Dodecanoylcarnitine
Dodecanoylcarnitine (C12:0 carnitine) is a medium-chain acylcarnitine, a class of molecules formed when a fatty acid is chemically linked to carnitine. These compounds are essential intermediates in the body’s metabolic pathways, primarily functioning to transport fatty acids into the mitochondria for beta-oxidation, the process through which cells generate energy. Specifically, dodecanoylcarnitine participates in the metabolism of medium-chain fatty acids, which typically range from 6 to 12 carbon atoms in length.
Biological Basis
Section titled “Biological Basis”The efficient processing of fatty acids is fundamental for maintaining cellular energy balance. Fatty acids must be bound to free carnitine to be transported across the mitochondrial membrane, where beta-oxidation takes place.[1] A key enzyme involved in the beta-oxidation of medium-chain fatty acids is Medium-chain acyl-Coenzyme A dehydrogenase (MCAD), which is encoded by the ACADMgene. Research has shown a strong association between genetic variations, such as the intronic single nucleotide polymorphism (SNP)rs11161510 within the MCADgene, and the ratios of various medium-chain acylcarnitines, including dodecanoylcarnitine.[1]This indicates that these genetic differences can influence the metabolic rate of fatty acid breakdown, with individuals homozygous for the minor allele potentially exhibiting reduced enzymatic activity in these reactions.[1]
Clinical Relevance
Section titled “Clinical Relevance”Fluctuations or abnormal levels of dodecanoylcarnitine can serve as indicators of underlying disturbances in fatty acid metabolism. For instance, conditions such as medium-chain acyl-CoA dehydrogenase deficiency (MCAD) are characterized by an accumulation of medium-chain acylcarnitines due to impaired beta-oxidation. [1]Such metabolic disorders, if left undiagnosed or untreated, can lead to significant health complications. Genome-wide association studies (GWAS) have been instrumental in identifying genetic loci that impact metabolite profiles, including acylcarnitines, thereby linking these metabolic variations to the development of common multi-factorial diseases.[1]Insights gleaned from these genetic influences can help predict an individual’s susceptibility to specific health conditions, particularly when interacting with environmental factors like diet and lifestyle.[1]
Social Importance
Section titled “Social Importance”The critical clinical implications of acylcarnitine metabolism, particularly in the context of MCADdeficiency, have led to its inclusion in routine newborn screening programs. Early identification of such disorders through these screenings enables prompt medical intervention, which is crucial for preventing severe outcomes and improving the long-term health and quality of life for affected infants. Ongoing research into the genetic determinants of metabolite levels, including dodecanoylcarnitine, contributes to the advancement of personalized medicine. This field aims to develop individualized dietary recommendations, lifestyle modifications, or therapeutic strategies based on an individual’s unique genetic and metabolic profile.[1]Furthermore, the broader investigation into genetic factors influencing lipid concentrations, in which acylcarnitines play a role, is vital for understanding and mitigating the risk of prevalent conditions like coronary artery disease.[2]
Limitations
Section titled “Limitations”Generalizability and Population Specificity
Section titled “Generalizability and Population Specificity”The majority of the genetic association studies contributing to the understanding of metabolites, including acylcarnitines, have primarily focused on cohorts of European ancestry. [3]This demographic limitation restricts the direct generalizability of identified genetic associations for dodecanoylcarnitine levels to other global populations. While some efforts were made to include multiethnic samples, such as those from Singapore encompassing Chinese, Malay, and Asian Indian individuals, the extent to which these findings translate across diverse ancestries remains largely unexplored.[3] Genetic architecture, allele frequencies, and patterns of linkage disequilibrium can vary significantly among different ethnic groups, meaning that associations identified in one population may not be present or may have different effect sizes in another.
