysophosphatidylcholine (LPC) is a multifaceted lipid molecule with crucial roles in cellular function, metabolism, and disease pathophysiology. As a derivative of phosphatidylcholine (PC), LPC plays a part in complex lipid signaling networks and metabolic pathways, influencing various physiological processes across different tissues and organs. Its levels are tightly regulated by genetic and environmental factors, and imbalances are often linked to a range of metabolic disorders.
Lysophosphatidylcholine Formation and Metabolic Pathways
Section titled “Lysophosphatidylcholine Formation and Metabolic Pathways”Lysophosphatidylcholine (LPC) is a class of glycerophospholipids characterized by possessing a single fatty acid residue attached to its glycerol backbone, in contrast to phosphatidylcholine (PC) which has two. LPCs, such as PC a C20:4, are primarily generated through the hydrolysis of phosphatidylcholines, often involving the enzymatic removal of a specific fatty acid moiety, like arachidonic acid.[5]This process positions LPC as an intermediate metabolite within the broader glycerophospholipid metabolism, where it can also function as a signaling molecule.
The precursor phosphatidylcholines are predominantly synthesized via the Kennedy pathway, a fundamental metabolic route in which two fatty acid moieties are sequentially linked to glycerol 3-phosphate. This is followed by a dephosphorylation step and the subsequent addition of a phosphocholine group.[5]The availability of specific fatty acids, particularly essential polyunsaturated fatty acids (PUFAs) like linoleic acid (C18:2), is critical for this synthesis, as they undergo desaturation and elongation to produce longer-chain PUFAs, such as arachidonic acid (C20:4), which are then incorporated into phospholipids.[5]
Genetic Influences on Lysophosphatidylcholine Levels and Fatty Acid Desaturation
Section titled “Genetic Influences on Lysophosphatidylcholine Levels and Fatty Acid Desaturation”Genetic variations exert a significant impact on both the synthesis and circulating levels of LPC and its precursor molecules. A pivotal enzyme in this process is Fatty Acid Desaturase 1 (FADS1), encoded by the FADS1 gene, which is essential for the conversion of eicosatrienoyl-CoA (C20:3) to arachidonyl-CoA (C20:4) within the omega-6 fatty acid synthesis pathway.[5] Polymorphisms located within the FADS1 gene, such as rs174548 , can diminish the enzyme’s catalytic efficiency, consequently leading to reduced concentrations of both arachidonic acid and its derivative, lyso-phosphatidylcholine PC a C20:4.[5]This genetic influence extends beyond individual LPC species to the overall glycerophospholipid profile. ImpairedFADS1 activity, for example, results in elevated concentrations of glycerophospholipids containing three double bonds, such as PC aa C36:3, while simultaneously decreasing the levels of those with four or more double bonds, like PC aa C36:4.[5] Furthermore, the gene encoding hepatic lipase (LIPC) also contributes to lipid metabolism, with a polymorphism such as rs4775041 in the LIPC locus being associated with the concentrations of numerous glycerophosphatidylcholines, glycerophosphatidylethanolamines, and sphingomyelins, thereby highlighting a broader genetic regulation of phospholipid homeostasis.[5]
Lysophosphatidylcholine and Systemic Lipid Homeostasis
Section titled “Lysophosphatidylcholine and Systemic Lipid Homeostasis”Lysophosphatidylcholine metabolism is intricately interwoven with the broader regulatory mechanisms governing systemic lipid homeostasis, influencing the delicate balance of various lipid classes and lipoproteins throughout the body. For instance, the enzymatic breakdown of triglycerides into diacyl- and monoacylglycerols and free fatty acids by enzymes such asLIPC directly affects the pool of available fatty acid moieties that can be utilized for phospholipid synthesis, thereby indirectly influencing LPC levels.[5]Moreover, shifts in the overall balance of glycerophospholipid metabolism can promote the generation of other lysophospholipids, including lyso-phosphatidylethanolamines, through the enzymatic abstraction of specific fatty acid moieties.[5]The dynamic interconversion between different phospholipid types further underscores this metabolic interconnectedness; for example, sphingomyelin can be synthesized from phosphatidylcholine through the action of sphingomyelin synthase. This process suggests a complex regulatory network where changes in PC concentrations, and consequently LPC levels, can have ripple effects across related lipid pathways, impacting cellular membrane integrity, lipid-mediated signaling, and the overall energetic state within cells and tissues.[5] Such molecular pathways are fundamental for maintaining cellular functions and systemic metabolic health.