The specific genetic variants influencing dodecanoylcarnitine levels might therefore be population-specific, potentially leading to an incomplete understanding of its genetic determinants in non-European populations. Such population differences are critical because they can influence disease susceptibility and drug response, as evidenced by variations in lipid-lowering drug efficacy across racial groups.[4]Consequently, a comprehensive understanding of the genetic factors influencing dodecanoylcarnitine necessitates expanded research across a broader spectrum of ancestries to ensure equitable applicability of findings.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”The power to detect modest genetic effects on dodecanoylcarnitine levels is directly influenced by sample size and the rigorous statistical thresholds applied to account for multiple testing.[5] Without external replication in independent cohorts, associations, particularly those with moderate statistical support, carry a risk of being false positives. [6] Replication itself can be challenging due to differences in study design, genotyping platforms, and partial coverage of genetic variation, which may contribute to non-replication of previously reported signals. [7] Furthermore, the reliance on imputed genotypes, derived from reference panels, introduces an inherent error rate, typically between 1.46% and 2.14% per allele, which can impact the precision of genetic associations. [2]
The measurement of dodecanoylcarnitine, typically as one of many acylcarnitines within a targeted metabolomics panel using techniques like electrospray ionization tandem mass spectrometry, requires careful standardization.[1] Inconsistencies in phenotype definition or handling of confounding factors across studies, such as the variable exclusion or imputation of values for individuals on lipid-lowering therapy, can introduce bias. [3] The common assumption of an additive genetic model for association analyses may also oversimplify the true biological mechanisms, potentially missing more complex genetic interactions or non-additive effects. [8] These methodological and statistical considerations highlight the need for careful interpretation and further validation of findings.
Unaccounted Environmental and Genetic Complexity
Section titled “Unaccounted Environmental and Genetic Complexity”Genetic variants influencing dodecanoylcarnitine levels do not act in isolation but are often modulated by environmental factors, leading to context-specific genetic effects.[5]Many studies, including those informing the current understanding of metabolite genetics, often do not extensively investigate these gene-environment interactions, which can obscure a significant portion of the total phenotypic variance. The absence of such analyses means that important environmental modifiers of dodecanoylcarnitine levels may be overlooked, contributing to the “missing heritability” – the unexplained gap between the heritability estimated from family studies and the variance accounted for by identified genetic variants.
Beyond common single nucleotide polymorphisms, current genome-wide association studies may not fully capture the influence of rare variants or those with very small individual effects, which could collectively contribute substantially to dodecanoylcarnitine levels. While some identified associations highlight cis-acting regulatory variants that influence gene expression, the broader landscape of genetic regulation, including trans-acting effects or more complex gene-gene interactions, may remain largely unexplored.[6]Therefore, the current understanding of dodecanoylcarnitine’s genetic architecture remains incomplete, underscoring the necessity for future research to integrate environmental factors and explore a wider spectrum of genetic variation through functional validation studies.
Variants
Section titled “Variants”Genetic variations play a crucial role in influencing an individual’s metabolic profile, including the levels of specific acylcarnitines like dodecanoylcarnitine (C12 carnitine). This metabolic biomarker is often indicative of the efficiency of fatty acid oxidation, a fundamental process for energy production. Several genes and their associated variants can impact this pathway, either directly through enzymatic function or indirectly through broader cellular processes. Research in genomics often identifies such connections through genome-wide association studies that link genetic markers to various metabolic traits.[1]
The genes ETFDH and ACADVL are directly involved in mitochondrial fatty acid oxidation, a pathway critical for breaking down fatty acids into energy. ETFDH (Electron Transfer Flavoprotein Dehydrogenase) is essential for transferring electrons from various acyl-CoA dehydrogenases to the electron transport chain. Variants within ETFDH, such as rs17843966 and rs7679753 , can impair this electron transfer, leading to a buildup of fatty acid intermediates and their corresponding acylcarnitines, including very long-chain and medium-chain species like dodecanoylcarnitine. Similarly,ACADVL (Acyl-CoA Dehydrogenase, Very Long Chain) is responsible for the initial step in the beta-oxidation of very long-chain fatty acids. The variant rs28934585 in ACADVLcan affect its enzymatic activity, leading to an accumulation of very long-chain acyl-CoA esters. This disruption in very long-chain fatty acid metabolism can indirectly impact the overall acylcarnitine profile, potentially elevating dodecanoylcarnitine as the body attempts to process fatty acids through alternative or compensatory pathways.[3]
Other genes, such as PPID and ABCC1, contribute to cellular function through different mechanisms that can indirectly influence metabolic homeostasis. PPID (Peptidylprolyl Isomerase D) is a cyclophilin that functions as a chaperone protein, assisting in protein folding and cellular signaling pathways. While not directly oxidizing fatty acids, variants like rs9410 in PPID could potentially alter the stability or activity of metabolic enzymes, thereby indirectly affecting fatty acid oxidation and acylcarnitine levels. ABCC1(ATP Binding Cassette Subfamily C Member 1), also known as MRP1, is an ABC transporter involved in moving a wide range of substrates, including various endogenous metabolites and xenobiotics, out of cells. Variants such asrs924138 , rs924136 , and rs35587 in ABCC1 could affect its transport efficiency. If ABCC1or other related transporters are involved in the efflux of acylcarnitines or their precursors, altered function due to these variants could impact the cellular or systemic concentrations of dodecanoylcarnitine.[8]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs17843966 rs7679753 | ETFDH | blood protein amount protein measurement octanoylcarnitine measurement decanoylcarnitine measurement dodecanoylcarnitine measurement |
| rs9410 | PPID | decenoylcarnitine measurement hexanoylcarnitine measurement dodecanoylcarnitine measurement cerebrospinal fluid composition attribute, glutarylcarnitine (C5-DC) measurement |
| rs28934585 | ACADVL | dodecanoylcarnitine measurement myristoleoylcarnitine (C14:1) measurement C14:2 carnitine measurement metabolite measurement |
| rs924138 rs924136 rs35587 | ABCC1 | metabolite measurement laurylcarnitine measurement succinylcarnitine measurement X-13431 measurement Cis-4-decenoyl carnitine measurement |
Classification, Definition, and Terminology
Section titled “Classification, Definition, and Terminology”Chemical Identity and Classification
Section titled “Chemical Identity and Classification”Dodecanoylcarnitine is precisely defined as an acylcarnitine, a class of lipid metabolites formed by the esterification of a fatty acid with carnitine. The “dodecanoyl” prefix specifically denotes a saturated fatty acyl chain consisting of twelve carbon atoms (C12:0), placing it within the category of medium-chain acylcarnitines. These molecules are integral to the conceptual framework of lipid metabolism, serving as key intermediates in the transport and beta-oxidation of fatty acids within cellular compartments.[1] The standardized terminology for describing lipid side chain composition, as used in metabolomics, abbreviates such structures as Cx:y, where ‘x’ signifies the number of carbons and ‘y’ represents the number of double bonds, making dodecanoylcarnitine a C12:0 acylcarnitine.[1]
Metabolic Significance and Biological Role
Section titled “Metabolic Significance and Biological Role”The primary biological role of dodecanoylcarnitine, like other acylcarnitines, is to facilitate the shuttling of fatty acids across mitochondrial membranes, a crucial step for their subsequent breakdown to produce energy. Medium-chain acylcarnitines, in particular, reflect the cellular processing of medium-chain fatty acids, which can be metabolized rapidly. Variations in the levels of dodecanoylcarnitine in biological fluids can serve as indicators of metabolic pathway activity and are often investigated in the context of broader metabolic traits[1]. [7] These metabolites are therefore key components in understanding systemic energy homeostasis and lipid utilization.