Pathophysiological Implications and Disease Associations
Section titled “Pathophysiological Implications and Disease Associations”Dysregulations in lysophosphatidylcholine metabolism and its associated lipid pathways are strongly linked to the etiology and progression of several pathophysiological conditions, notably those involving dyslipidemia and cardiovascular disease. Genetic variants that affect the function of key enzymes likeLIPChave been consistently associated with alterations in plasma levels of HDL cholesterol and triglycerides, which are critical biomarkers for assessing cardiovascular risk.[5] Similarly, research has indicated that a null mutation in human APOC3can lead to a favorable plasma lipid profile and offer apparent cardioprotection, emphasizing the profound genetic underpinnings of lipid-related disease susceptibility.[7]Furthermore, imbalances in phospholipid metabolism, which may involve LPC, are observed in metabolic disorders such as nonalcoholic fatty liver disease (NAFLD). In this condition, elevated serum levels and increased hepatic mRNA expression ofGPLD1 have been reported, pointing to a direct involvement of phospholipid-modifying enzymes in liver pathology.[8] The precise regulation of hepatic lipid metabolism by crucial transcription factors like HNF4alpha and HNF1alpha further highlights the tissue-specific and systemic ramifications of disrupted lipid homeostasis, which collectively contribute to the development and advancement of various metabolic and chronic diseases.[9]
The Critical Role of Lecithin:Cholesterol Acyltransferase (LCAT)
Section titled “The Critical Role of Lecithin:Cholesterol Acyltransferase (LCAT)”Lecithin:cholesterol acyltransferase (LCAT) is a pivotal enzyme directly involved in the metabolism of phosphatidylcholine and the subsequent generation of lysophosphatidylcholine.LCAT catalyzes the transfer of a fatty acid from phosphatidylcholine to cholesterol, a reaction that results in the formation of cholesterol esters and the concomitant release of LPC.[10]This enzymatic activity is indispensable for the maturation of high-density lipoprotein (HDL) particles and plays a central role in reverse cholesterol transport, both of which are critical processes for maintaining cholesterol balance within the body.
Deficiencies in LCAT activity, as observed in LCAT deficiency syndromes, lead to significant disruptions in plasma lipid profiles, manifesting as altered levels of various phospholipids and cholesterol.[10] Such conditions illustrate how alterations in LCAT function can profoundly impact LPC generation and broader lipid metabolism, contributing to various clinical manifestations and systemic metabolic imbalances.
Lysophosphatidylcholine Metabolism and Lipid Homeostasis
Section titled “Lysophosphatidylcholine Metabolism and Lipid Homeostasis”Lysophosphatidylcholine (LPC) plays a crucial role within the broader framework of lipid metabolism, particularly in the synthesis and remodeling of more complex phospholipids. Phosphatidylcholine (PC), a direct precursor and product related to LPC, is primarily synthesized via the Kennedy pathway, where two fatty acid moieties are linked to glycerol 3-phosphate, followed by dephosphorylation and the addition of a phosphocholine group. This pathway dictates the overall availability of PC species, which can then be modified or broken down to yield LPC . Homozygotes carrying the minor allele ofrs4775041 exhibit significantly higher concentrations of certain phosphatidylethanolamines, indicating a direct genetic impact on phospholipid profiles.[5] The LIPCgene encodes hepatic lipase, an enzyme crucial for long-chain lipid metabolism, and its variants have been linked to lower hepatic lipase activity and higher HDL cholesterol, as well as lower triglyceride levels.[1]These genetic insights provide a foundational understanding of how variations in lipid-metabolizing enzymes can directly modulate lysophosphatidylcholine and related phospholipid levels, thereby influencing overall lipid homeostasis.
Further genetic associations highlight the role of the FADS1-FADS2 gene cluster, which encodes desaturases essential for the synthesis of long-chain poly-unsaturated fatty acids from linoleic acids, a key step in phosphatidylcholine formation.[5] Polymorphisms within FADS1are significantly associated with various glycerophospholipid species, including lyso-phosphatidylcholine PC a C20:4, which is formed from an arachidonyl-moiety.[5] The observed strong effect sizes for these FADS1polymorphisms on glycerophospholipid concentrations underscore their biochemical significance and potential impact on cellular function and overall lipid profiles. Understanding these genetic determinants of lysophosphatidylcholine levels is crucial for elucidating the underlying mechanisms of dyslipidemia and related metabolic conditions.
Diagnostic Utility and Risk Assessment in Dyslipidemia
Section titled “Diagnostic Utility and Risk Assessment in Dyslipidemia”The association of genetic variants with lysophosphatidylcholine and other phospholipid levels presents opportunities for improved diagnostic utility and risk assessment, particularly in the context of dyslipidemia. For example, the strong link betweenLIPCpolymorphisms and HDL cholesterol and triglyceride levels, mediated by changes in hepatic lipase activity, suggests that genetic testing for variants likers4775041 could contribute to identifying individuals predisposed to specific lipid profiles.[5]Such genetic information, combined with direct measurement of lysophosphatidylcholine or related metabolites, could serve as a more precise biomarker panel for early detection of metabolic imbalances that might not be fully captured by conventional lipid panels. This could lead to earlier interventions and personalized management strategies for patients at risk.
Furthermore, the influence of FADS1 polymorphisms on the composition of various glycerophospholipids, including lyso-phosphatidylcholine, provides a deeper mechanistic understanding of how genetic factors contribute to individual differences in fatty acid metabolism.[5]Monitoring specific lysophosphatidylcholine species, especially those with arachidonyl-moieties, in conjunction withFADS1 genotype, could offer a refined approach to assess an individual’s metabolic status and their capacity for essential fatty acid conversion. This integrated approach has the potential to enhance risk stratification for conditions where phospholipid metabolism plays a significant role, moving beyond broad lipid categories to more specific biochemical markers.
Prognostic Value and Personalized Prevention Strategies
Section titled “Prognostic Value and Personalized Prevention Strategies”The genetic and metabolic insights into lysophosphatidylcholine hold significant prognostic value, aiding in the prediction of disease progression and guiding personalized prevention strategies. Variations in genes likeLIPC and FADS1, which impact lysophosphatidylcholine and other phospholipid concentrations, are functionally plausible mechanisms influencing lipid-related health outcomes.[5] Identifying individuals carrying specific alleles, such as the minor allele of LIPC rs4775041 associated with altered phosphatidylethanolamine levels, could help predict their long-term risk for dyslipidemia and potentially associated cardiovascular complications.[5]This allows for the development of targeted prevention strategies, including dietary modifications or lifestyle interventions, tailored to an individual’s specific genetic predisposition and metabolic profile.
Leveraging these genetic markers and metabolite profiles can also inform personalized medicine approaches by refining risk stratification. For example, understanding howFADS1polymorphisms affect the synthesis of specific poly-unsaturated fatty acids and their incorporation into phospholipids, including lysophosphatidylcholine, could guide nutritional recommendations or supplement choices aimed at optimizing an individual’s fatty acid balance.[5]Such precision in risk assessment and intervention is crucial for moving beyond a one-size-fits-all approach, enabling clinicians to identify high-risk individuals and implement more effective, genetically informed prevention and management plans to improve patient care and outcomes.
References
Section titled “References”[1] Kathiresan S, et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet. 2009; 41(5):567–75.
[2] 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).
[3] Benjamin, Emelia J., et al. “Genome-Wide Association with Select Biomarker Traits in the Framingham Heart Study.” BMC Medical Genetics, vol. 8, 2007, p. 62.
[4] Melzer, D., et al. “A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs).” PLoS Genetics, vol. 4, no. 5, 2008, e1000072.
[5] Gieger C, et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet (2008).
[6] Sabatti, Chiara, et al. “Genome-Wide Association Analysis of Metabolic Traits in a Birth Cohort from a Founder Population.”Nature Genetics, vol. 40, no. 11, 2008, pp. 1321-28.
[7] Pollin TI, et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science. 2009; 326(5950):149-53.
[8] Yuan X, et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” Am J Hum Genet (2008).
[9] Hayhurst GP, et al. “Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.” Mol. Cell. Biol. 2001; 21:1393–1403.
[10] Kuivenhoven JA, et al. “The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes.” J Lipid Res. 1997; 38:191–205.