Measurement and Biomarker Application
Section titled “Measurement and Biomarker Application”Dodecanoylcarnitine is typically measured as part of comprehensive “metabolite profiles in human serum,” employing advanced analytical techniques such as mass spectrometry.[1] This measurement approach allows for the operational definition of its concentration, which can then be used as a quantitative biomarker in research studies. While the technology can identify the overall carbon count and degree of saturation (Cx:y), the precise position of double bonds or the distribution of carbon atoms across different fatty acid side chains cannot always be definitively determined, introducing potential ambiguities in mapping metabolite names to exact masses. [1]In genome-wide association studies (GWAS), plasma or serum levels of metabolites like dodecanoylcarnitine are assessed as quantitative traits to identify genetic variants influencing lipid metabolism and metabolic health, thereby contributing to research criteria for understanding dyslipidemia and related conditions.[3]
Biological Background of Dodecanoylcarnitine
Section titled “Biological Background of Dodecanoylcarnitine”Dodecanoylcarnitine, a medium-chain acylcarnitine, plays a central role in the cellular processing of fatty acids, particularly those of medium chain length. Its biological significance is primarily linked to energy metabolism, specifically the transport and breakdown of fatty acids within mitochondria. Understanding dodecanoylcarnitine involves exploring the intricate molecular pathways, genetic controls, and systemic consequences that govern lipid homeostasis in the body.
Fatty Acid Metabolism and Carnitine Shuttle
Section titled “Fatty Acid Metabolism and Carnitine Shuttle”Dodecanoylcarnitine is a crucial intermediate in the beta-oxidation of medium-chain fatty acids, a process that generates energy for cells. For these fatty acids to be utilized, they must first be bound to free carnitine, forming acylcarnitines like dodecanoylcarnitine, which enables their transport across the mitochondrial membrane for subsequent breakdown[1] Once inside the mitochondria, enzymes such as medium-chain acyl-Coenzyme A dehydrogenase (MCAD) initiate the beta-oxidation pathway, progressively shortening the fatty acid chains and releasing energy [1]
Genetic Influence on Lipid Processing
Section titled “Genetic Influence on Lipid Processing”The regulation of dodecanoylcarnitine levels and overall lipid metabolism is significantly influenced by genetic factors. Polymorphisms within genes encoding enzymes likeMCAD can have a profound impact; for instance, genetic variants such as rs11161510 in MCADare strongly associated with the ratios of various medium-chain acylcarnitines, reflecting changes in enzyme activity . Fatty acids must be bound to free carnitine to be transported across the mitochondrial membrane, where they undergo beta-oxidation.[1] This process, initiated by specific acyl-Coenzyme A dehydrogenases, systematically shortens fatty acid chains, releasing acetyl-CoA for the citric acid cycle.
Genetic variations significantly influence the efficiency of this pathway. For instance, polymorphisms in the gene encoding medium-chain acyl-Coenzyme A dehydrogenase (MCAD), such as rs11161510 , are strongly associated with altered ratios of medium-chain acylcarnitines in serum. [1] Individuals with minor allele homozygosity for these variants often exhibit reduced enzymatic turnover, leading to higher concentrations of longer-chain fatty acid substrates and lower concentrations of their shorter-chain products, thereby impacting overall fatty acid catabolism. [1]
Regulation of Lipid Biosynthesis and Homeostasis
Section titled “Regulation of Lipid Biosynthesis and Homeostasis”Beyond catabolism, the regulation of lipid biosynthesis and overall lipid homeostasis involves intricate molecular pathways. The mevalonate pathway, responsible for cholesterol synthesis, is tightly controlled by enzymes such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). [9] Genetic variants in HMGCRcan influence alternative splicing of its exon 13, consequently affecting LDL-cholesterol levels and impacting cardiovascular health.[4] Furthermore, the transcription factor SREBP-2 (Sterol Regulatory Element-Binding Protein 2) plays a central role in regulating not only the mevalonate pathway but also broader isoprenoid and adenosylcobalamin metabolism, underscoring transcriptional control as a key regulatory mechanism. [10]
Other critical players in lipid homeostasis include angiopoietin-like proteins and lipogenic enzymes. ANGPTL3 is known to regulate lipid metabolism, while variations in ANGPTL4have been linked to reduced triglycerides and increased high-density lipoprotein (HDL) levels.[11] Similarly, variants in MLXIPLare associated with plasma triglyceride levels, and theFADS1/FADS2 gene cluster influences the fatty acid composition of phospholipids, demonstrating how genetic factors modulate diverse aspects of lipid biosynthesis and circulating lipid profiles. [12]
Molecular Regulatory Mechanisms
Section titled “Molecular Regulatory Mechanisms”Gene regulation and post-translational modifications are central to controlling metabolic pathways and cellular functions. Alternative splicing, a mechanism allowing multiple protein isoforms to be produced from a single gene, represents a significant layer of post-transcriptional regulation. [13] This process is exemplified by the alternative splicing of HMGCR mRNA, which impacts its function and is associated with LDL-cholesterol levels. [4] The generation of novel APOBisoforms through alternative splicing further illustrates the dynamic nature of this regulatory mechanism and its potential implications for disease.[14]
Beyond gene expression, protein modification plays a vital role in intracellular signaling. The human Tribbles protein family, for instance, is known to control mitogen-activated protein kinase (MAPK) cascades. [15] These cascades are fundamental signaling pathways that regulate cell growth, differentiation, and stress responses, demonstrating how specific protein families mediate complex cellular communication and integrate various upstream signals into downstream cellular outcomes.
Systems-Level Metabolic Integration and Disease Implications
Section titled “Systems-Level Metabolic Integration and Disease Implications”The interplay between genetic predispositions, metabolic pathways, and environmental factors culminates in complex systems-level integration that influences disease susceptibility. Genetically determined metabotypes, which are unique metabolic profiles shaped by an individual’s genetic makeup, interact with lifestyle and nutritional factors to modulate the risk of multifactorial diseases.[1]Acylcarnitines, including dodecanoylcarnitine, serve as functional readouts of the physiological state, reflecting the efficiency of fatty acid metabolism and providing insights into overall metabolic health.[1]
Dysregulation within these integrated metabolic networks is frequently observed in common diseases. For example, loci influencing lipid concentrations are closely linked to the risk of coronary artery disease, highlighting the systemic impact of lipid metabolism on cardiovascular health.[2] Furthermore, common variants in genes such as MC4Rare associated with waist circumference and insulin resistance, while loci related to metabolic syndrome pathways, includingLEPR, HNF1A, IL6R, and GCKR, associate with plasma C-reactive protein, linking metabolic disturbances to inflammation.[16]These examples underscore the intricate crosstalk between diverse metabolic and inflammatory pathways, ultimately contributing to the complex etiology of metabolic and cardiovascular disorders.
References
Section titled “References”[1] Gieger C et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.”PLoS Genet (2008).
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[3] Kathiresan S et al. “Common variants at 30 loci contribute to polygenic dyslipidemia.” Nat Genet (2008).
[4] 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.
[5] Vasan, Ramachandran S., et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Medical Genetics, vol. 8, suppl. 1, 2007, S2.
[6] Benjamin EJ et al. “Genome-wide association with select biomarker traits in the Framingham Heart Study.” BMC Med Genet (2007).
[7] Sabatti C et al. “Genome-wide association analysis of metabolic traits in a birth cohort from a founder population.”Nat Genet (2008).
[8] Aulchenko, Yurii S., et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.”Nature Genetics, vol. 40, no. 12, 2008, pp. 1412-20.
[9] Goldstein, J.L., and Brown, M.S. “Regulation of the mevalonate pathway.” Nature, 1990, 343:425–430.
[10] Murphy, C. et al. “Regulation by SREBP-2 defines a potential link between isoprenoid and adenosylcobalamin metabolism.” Biochem Biophys Res Commun, 2007.
[11] Koishi, R. et al. “Angptl3 regulates lipid metabolism in mice.” Nat Genet, 2002.
[12] Kooner, J.S. et al. “Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.” Nat Genet, 2008.
[13] Matlin, A.J. et al. “Understanding alternative splicing: towards a cellular code.” Nat Rev Mol Cell Biol, 2005.
[14] Khoo, B. et al. “Antisense oligonucleotide-induced alternative splicing of the APOB mRNA generates a novel isoform of APOB.” BMC Mol Biol, 2007.
[15] Kiss-Toth, E. et al. “Human tribbles, a protein family controlling mitogen-activated protein kinase cascades.” J Biol Chem, 2004.
[16] Yuan, X. et al. “Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes.” Am J Hum Genet, 2008.